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Sample records for guanosine analogue 2-amino-6-mercapto-7-methylpurine

  1. Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G-Clamp

    SciTech Connect

    Wilds, C.J.; Maier, M.A.; Manoharan, M.; Egli, M.

    2010-03-08

    An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G-clamp, was designed to allow formation of five H-bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H-pyrazole-1-carboxamidine and purified by a combination of size-exclusion chromatography and reversed-phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13{sup o} and 16{sup o} per modification to RNA and DNA, respectively. Crystals of a self-complementary decamer sequence containing this modification were grown and diffracted to 1-{angstrom} resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H-bonds to O(6) and N(7) of guanosine through the amino and imino N-atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G-clamp and formation of H-bond networks between the positively charged guanidinium group, H{sub 2}O molecules, and negatively charged O-atoms from phosphates on the adjacent strand.

  2. Direct Observation of a Cytosine Analogue that Forms Five Hydrogen Bonds to Guanosine: Guanyl G-Clamp

    SciTech Connect

    Wilds, C.J.; Maier, M.A.; Tereshko, V.; Manoharan, M.; Egli, M.

    2010-03-08

    A novel heterocyclic base modification, the guanidino G-clamp, is designed to allow two Hoogsteen-type hydrogen bonds to form between the amino and imino nitrogen atoms of a tethered guanidinium group to O6 and N7 of guanosine, which results in a total of five hydrogen bonds (broken lines, see picture). Details of a crystal structure at 1.0-{angstrom} resolution of a modified DNA decamer containing this guanidino G-clamp analogue demonstrate its mechanism of binding.

  3. Potentiation of Muscarinic and α -adrenergic Responses by an Analogue of Guanosine 5'-triphosphate

    NASA Astrophysics Data System (ADS)

    Evans, M. G.; Marty, A.

    1986-06-01

    Ca2+-dependent K+ and Cl- currents were recorded in isolated and dialyzed rat lacrimal gland cells by use of the tight-seal whole-cell recording technique. Under control conditions, application of acetylcholine (0.5-1.0 μ M) resulted in the full activation of both types of current. When 50-200 μ M guanosine 5'-[γ -thio]triphosphate (GTP[S], a nonhydrolyzable GTP analogue) was added to the intracellular solution, activation of both currents was seen with 1 nM acetylcholine, a dose 1/100th that needed under control conditions. Dialysis with solutions containing 200 μ M GTP or cAMP had no, or only slight, potentiation effects. The effects of GTP[S] were obtained only when ATP was included in the intracellular solution. The potentiated responses to acetylcholine were blocked by increasing 10-fold the intracellular Ca2+-buffering capacity and were not dependent on external Ca2+. Thus, the potentiated responses appeared to result from a release of Ca2+ from internal stores. GTP[S] also greatly potentiated the Ca2+-dependent adrenergic (norepinephrine) response of this preparation. In addition, GTP[S] elicited in some cells transient responses without application of acetylcholine or norepinephrine. Finally, rapid and sustained responses were seen as soon as the cells were dialyzed with inositol trisphosphate (20 μ M). These findings are discussed in terms of a possible role of a GTP-binding protein as a link between activation of muscarinic or adrenergic receptors and initiation of Ca2+ release by inositol trisphosphate.

  4. Adenosine(5') oligophospho-(5') guanosines and guanosine(5') oligophospho-(5') guanosines in human platelets.

    PubMed Central

    Schlüter, H; Grobeta, I; Bachmann, J; Kaufmann, R; van der Giet, M; Tepel, M; Nofer, J R; Assmann, G; Karas, M; Jankowski, J; Zidek, W

    1998-01-01

    We isolated and identified nucleoside(5') oligophospho-(5') nucleosides containing adenosine and guanosine (ApnG; n = 3-6) as well as diguanosine polyphosphates (GpnG; n = 3-6) in human platelets. For identification, UV spectrometry, matrix-assisted laser desorption/ionization, postsource decay matrix-assisted laser desorption/ionization mass spectrometry, and enzymatic cleavage experiments were used. The adenosine(5') oligophospho-(5') guanosines act as vasoconstrictors and growth factors. The diguanosine polyphosphates are potent modulators of growth in vascular smooth muscle cells, but do not affect vascular tone. PMID:9449703

  5. A new nonhydrolyzable reactive cGMP analogue, (Rp)-Guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate, which targets the cGMP binding site of human platelet PDE3A

    PubMed Central

    Hung, Su H.; Liu, Andy H.; Pixley, Robin A.; Francis, Penelope; Williams, LaTeeka D.; Matsko, Christopher M.; Barnes, Karine D.; Sivendran, Sharmila; Colman, Roberta F.; Colman, Robert W.

    2008-01-01

    The amino acids involved in substrate (cAMP) binding to human platelet cGMP-inhibited cAMP phosphodiesterase (PDE3A) are identified. Less is known about the inhibitor (cGMP) binding site. We have now synthesized a nonhydrolyzable reactive cGMP analog, Rp-guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate (Rp-cGMPS-BDB). Rp-cGMPS-BDB irreversibly inactivates PDE3A (KI = 43.4 ± 7.2 μM and kcart = 0.007 ± 0.0006 min−1). The effectiveness of protectants in decreasing the rate of inactivation by Rp-cGMPS-BDB is: Rp-cGMPS (Kd = 72 μM) > Sp-cGMPS (124), Sp-cAMPS (182) > GMP (1517), Rp-cAMPS (3762), AMP (4370 μM). NAD+, neither a substrate nor an inhibitor of PDE3A, does not protect. Nonhydrolyzable cGMP analogs exhibit greater affinity than the cAMP analogs. These results indicate that Rp-cGMPS-BDB targets favorably the cGMP binding site consistent with a docking model of PDE3A-Rp-cGMPS-BDB active site. We conclude that Rp-cGMPS-BDB is an effective active site-directed affinity label for PDE3A with potential for other cGMP-dependent enzymes. PMID:18394675

  6. Affinity of guanosine derivatives for polycytidylate revisited

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Hurley, T. B.; Baird, E. E.

    1995-01-01

    Evidence is presented for complexation of guanosine 5'-monophosphate 2-methylimidazolide (2-MeImpG) with polycytidylate (poly(C)) at pH 8.0 and 23 degrees C in the presence of 1.0 M NaCl2 and 0.2 M MgCl2 in water. The association of 2-MeImpG with poly(C) was investigated using UV-vis spectroscopy as well as by monitoring the kinetics of the nucleophilic substitution reaction of the imidazole moiety by amines. The results of both methods are consistent with moderately strong poly(C) 2-MeImpG complexation and the spectrophotometric measurements allowed the construction of a binding isotherm with a concentration of 2-MeImpG equal to 5.55 +/- 0.15 mM at half occupancy. UV spectroscopy was employed to establish the binding of other guanosine derivatives on poly(C). These derivatives are guanosine 5'-monophosphate (5'GMP), guanosine 5'-monophosphate imidazolide (ImpG), and guanosine 5'-monophosphate morpholidate (morpG). Within experimental error these guanosine derivatives exhibit the same affinity for poly(C) as 2-MeImpG.

  7. Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders

    PubMed Central

    Lanznaster, Débora; Dal-Cim, Tharine; Piermartiri, Tetsadê C. B.; Tasca, Carla I.

    2016-01-01

    Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson’s and Alzheimer’s diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calcium-activated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases. PMID:27699087

  8. Anti-aging effects of guanosine in glial cells.

    PubMed

    Souza, Débora Guerini; Bellaver, Bruna; Bobermin, Larissa Daniele; Souza, Diogo Onofre; Quincozes-Santos, André

    2016-12-01

    Guanosine, a guanine-based purine, has been shown to exert beneficial roles in in vitro and in vivo injury models of neural cells. Guanosine is released from astrocytes and modulates important astroglial functions, including glutamatergic metabolism, antioxidant, and anti-inflammatory activities. Astrocytes are crucial for regulating the neurotransmitter system and synaptic information processes, ionic homeostasis, energy metabolism, antioxidant defenses, and the inflammatory response. Aging is a natural process that induces numerous changes in the astrocyte functionality. Thus, the search for molecules able to reduce the glial dysfunction associated with aging may represent an approach for avoiding the onset of age-related neurological diseases. Hence, the aim of this study was to evaluate the anti-aging effects of guanosine, using primary astrocyte cultures from newborn, adult, and aged Wistar rats. Concomitantly, we evaluated the role of heme oxygenase 1 (HO-1) in guanosine-mediated glioprotection. We observed age-dependent changes in glutamate uptake, glutamine synthetase (GS) activity, the glutathione (GSH) system, pro-inflammatory cytokine (tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β)) release, and the transcriptional activity of nuclear factor kB (NFkB), which were prevented by guanosine in an HO-1-dependent manner. Our findings suggest guanosine to be a promising therapeutic agent able to provide glioprotection during the aging process. Thus, this study contributes to the understanding of the cellular and molecular mechanisms of guanosine in the aging process.

  9. 2'-F-ANA-guanosine and 2'-F-guanosine as powerful tools for structural manipulation of G-quadruplexes.

    PubMed

    Lech, Christopher Jacques; Li, Zhe; Heddi, Brahim; Phan, Anh Tuân

    2012-12-04

    Here we demonstrate the applicability of 2'-F-ANA-guanosine and 2'-F-guanosine as powerful tools for manipulating G-quadruplex folding by anti-position-favoring substitutions. A single guanine to 2'-F-ANA-guanine substitution can favor a single (3+1) hybrid conformation from a mixture of conformers. Rational substitutions of either type of 2'-F-modified nucleotide enable conformational switching from a (3+1) hybrid to a parallel folding topology.

  10. The roles of initiation factor 2 and guanosine triphosphate in initiation of protein synthesis

    PubMed Central

    Antoun, Ayman; Pavlov, Michael Y.; Andersson, Kerstin; Tenson, Tanel; Ehrenberg, Måns

    2003-01-01

    The role of IF2 from Escherichia coli was studied in vitro using a system for protein synthesis with purified components. Stopped flow experiments with light scattering show that IF2 in complex with guanosine triphosphate (GTP) or a non-cleavable GTP analogue (GDPNP), but not with guanosine diphosphate (GDP), promotes fast association of ribosomal subunits during initiation. Biochemical experiments show that IF2 promotes fast formation of the first peptide bond in the presence of GTP, but not GDPNP or GDP, and that IF2–GDPNP binds strongly to post-initiation ribosomes. We conclude that the GTP form of IF2 accelerates formation of the 70S ribosome from subunits and that GTP hydrolysis accelerates release of IF2 from the 70S ribosome. The results of a recent report, suggesting that GTP and GDP promote initiation equally fast, have been addressed. Our data, indicating that eIF5B and IF2 have similar functions, are used to rationalize the phenotypes of GTPase-deficient mutants of eIF5B and IF2. PMID:14532131

  11. Self-Assembly of Guanosine Molecules in Solutions

    NASA Astrophysics Data System (ADS)

    Li, Zheng; Orseno, Maxwell; Bose, Prasenjit; Streletzky, Kiril; Jamieson, Alex

    2009-10-01

    Guanosine and 3-Acetyl Guanosine monomers are expected to form cylindrical polymeric rods in a solution of KCl and H2O. Multi-angle Depolarized Dynamic Light Scattering (DDLS) and Static Light Scattering were used to study these solutions at various monomer concentrations. The correlation functions obtained from VV and VH experiments of DDLS were fitted to a sum of two stretched exponentials and their decay rates (G) were obtained using spectral time moment analysis. The diffusion coefficients deduced from G were analyzed to find length of the rods formed by Guanosine monomers. The concentration dependences of diffusion coefficients were compared with theoretical models of dilute and semi-dilute regimes. The fast mode of VV DDLS measurements was attributed to pure translation diffusion of rods; the slow VV mode had properties of large dynamic aggregates formed in solutions. The fast mode of VH DDLS had properties rotational diffusion, while the slow VH mode was found to be similar to the slow VV mode (large dynamic aggregates). SLS measurements at different solution concentrations yielded the aggregation concentration at which significant formation of rods occurs. The apparent molecular weight and radius of gyration of the rods were inferred from SLS spectra at different concentrations of Guanosine.

  12. Analogue Gravity.

    PubMed

    Barceló, Carlos; Liberati, Stefano; Visser, Matt

    2011-01-01

    Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for) gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing) and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity).

  13. Some acyclic analogues of nucleotides and their template-directed reactions

    NASA Technical Reports Server (NTRS)

    Tohidi, Mahrokh; Orgel, Leslie E.

    1989-01-01

    Bismonophosphoimidazolides of acyclic analogues of guanosine IV and adenosine V were synthesized. They undergo oligomerization in the presence of complementary polynucleotide templates. Details of their synthesis and their subsequent template- and nontemplate-directed reactions are described, and their possible relevance to the origin of life is discussed.

  14. Low-temperature photosensitized oxidation of a guanosine derivative and formation of an imidazole ring-opened product.

    PubMed

    Sheu, Chimin; Kang, Ping; Khan, Saeed; Foote, Christopher S

    2002-04-17

    An organic-soluble guanosine derivative, 2',3',5'-O-(tert-butyldimethylsilyl)guanosine (1), was prepared and its photosensitized oxidation was carried out in several solvents at various temperatures. Singlet oxygen is the reactive oxidizing agent responsible for this reaction. Neither an endoperoxide nor a dioxetane intermediate was detected by low-temperature NMR even at -78 degrees C. A product (A) with an oxidized imidazole ring was the only major product detected at room temperature; this compound could be isolated by low-temperature column chromatography and was characterized by (1)H and (13)C and mass spectroscopy. CO(2) was the other major product. A small amount of the corresponding 8-oxo-7,8-dihydroguanosine derivative B was detected during the initial stage of the photooxidation and was shown to be intermediate in the formation of two products of extensive degradation, C and D. Reaction of 1 with the singlet oxygen analogues 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) gave products consistent with a proposed mechanism involving the rearrangement of an initially formed endoperoxide to give A and B from reaction of 1 with singlet oxygen.

  15. Effects of guanosine tetraphosphate, guanosine pentaphosphate, and beta-gamma methylenyl-guanosine pentaphosphate on gene expression of Escherichia coli in vitro.

    PubMed

    Yang, H L; Zubay, G; Urm, E; Heiness, G; Cashel, M

    1974-01-01

    The effects of guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), both produced by E. coli, were measured on the activities of several genes in a cell-free system. Gene activity is measured as gene-directed synthesis of biochemically competent protein or transfer RNA. Both ppGpp and pppGpp stimulated the activities of the ara, lac, and trp operons and inhibited the arg operon. Production of transfer-RNA(Tyr) was unaffected by moderate levels of either ppGpp or pppGpp and only slightly inhibited at higher levels of ppGpp. Since the cell-free reaction mixtures hydrolyze pppGpp to ppGpp, we performed similar studies with a hydrolysis-resistant analog of pppGpp, the beta-gamma methylenyl derivative (pcppGpp). In general, pcppGpp shows the same inhibitory potency as pppGpp for the arg operon, but lacks the stimulatory effects on the ara, lac, and trp operons. This result suggests that the stimulation of these gene activities is specific for ppGpp.Under similar conditions, pppGpp and ppGpp show a slight inhibitory effect on the messenger-directed synthesis of beta-galactosidase and no effect on the messenger-directed synthesis of MS2 viral-coat protein. These observations, together with the fact that in the same system these nucleotides affect coupled transcription and translation, lead us to surmise that the activities of pppGpp and ppGpp are exerted at the level of RNA polymerase activity.

  16. The synthesis of 2'-methylseleno adenosine and guanosine 5'-triphosphates.

    PubMed

    Santner, Tobias; Siegmund, Vanessa; Marx, Andreas; Micura, Ronald

    2012-04-01

    Modified nucleoside triphosphates (NTPs) represent powerful building blocks to generate nucleic acids with novel properties by enzymatic synthesis. We have recently demonstrated the access to 2'-SeCH(3)-uridine and 2'-SeCH(3)-cytidine derivatized RNAs for applications in RNA crystallography, using the corresponding nucleoside triphosphates and distinct mutants of T7 RNA polymerase. In the present note, we introduce the chemical synthesis of the novel 2'-methylseleno-2'-deoxyadenosine and -guanosine 5'-triphosphates (2'-SeCH(3)-ATP and 2'-SeCH(3)-GTP) that represent further candidates for the enzymatic RNA synthesis with engineered RNA polymerases.

  17. Kinetics of the hydrolysis of guanosine 5'-phospho-2-methylimidazolide

    NASA Technical Reports Server (NTRS)

    Kanavarioti, Anastassia

    1986-01-01

    The hydrolysis kinetics of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) in aqueous buffered solutions of various pH's was studied at 75 and 37 C, using spectrophotometric and HPLC techniques. The hydrolysis was found to be very slow even at low pH. At 75 C and pH at or below l.0, two kinetic processes were observed: the more rapid one was attributed to the hydrolysis of the phosphoimidazolide P-N bond; the second, much slower one, was attributed to the cleavage of the glycosidic bond. It is noted that the P-N hydrolysis in phosphoimidazolides is very slow compared to other phosphoramidates, and that this might be one of the reasons why the phosphoimidazolides showed an extraordinary ability to form long oligomers under template-directed conditions.

  18. Nucleotides as nucleophiles: reactions of nucleotides with phosphoimidazolide activated guanosine

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Rosenbach, M. T.; Hurley, T. B.

    1991-01-01

    An earlier study of the reaction of phosphoimidazolide activated nucleosides (ImpN) in aqueous phosphate buffers indicated two modes of reaction of the phosphate monoanion and dianion. The first mode is catalysis of the hydrolysis of the P-N bond in ImpN's which leads to imidazole and nucleoside 5'-monophosphate. The second represents a nucleophilic substitution of the imidazole to yield the nucleoside 5'-diphosphate. This earlier study thus served as a model for the reaction of ImpN with nucleoside monophosphates (pN) because the latter can be regarded as phosphate derivatives. In the present study we investigated the reaction of guanosine 5'-phosphate-2-methylimidazolide, 2-MeImpG, in the presence of pN (N = guanosine, adenosine and uridine) in the range 6.9 less than or equal to pH less than or equal to 7.7. We observed that pN's do act as nucleophiles to form NppG, and as general base to enhance the hydrolysis of the P-N bond in 2-MeImpG, i.e. pN show the same behavior as inorganic phosphate. The kinetic analysis yields the following rate constants for the dianion pN2-: knpN = 0.17 +/- 0.02 M-1 h-1 for nucleophilic attack and khpN = 0.11 +/- 0.07 M-1 h-1 for general base catalysis of the hydrolysis. These rate constants which are independent of the nucleobase compare with kp.2 = 0.415 M-1 h-1 and khp2. = 0.217 M-1 h-1 for the reactions of HPO4(2-). In addition, this study shows that under conditions where pN presumably form stacks, the reaction mechanism remains unchanged although in quantitative terms stacked pN are somewhat less reactive. Attack by the 2'-OH and 3'-OH groups of the ribose moiety in amounts greater than or equal to 1% is not observed; this is attributed to the large difference in nucleophilicity in the neutral pH range between the phosphate group and the ribose hydroxyls. This nucleophilicity rank is not altered by stacking.

  19. Guanosine triphosphatases as novel therapeutic targets in tuberculosis.

    PubMed

    Rajni; Meena, Laxman S

    2010-08-01

    Tuberculosis (TB) is an infectious disease caused by the aerobic microbe Mycobacterium tuberculosis H(37)Rv. Despite the availability of the Bacille Calmette-Guérin (BCG) vaccine and directly observed treatment, short-course (DOTS), TB is a leading cause of death and affects a third of the world's population. The most important factor associated with disease severity is the development of antibiotic-resistant strains, including multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB. In order to understand disease pathogenesis, it is necessary to delineate the specific features of M. tuberculosis that enable it to evade the host defense system and contribute to its virulence. Here, we have reviewed the various characteristics, such as cell wall components, virulence genes, and the role of small guanosine triphosphatases (GTPases) in the pathogenesis of TB. GTPases are known to play a crucial role in the survival and pathogenesis of various pathogens. The key role of these proteins involves interference in phagosome maturation arrest, enabling pathogens to survive by escaping from lysozymes and toxic free radicals. This observation provides a new avenue for the development of anti-TB drugs.

  20. Influenza virion RNA-dependent RNA polymerase: stimulation by guanosine and related compounds.

    PubMed Central

    McGeoch, D; Kitron, N

    1975-01-01

    The activity of RNA-dependent RNA polymerase of several influenza viruses is stimulated by guanosine. Depending upon the virus strain used, the stimulation of initial reaction rate is up to 10-fold. 5'-GMP, 3',5'-cyclic GMP, and 5'-GDP show lesser stimulation effects. No other nucleosides of 5'-NMPs stimulate, but the dinucleoside monophosphates GpG and GpC show large stimulations. We present evidence that the stimulation represents preferential initiation of genome complementary RNA chains with guanosine: (i) [3-H] guanosine is incorporated specifically at the 5'terminus of RNA in polymerase reaction mixes in vitro. (ii) This incorporation reaction has several properties similar to those of the virion polymerase elongation reaction. (iii) RNA made in the stimulated reaction behaves as complementary RNA in annealing kinetic studies, as does RNA labeled with [3-H]guanosine. PMID:163915

  1. Determination of phosphate in soil extracts in the field: A green chemistry enzymatic method

    PubMed Central

    Campbell, Ellen R.; Warsko, Kayla; Davidson, Anna-Marie; (Bill) Campbell, Wilbur H.

    2015-01-01

    Measurement of ortho-phosphate in soil extracts usually involves sending dried samples of soil to a laboratory for analysis and waiting several weeks for the results. Phosphate determination methods often involve use of strong acids, heavy metals, and organic dyes. To overcome limitations of this approach, we have developed a phosphate determination method which can be carried out in the field to obtain results on the spot. This new method uses: • Small volumes. • An enzymatic reaction. • Green chemistry. First, the soil sample is extracted with deionized water and filtered. Next, an aliquot of the soil extract (0.5 mL) is transferred to a disposable cuvette, containing 0.5 mL of reaction mixture [200 mM HEPES, pH 7.6, 20 mM MgCl2, with 80 nmol 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) and 1 unit of recombinant purine nucleoside phosphorylase (PNP; EC 2.4.2.1)], mixed, and incubated for 10 min at field temperature. Absorbance of the completed reaction is measured at 360 nm in open-source, portable photometer linked by bluetooth to a smartphone. The phosphate and phosphorus content of the soil is determined by comparison of its absorbance at 360 nm to a previously prepared standard phosphate curve, which is stored in the smartphone app. PMID:26150991

  2. Determination of phosphate in soil extracts in the field: A green chemistry enzymatic method.

    PubMed

    Campbell, Ellen R; Warsko, Kayla; Davidson, Anna-Marie; Bill Campbell, Wilbur H

    2015-01-01

    Measurement of ortho-phosphate in soil extracts usually involves sending dried samples of soil to a laboratory for analysis and waiting several weeks for the results. Phosphate determination methods often involve use of strong acids, heavy metals, and organic dyes. To overcome limitations of this approach, we have developed a phosphate determination method which can be carried out in the field to obtain results on the spot. This new method uses: •Small volumes.•An enzymatic reaction.•Green chemistry. First, the soil sample is extracted with deionized water and filtered. Next, an aliquot of the soil extract (0.5 mL) is transferred to a disposable cuvette, containing 0.5 mL of reaction mixture [200 mM HEPES, pH 7.6, 20 mM MgCl2, with 80 nmol 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) and 1 unit of recombinant purine nucleoside phosphorylase (PNP; EC 2.4.2.1)], mixed, and incubated for 10 min at field temperature. Absorbance of the completed reaction is measured at 360 nm in open-source, portable photometer linked by bluetooth to a smartphone. The phosphate and phosphorus content of the soil is determined by comparison of its absorbance at 360 nm to a previously prepared standard phosphate curve, which is stored in the smartphone app.

  3. Defective cyclic guanosine monophosphate-gated calcium channels and the pathogenesis of psoriasis.

    PubMed

    McKenzie, Roddie C; Oda, Yuko; Szepietowski, Jacek C; Behne, Martin J; Mauro, Theodora

    2003-01-01

    A positive association between intake of calcium channel blockers and psoriasis has been observed recently. Intake of blockers of voltage-gated calcium ion channels is associated with outbreaks of psoriasis after a latent period in patients with and without a previous family history of psoriasis. This suggests that interfering with calcium influx may trigger psoriasis. Calcium influx also occurs via cyclic guanosine monophosphate-gated channels; human keratinocytes contain functional and non-functional (splice variants) versions of these channels. We show here that keratinocytes and skin from psoriatic individuals express higher levels of mRNA encoding a non-functional cyclic guanosine monophosphate-gated calcium channel and that high expression of the splice variant by transfection of cells in culture leads to loss of protein expression for the functional cyclic guanosine monophosphate-gated Ca2+ channels.

  4. Evidence that hyperprolinemia alters glutamatergic homeostasis in rat brain: neuroprotector effect of guanosine.

    PubMed

    Ferreira, Andréa G K; da Cunha, Aline A; Scherer, Emilene B; Machado, Fernanda R; da Cunha, Maira J; Braga, Andressa; Mussulini, Ben Hur; Moreira, Júlia D; Wofchuk, Susana; Souza, Diogo O; Wyse, Angela T S

    2012-01-01

    This study investigated the effects of acute and chronic hyperprolinemia on glutamate uptake, as well as some mechanisms underlying the proline effects on glutamatergic system in rat cerebral cortex. The protective role of guanosine on effects mediated by proline was also evaluated. Results showed that acute and chronic hyperprolinemia reduced glutamate uptake, Na(+), K(+)-ATPase activity, ATP levels and increased lipoperoxidation. GLAST and GLT-1 immunocontent were increased in acute, but not in chronic hyperprolinemic rats. Our data suggest that the effects of proline on glutamate uptake may be mediated by lipid peroxidation and disruption of Na(+), K(+)-ATPase activity, but not by decreasing in glutamate transporters. This probably induces excitotoxicity and subsequent energy deficit. Guanosine was effective to prevent most of the effects promoted by proline, reinforcing its modulator role in counteracting the glutamate toxicity. However, further studies are needed to assess the modulatory effects of guanosine on experimental hyperprolinemia.

  5. Supramolecular polymers based on the quadruplex formation of ditopic guanosine macromonomers in nonaqueous media.

    PubMed

    Pintér, Gabor; Batta, Gyula; Horvath, Pal; Löki, Istvan; Kurtan, Tibor; Antus, Sandor; Kéki, Sandor; Zsuga, Miklós; Nagy, Gabor; Aradi, Janos; Gunda, Tamas; Herczegh, Pal

    2007-05-08

    The formation of supramolecular polymeric aggregates with a molecular mass of 100 kDa in a nonaqueous solution from a telechelic dimer of isopropylidene guanosine in the presence of K(+) ions is reported. The possible structure of macromonomers resulting from the development of G4 quartets was deduced from DOSY NMR, circular dichroism spectra, and dynamic light scattering measurements.

  6. Guanosine Diphosphate-l-Fucose Glycopeptide Fucosyltransferase Activity in Corynebacterium insidiosum1

    PubMed Central

    Sadowski, Peter L.; Strobel, Gary A.

    1973-01-01

    The biosynthesis of a phytotoxic glycopeptide of Corynebacterium insidiosum involves guanosine diphosphate-l-fucosyltransferase activity. This enzyme activity is most consistently associated with the cellular membranes fraction. The optimal pH for the transfer reaction is 7.5. The partially hydrolyzed toxin serves as an acceptor (primer) of l-fucose. PMID:4199136

  7. The effect of purine and pyrimidine analogues and virazole on adenovirus replication.

    PubMed

    Scheffler, P; Haghchenas, D; Wigand, R

    1975-04-01

    The multiplication of adenovirus 19 in HeLa cells was inhibited by various purine and pyrimidine analogues and by virazole. The formation of infectious virus and of capsid proteins (haemagglutin, group-specific complement-fixing antigen) was inhibited to the same degree, while the viral cytopathic effect (CPE) was not inhibited. The reversibility of the inhibition after removal of the substances was more complete for purine than for pyrimidine analogues. The inhibition was counteracted by simulataneous addition of the corresponding nucleosides. Adenosine was more effected than guanosine against purine analogues; both were partially effective against virazole, but none of them against arabinofuranosyladenine. The time-dependence of inhibition, the ensuing eclipse period after removal of the inhibitors, and the successive application of two inhibitors led to the conclusion that most of them affect the viral multiplication mainly by inhibition of DNA synthesis. Azacytidine inhibits the synthesis of structural proteins as well.

  8. Screening of free radical formation in crystals of guanosine by ESR study

    NASA Astrophysics Data System (ADS)

    Usta, Ayhan; Vural, Hasibe Cingilli; Asik, Biray; Usta, Keziban

    2011-10-01

    In this study, to obtain guanosine polycrystalline, novel crystallization method was performed on powder guanosine material. Effective crystallization conditions were achieved by adjustment of the concentration of the metal ions, chemical solutions, NaCl, KCl, glacial acetic acid, nitric oxide, perchloric acid, glutamic acid, and pH of buffer. Behaviors of the guanosine polycrystal samples exposed to high-energy values were investigated using ESR method. The polycrystal samples were exposed to gamma-rays for 48 and 72 h. ESR signals were not recorded from the non-irradiated sample and the sample irradiated for 48 h, but the polycrystalline sample irradiated for 72 h exhibited complex ESR spectra. ESR measurements were taken on the irradiated sample in temperature range from 300 to 450 K. On the basis of all these measurements dependence temperature, it can be said that the shape of the spectrum was to be dependent on temperature slightly. Hence, we assume that the radical structure occurred was resistance to high temperature. Two radicals were determined in the structure irradiated and these were called radical I and radical II. The g, hyperfine constants, and spin density were found to be ρ = 0.96, a=2.7 mT, a=1.155 mT, aN = 0.35 mT and g1 = 2.0093 for the radical I; aN = 4.7 mT and g2 = 2.0094 for the radical II.

  9. Survey of Analogue Spacetimes

    NASA Astrophysics Data System (ADS)

    Visser, Matt

    Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  10. Coupling of the guanosine glycosidic bond conformation and the ribonucleotide cleavage reaction: implications for barnase catalysis.

    PubMed

    Roca, Maite; De Maria, Leonardo; Wodak, Shoshana J; Moliner, Vicente; Tuñón, Iñaki; Giraldo, Jesús

    2008-02-01

    To examine the possible relationship of guanine-dependent GpA conformations with ribonucleotide cleavage, two potential of mean force (PMF) calculations were performed in aqueous solution. In the first calculation, the guanosine glycosidic (Gchi) angle was used as the reaction coordinate, and computations were performed on two GpA ionic species: protonated (neutral) or deprotonated (negatively charged) guanosine ribose O2 '. Similar energetic profiles featuring two minima corresponding to the anti and syn Gchi regions were obtained for both ionic forms. For both forms the anti conformation was more stable than the syn, and barriers of approximately 4 kcal/mol were obtained for the anti --> syn transition. Structural analysis showed a remarkable sensitivity of the phosphate moiety to the conformation of the Gchi angle, suggesting a possible connection between this conformation and the mechanism of ribonucleotide cleavage. This hypothesis was confirmed by the second PMF calculations, for which the O2 '--P distance for the deprotonated GpA was used as reaction coordinate. The computations were performed from two selected starting points: the anti and syn minima determined in the first PMF study of the deprotonated guanosine ribose O2'. The simulations revealed that the O2 ' attack along the syn Gchi was more favorable than that along the anti Gchi: energetically, significantly lower barriers were obtained in the syn than in the anti conformation for the O--P bond formation; structurally, a lesser O2 '--P initial distance, and a better suited orientation for an in-line attack was observed in the syn relative to the anti conformation. These results are consistent with the catalytically competent conformation of barnase-ribonucleotide complex, which requires a guanine syn conformation of the substrate to enable abstraction of the ribose H2 ' proton by the general base Glu73, thereby suggesting a coupling between the reactive substrate conformation and enzyme structure

  11. Use of phosphoimidazolide-activated guanosine to investigate the nucleophilicity of spermine and spermidine

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Baird, E. E.; Smith, P. J.

    1995-01-01

    Guanosine 5'-phosphate 2-methylimidazolide (2-MeImpG), a labile phosphoimidazolide analog of guanosine triphosphate, was used to test the reactivity of the natural polyamines (PAs), spermine (spm) and spermidine (spd). The products are the guanosine 5'-phosphate-polyamine derivatives (PA-pG: spd-pG and spm-pG) which are quite stable in the range 4 < pH < 11. Our study is the first of which we are aware that reports on the nucleophilicity of these amines. The main findings are as follows. (i) HPLC analysis of the products indicates the formation of only two of the three possible spd products and only one of the two possible spm products. These results can be explained if only the primary amino groups of the two polyamines are reactive, while the secondary amino groups are rendered unreactive by a steric effect. The reactions of 2-MeImpG and other phosphoimidazolide derivatives of nucleosides (ImpNs) with primary and secondary monoamines support this interpretation (Kanavarioti et al. J. Org. Chem. 1995, 60, 632). (ii) The product ratio of the two spd-pG adducts derived from the primary amino groups varies between 2.40 and 0.71 in the range 6.1 < or equal to pH < or equal to 11.9. Such small variation in the product ratio can only be rationalized by the similar, but not identical, basicity of the two primary amino groups and provides strong support for a previously reported model for polyamine ionization (Onasch et. al. Biophys. Chem. 1984, 19, 245). (iii) On the basis of our kinetic determinations conditions at which the nucleophilicity of these amines is at a minimum and at which other interactions with ImpNs could be tested can be chosen.

  12. Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.

    PubMed

    Lin, Q; Wu, J; Peng, Y B; Cui, M; Willis, W D

    1999-03-01

    Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR

  13. Fluorescent Sensing of Guanine and Guanosine Monophosphate with Conjugated Receptors Incorporating Aniline and Naphthyridine Moieties.

    PubMed

    Lu, Shao-Hung; Phang, Riping; Fang, Jim-Min

    2016-04-15

    Ethyne-linked naphthyridine-aniline conjugated molecules are selective sensors of decylguanine in dichloromethane and guanosine monophosphate in water (Kass = 16,000 M(-1)). The 2-acetamido-1,8-naphthyridine moiety binds with guanine in a DAA-ADD triply hydrogen-bonded motif. The aniline moiety enhances an electron-donating effect, and the substituent is tuned to attain extra hydrogen bonds, π-π stacking, and electrostatic interactions. The proposed binding modes are supported by a Job plot, ESI-MS, (1)H NMR, UV-vis, and fluorescence spectral analyses.

  14. Persistence Increases in the Absence of the Alarmone Guanosine Tetraphosphate by Reducing Cell Growth

    DTIC Science & Technology

    2016-08-16

    Guanosine Tetraphosphate by Reducing Cell Growth Nityananda Chowdhury1, Brian W. Kwan1 & Thomas K. Wood1,2 Most bacterial cells are stressed, and as a...proteins, YihS, PntA, YqjE, FocA, and Zur, that increase persistence simply by reducing cell growth . Microbial infections are the leading cause of death...discoverers of persisters3,4 and by a subsequent study showing a reduction in protein translation and ATP produc- tion converts nearly all exponentially

  15. A new deletion in autosomal dominant guanosine triphosphate cyclohydrolase I deficiency gene--Segawa disease.

    PubMed

    Bianca, S; Bianca, M

    2006-02-01

    Hereditary Progressive Dystonia with marked diurnal fluctuation (HPD) is an autosomally dominantly inherited dystonia which is characterized by marked diurnal fluctuation of symptoms and by marked and sustained response to levodopa associated with mutations in guanosine triphosphate cyclohydrolase (GCH-1) deficiency gene. We report an italian patient with a new 18 bp deletion at 267 in exon 1 in the GCH-1 gene. The peculiarity of our patient is the new mutations never reported and mnemonic disturbances that are also not reported in the classical HPD.A genotype-phenotype relationship may be suggested between different gene mutations and non classical clinical manifestations.

  16. Some selective serotonin reuptake inhibitors inhibit dynamin I guanosine triphosphatase (GTPase).

    PubMed

    Otomo, Masahiro; Takahashi, Kiyofumi; Miyoshi, Hiroshi; Osada, Kenichi; Nakashima, Hideki; Yamaguchi, Noboru

    2008-08-01

    Neuronal dynamin I plays a critical role in the recycling of synaptic vesicles, and thus in nervous system function. We expressed and purified dynamin I to explore potentially clinically useful endocytosis inhibitors and to examine the mechanism of their action. We estimated the IC(50) of nineteen psychotropic drugs for dynamin I. The IC(50) values of two selective serotonin reuptake inhibitors (sertraline and fluvoxamine) were 7.3+/-1.0 and 14.7+/-1.6 microM, respectively. Kinetic analyses revealed that fluvoxamine is a noncompetitive inhibitor of dynamin I guanosine triphosphatase (GTPase) with respect to guanosine 5'-triphosphate (GTP) and a competitive inhibitor with respect to L-phosphatidylserine (PS). Fluvoxamine may compete with PS for binding to the pleckstrin homology domain of dynamin I. On the other hand, sertraline was a mixed type inhibitor with respect to both GTP and PS. Our results indicate that sertraline and fluvoxamine may regulate the transportation of neurotransmitters by modulating synaptic vesicle endocytosis via the inhibition of dynamin I GTPase.

  17. Synthesis, Oxidation Behavior, Crystallization and Structure of 2'-Methylseleno Guanosine Containing RNAs

    SciTech Connect

    Moroder,H.; Kreutz, C.; Lang, K.; Serganov, A.; Micura, R.

    2006-01-01

    We have recently introduced a basic concept for the combined chemical and enzymatic preparation of site-specifically modified 2'-methylseleno RNAs which represent useful derivatives for phasing of X-ray crystallographic data during their three-dimensional structure determination. Here, we introduce the first synthesis of an appropriate guanosine phosphoramidite, which complements the thus far established set of 2'-methylseleno-modified uridine, cytidine, and adenosine building blocks for solid-phase synthesis. The novel building block was readily incorporated into RNA. Importantly, it was the 2'-methylseleno-guanosine-labeled RNA that allowed us to reveal the reversible oxidation/reduction behavior of the Se moiety and thus it represents a valuable contribution to the understanding of the action of threo-1,4-dimercapto-2,3-butanediol (DTT) required during solid-phase synthesis, deprotection, and crystallization of selenium-containing RNA. In addition, we investigated 2'-methylseleno RNA with respect to crystallization properties. Our studies revealed that the Se modification significantly increases the range of conditions leading to crystal growth. Moreover, we determined the crystal structures of model RNA helices and showed that the Se modification can affect crystal packing interactions, thus potentially expanding the possibilities for obtaining the best crystal form.

  18. Interaction of the tobacco-specific nitrosamines, methylethylnitrosamine and N-nitrosonornicotine, with DNA and guanosine.

    PubMed

    Lai, D Y; Arcos, J C; Argus, M F

    1980-04-01

    In vitro binding of the tobacco-specific nitrosamines, methylethylnitrosamine (MEN) and nitrosonornicotine (NNN), to exogenous DNA and guanosine was studies in a rat liver microsome-catalyzed system. MEN (N-[ethyl-1-14C]) binds covalently to calf thymus DNA whereas NNN (N'-[pyrrolidine-2-14C]) binds only to guanosine but not to DNA. Pretreatment of the rats with either phenobarbital (PB) or 3-methylcholanthrene (MC) greatly diminishes the binding of 14C-MEN to DNA. Both MEN-demethylase and -deethylase activities are stimulated by PB pretreatment and inhibited by MC pretreatment, but the degree of stimulation and inhibition of the two dealkylases are not the same. Addition of cytosol to the incubation system does not enhance but suppresses the binding of 14C-MEN to DNA. Inclusion of mitochondria in the system has no effect on the binding. Addition of benzylamine (250 microM), which is a potent inhibitor of dimethylnitrosamine-demethylase, however totally abolishes the binding of 14C-MEN catalyzed by microsomes. The data suggest that ethylcarbonium ion may be the metabolically activated intermediate of MEN that binds to DNA.

  19. The state of the guanosine nucleotide allosterically affects the interfaces of tubulin in protofilament

    NASA Astrophysics Data System (ADS)

    André, Joseph R.; Clément, Marie-Jeanne; Adjadj, Elisabeth; Toma, Flavio; Curmi, Patrick A.; Manivet, Philippe

    2012-04-01

    The dynamics of microtubules is essential for many microtubule-dependent cellular functions such as the mitosis. It has been recognized for a long time that GTP hydrolysis in αβ-tubulin polymers plays a critical role in this dynamics. However, the effects of the changes in the nature of the guanosine nucleotide at the E-site in β-tubulin on microtubule structure and stability are still not well understood. In the present work, we performed all-atom molecular dynamics simulations of a αβα-tubulin heterotrimer harboring a guanosine nucleotide in three different states at the E-site: GTP, GDP-Pi and GDP. We found that changes in the nucleotide state is associated with significant conformational variations at the α-tubulin N- and β-tubulin M-loops which impact the interactions between tubulin protofilaments. The results also show that GTP hydrolysis reduces αβ-tubulin interdimer contacts in favor of intradimer interface. From an atomistic point view, we propose a role for α-tubulin glutamate residue 254 in catalytic magnesium coordination and identified a water molecule in the nucleotide binding pocket which is most probably required for nucleotide hydrolysis. Finally, the results are discussed with reference to the role of taxol in microtubule stability and the recent tubulin-sT2R crystal structures.

  20. Polyphosphate, cyclic AMP, guanosine tetraphosphate, and c-di-GMP reduce in vitro Lon activity

    PubMed Central

    Osbourne, Devon O; Soo, Valerie WC; Konieczny, Igor; Wood, Thomas K

    2014-01-01

    Lon protease is conserved from bacteria to humans and regulates cellular processes by degrading different classes of proteins including antitoxins, transcriptional activators, unfolded proteins, and free ribosomal proteins. Since we found that Lon has several putative cyclic diguanylate (c-di-GMP) binding sites and since Lon binds polyphosphate (polyP) and lipid polysaccharide, we hypothesized that Lon has an affinity for phosphate-based molecules that might regulate its activity. Hence we tested the effect of polyP, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), guanosine tetraphosphate (ppGpp), c-di-GMP, and GMP on the ability of Lon to degrade α-casein. Inhibition of in vitro Lon activity occurred for polyP, cAMP, ppGpp, and c-di-GMP. We also demonstrated by HPLC that Lon is able to bind c-di-GMP. Therefore, four cell signals were found to regulate the activity of Lon protease. PMID:24874800

  1. Dinucleosidetetraphosphatase from Ehrlich ascites tumour cells: inhibition by adenosine, guanosine and uridine 5'-tetraphosphates.

    PubMed

    Moreno, A; Lobatón, C D; Sillero, M A; Sillero, A

    1982-01-01

    1. An enzyme has been partially purified from Ehrlich ascites tumour cells which specifically hydrolyses dinucleosidetetraphosphates, with Km values of around 2 microM. The products of the hydrolysis are the corresponding nucleoside tri- and monophosphates. Dinucleoside Tri- and diphosphates were not substrates of the reaction. 2. The enzyme requires Mg2+ or Mn2+, is maximally active at a pH value of approx. 7.5 and has a mol, wt of 19,800 as estimated by filtration on Sephadex G-75. Nucleoside mono-, di- and triphosphates were competitive inhibitors of the reaction with Ki values in the 0.1 mM range. 3. Particularly relevant is the inhibition of this enzyme by adenosine and guanosine 5'tetraphosphates. In the course of this investigation, the presence of uridine 5'-tetraphosphate was detected in a commercial preparation of UTP. Adenosine, guanosine and uridine 5'-tetraphosphates were very strong inhibitors of the reaction with Ki values in the nM range.

  2. Controlled supramolecular structure of guanosine monophosphate in the interlayer space of layered double hydroxide

    PubMed Central

    2016-01-01

    Guanosine monophosphates (GMPs) were intercalated into the interlayer space of layered double hydroxides (LDHs) and the molecular arrangement of GMP was controlled in LDHs. The intercalation conditions such as GMP/LDH molar ratio and reaction temperature were systematically adjusted. When the GMP/LDH molar ratio was 1:2, which corresponds to the charge balance between positive LDH sheets and GMP anions, GMP molecules were well-intercalated to LDH. At high temperature (100 and 80 °C), a single GMP molecule existed separately in the LDH interlayer. On the other hand, at lower temperature (20, 40 and 60 °C), GMPs tended to form ribbon-type supramolecular assemblies. Differential scanning calorimetry showed that the ribbon-type GMP assembly had an intermolecular interaction energy of ≈101 kJ/mol, which corresponds to a double hydrogen bond between guanosine molecules. Once stabilized, the interlayer GMP orientations, single molecular and ribbon phase, were successfully converted to the other phase by adjusting the external environment by stoichiometry or temperature control. PMID:28144541

  3. Synthesis and photophysical characterisation of a fluorescent nucleoside analogue that signals the presence of an abasic site in RNA.

    PubMed

    Tanpure, Arun A; Srivatsan, Seergazhi G

    2012-11-05

    The synthesis and site-specific incorporation of an environment-sensitive fluorescent nucleoside analogue (2), based on a 5-(benzofuran-2-yl)pyrimidine core, into DNA oligonucleotides (ONs), and its photophysical properties within these ONs are described. Interestingly and unlike 2-aminopurine (a widely used nucleoside analogue probe), when incorporated into an ON and hybridised with a complementary ON, the emissive nucleoside 2 displays significantly higher emission intensity than the free nucleoside. Furthermore, photophysical characterisation shows that the fluorescence properties of the nucleoside analogue within ONs are significantly influenced by flanking bases, especially by guanosine. By utilising the responsiveness of the nucleoside to changes in base environment, a DNA ON reporter labelled with the emissive nucleoside 2 was constructed; this signalled the presence of an abasic site in a model depurinated sarcin/ricin RNA motif of a eukaryotic 28S rRNA.

  4. Guanosine Prevents Anhedonic-Like Behavior and Impairment in Hippocampal Glutamate Transport Following Amyloid-β1-40 Administration in Mice.

    PubMed

    Lanznaster, Débora; Mack, Josiel M; Coelho, Victor; Ganzella, Marcelo; Almeida, Roberto F; Dal-Cim, Tharine; Hansel, Gisele; Zimmer, Eduardo R; Souza, Diogo O; Prediger, Rui D; Tasca, Carla I

    2016-09-06

    Amyloid-beta (Aβ) peptides are the major neuropathological hallmarks related with Alzheimer's disease (AD). Aβ peptides trigger several biochemical mechanisms of neurotoxicity, including neuroinflammation and glutamatergic neurotransmission impairment. Guanosine is the endogenous guanine-derived nucleoside that modulates the glutamatergic system and the cellular redox status, thus acting as a neuroprotective agent. Here, we investigated the putative neuroprotective effect of guanosine in an AD-like mouse model. Adult mice received a single intracerebroventricular injection of Aβ1-40 (400 pmol/site) or vehicle and then were treated immediately, 3 h later, and once a day during the subsequent 14 days with guanosine (8 mg/kg, intraperitoneally). Aβ1-40 or guanosine did not alter mouse locomotor activity and anxiety-related behaviors. Aβ1-40-treated mice displayed short-term memory deficit in the object location task that was prevented by guanosine. Guanosine prevented the Aβ1-40-induced increase in latency to grooming in the splash test, an indicative of anhedonia. Aβ1-40 increased Na(+)-independent glutamate uptake in ex vivo hippocampal slices, and guanosine reversed it to control levels. The repeated administration of guanosine increased hippocampal GDP levels, which was not observed in the group treated with Aβ plus guanosine. Aβ1-40 induced an increase in hippocampal ADP levels. Aβ1-40 decreased GFAP expression in the hippocampal CA1 region, an effect not modified by guanosine. No differences were observed concerning synaptophysin and NeuN immunolabeling. Together, these results show that guanosine prevents memory deficit and anhedonic-like behavior induced by Aβ1-40 that seem to be linked to glutamate transport unbalance and alterations on purine and metabolite levels in mouse hippocampus.

  5. Rho and Rap guanosine triphosphatase signaling in B cells and chronic lymphocytic leukemia.

    PubMed

    Mele, Silvia; Devereux, Stephen; Ridley, Anne J

    2014-09-01

    Chronic lymphocytic leukemia (CLL) cells proliferate predominantly in niches in the lymph nodes, where signaling from the B cell receptor (BCR) and the surrounding microenvironment are critical for disease progression. In addition, leukemic cells traffic constantly from the bloodstream into the lymph nodes, migrate within lymphatic tissues and egress back to the bloodstream. These processes are driven by chemokines and their receptors, and depend on changes in cell migration and integrin-mediated adhesion. Here we describe how Rho and Rap guanosine triphosphatases (GTPases) contribute to both BCR signaling and chemokine receptor signaling, particularly by regulating cytoskeletal dynamics and integrin activity. We propose that new inhibitors of BCR-activated kinases are likely to affect CLL cell trafficking via Rho and Rap GTPases, and that upstream regulators or downstream effectors could be good targets for therapeutic intervention in CLL.

  6. Free energy barrier for dissociation of the guanosine monophosphate anion in water

    NASA Astrophysics Data System (ADS)

    Cornetta, Lucas M.; Coutinho, Kaline; Canuto, Sylvio; Varella, Márcio T. do N.

    2016-08-01

    We report free energy barriers for the ground-state dissociation of the guanosine nucleotide anion in solution, employing implicit and explicit solvation models. The latter was based on the Free Energy Perturbation technique and Monte Carlo simulations. For the lowest-energy structure, both solvation models indicate a solvent-induced transition from a dipole-bound state in the gas phase to a π∗ valence state in solution. The free barrier estimates obtained from explicit and implicit solvation are in fair agreement with each other, although significantly overestimated in comparison to a previously reported explicit solvation model based on ab initio molecular dynamics simulations. Accounting for corrections related to the different DFT functionals used in the present and previous studies significantly improves the agreement. Contribution to the Topical Issue "Advances in Positron and Electron Scattering", edited by Paulo Limao-Vieira, Gustavo Garcia, E. Krishnakumar, James Sullivan, Hajime Tanuma and Zoran Petrovic.

  7. Stathmin slows down guanosine diphosphate dissociation from tubulin in a phosphorylation-controlled fashion.

    PubMed

    Amayed, P; Carlier, M F; Pantaloni, D

    2000-10-10

    Stathmin is an important protein that interacts with tubulin and regulates microtubule dynamics in a phosphorylation-controlled fashion. Here we show that the dissociation of guanosine 5'-diphosphate (GDP) from beta-tubulin is slowed 20-fold in the (tubulin)(2)-stathmin ternary complex (T(2)S). The kinetics of GDP or guanosine 5'-triphosphate (GTP) dissociation from tubulin have been monitored by the change in tryptophan fluorescence of tubulin upon exchanging 2-amino-6-mercapto-9-beta-ribofuranosylpurine 5'-diphosphate (S6-GDP) for tubulin-bound guanine nucleotide. At molar ratios of stathmin to tubulin lower than 0.5, biphasic kinetics were observed, indicating that the dynamics of the complex is extremely slow, consistent with its high stability. The method was used to characterize the effects of phosphorylation of stathmin on its interaction with tubulin. The serine-to-glutamate substitution of all four phosphorylatable serines of stathmin (4E-stathmin) weakens the stability of the T(2)S complex by about 2 orders of magnitude. The phosphorylation of serines 16 and 63 in stathmin has a more severe effect and weakens the stability of T(2)S 10(4)-fold. The rate of GDP dissociation is lowered only 7-fold and 4-fold in the complexes of tubulin with 4E-stathmin and diphosphostathmin, respectively. Sedimentation velocity studies support the conclusions of nucleotide exchange data and show that the T(2)S complexes formed between tubulin and 4E-stathmin or diphosphostathmin are less compact than the highly stable T(2)S complex. The correlation between the effect of phosphorylation of stathmin on the stability of T(2)S complex measured in vitro and on the function of stathmin in vivo is discussed.

  8. Novel Characteristics of Trypanosoma brucei Guanosine 5'-monophosphate Reductase Distinct from Host Animals

    PubMed Central

    Kimura, Chihiro; Shinohara, Takahiro; Tomiyama, Ai; Imamura, Akira; Kuwamura, Mitsuru; Nishimura, Kazuhiko; Fujimori, Ko; Shuto, Satoshi; Ishibashi, Osamu; Kubata, Bruno Kilunga; Inui, Takashi

    2016-01-01

    The metabolic pathway of purine nucleotides in parasitic protozoa is a potent drug target for treatment of parasitemia. Guanosine 5’-monophosphate reductase (GMPR), which catalyzes the deamination of guanosine 5’-monophosphate (GMP) to inosine 5’-monophosphate (IMP), plays an important role in the interconversion of purine nucleotides to maintain the intracellular balance of their concentration. However, only a few studies on protozoan GMPR have been reported at present. Herein, we identified the GMPR in Trypanosoma brucei, a causative protozoan parasite of African trypanosomiasis, and found that the GMPR proteins were consistently localized to glycosomes in T. brucei bloodstream forms. We characterized its recombinant protein to investigate the enzymatic differences between GMPRs of T. brucei and its host animals. T. brucei GMPR was distinct in having an insertion of a tandem repeat of the cystathionine β-synthase (CBS) domain, which was absent in mammalian and bacterial GMPRs. The recombinant protein of T. brucei GMPR catalyzed the conversion of GMP to IMP in the presence of NADPH, and showed apparent affinities for both GMP and NADPH different from those of its mammalian counterparts. Interestingly, the addition of monovalent cations such as K+ and NH4+ to the enzymatic reaction increased the GMPR activity of T. brucei, whereas none of the mammalian GMPR’s was affected by these cations. The monophosphate form of the purine nucleoside analog ribavirin inhibited T. brucei GMPR activity, though mammalian GMPRs showed no or only a little inhibition by it. These results suggest that the mechanism of the GMPR reaction in T. brucei is distinct from that in the host organisms. Finally, we demonstrated the inhibitory effect of ribavirin on the proliferation of trypanosomes in a dose-dependent manner, suggesting the availability of ribavirin to develop a new therapeutic agent against African trypanosomiasis. PMID:26731263

  9. Synthesis of guanosine tetra- and pentaphosphates by the obligately anaerobic bacterium Bacteroides thetaiotaomicron in response to molecular oxygen.

    PubMed Central

    Glass, T L; Holmes, W M; Hylemon, P B; Stellwag, E J

    1979-01-01

    Guanosine 5'-diphosphate 3'-diphosphate (ppGpp) and guanosine 5'-triphosphate 3'-diphosphate (pppGpp) were detected in formic acid extracts of air-exposed culutres of Bacteroides thetaiotaomicron. The identification of ppGpp and pppGpp in B. thetaiotaomicron was based on the following results: (i) cochromatography of 32P-labeled hyperphosphorylated nucleotides in two different two-dimensional solvent systems with authentic ppGpp and pppGpp; (ii) incorporation of [3H]guanosine into the putative ppGpp and pppGpp; (iii) alkaline lability; and (iv) resistance, to periodate oxidation. There was a marked increase in the concentration of ppGpp and pppGpp after shift from anaerobic to aerobic conditions, and accumulation of both ppGpp and pppGpp was blocked under these conditions by pretreatment of the culture with rifampin or tetracycline. Growth and incorporation of [3H]guanosine, [3H]tymidine, [14C]succinate, and L-[35S]methionine into macromolecules were inhibited immediately upon exposure to air. The accumulation of ppGpp and pppGpp in B. thetaiotaomicron upon exposure to air may represent a novel signal for synthesis of these compounds. Images PMID:422517

  10. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

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

    1981-04-01

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

  11. Quantum analogue computing.

    PubMed

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

    2010-08-13

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

  12. Adenosine, but not guanosine, protects vaginal epithelial cells from Trichomonas vaginalis cytotoxicity.

    PubMed

    Menezes, Camila Braz; Frasson, Amanda Piccoli; Meirelles, Lucia Collares; Tasca, Tiana

    2017-02-01

    Trichomonas vaginalis causes the most common non-viral sexually transmitted disease worldwide. The cytoadherence and cytotoxicity upon the vaginal epithelial cells are crucial for the infection. Extracellular nucleotides are released during cell damage and, along with their nucleosides, can activate purinoceptors. The opposing effects of nucleotides versus nucleosides are regulated by ectonucleotidases. Herein we evaluated the hemolysis and cytolysis induced by T. vaginalis, as well as the extracellular nucleotide hydrolysis along with the effects mediated by nucleotides and nucleosides on cytotoxicity. In addition, the gene expression of purinoceptors in host cells was determined. The hemolysis and cytolysis exerted by all T. vaginalis isolates presented positive Pearson correlation. All T. vaginalis isolates were able to hydrolyze nucleotides, showing higher NTPDase than ecto-5'-nucleotidase activity. The most cytotoxic isolate, TV-LACM6, hydrolyzes ATP, GTP with more efficiency than AMP and GMP. The vaginal epithelial cell line (HMVII) expressed the genes for all subtypes of P1, P2X and P2Y receptors. Finally, when nucleotides and nucleosides were tested, the cytotoxic effect elicited by TV-LACM6 was increased with nucleotides. In contrast, the cytotoxicity was reversed by adenosine in presence of EHNA, but not by guanosine, contributing to the understanding of the purinergic signaling role on T. vaginalis cytotoxicity.

  13. Guanosine tetraphosphate modulates salicylic acid signaling and the resistance of Arabidopsis thaliana to Turnip Mosaic Virus.

    PubMed

    Abdelkefi, Hela; Sugliani, Matteo; Hang, Ke; Harchouni, Seddik; Soubigou-Taconnat, Ludivine; Citerne, Sylvie; Mouille, Gregory; Fakhfakh, Hatem; Robaglia, Christophe; Field, Ben

    2017-02-21

    Chloroplasts can act as key players in the perception and acclimation of plants to incoming environmental signals. A growing body of evidence indicates that chloroplasts play a critical role in plant immunity. Chloroplast function can be regulated by the nucleotides guanosine tetraphosphate and pentaphosphate ((p)ppGpp). In plants (p)ppGpp levels increase in response to abiotic stress and to plant hormones that are involved in abiotic and biotic stress signaling. Here we analyzed the transcriptome of Arabidopsis plants that over accumulate (p)ppGpp and unexpectedly found a decrease in the levels of a broad range of transcripts for plant defense and immunity. To determine whether (p)ppGpp is involved in modulating plant immunity we analysed the susceptibility of plants with different levels of (p)ppGpp to Turnip Mosaic Virus (TuMV) carrying a Green Fluorescent Protein (GFP) reporter. We found that (p)ppGpp accumulation is associated with increased susceptibility to TuMV and reduced levels of the defense hormone salicylic acid (SA). In contrast, plants with lower (p)ppGpp levels showed reduced susceptibility to TuMV, and this was associated with the precocious upregulation of defense-related genes and increased SA content. We therefore demonstrate a new link between (p)ppGpp metabolism and plant immunity in Arabidopsis. This article is protected by copyright. All rights reserved.

  14. Extracellular conversion of guanine-based purines to guanosine specifically enhances astrocyte glutamate uptake.

    PubMed

    Frizzo, Marcos Emílio dos Santos; Antunes Soares, Félix Alexandre; Dall'Onder, Leonara Patrícia; Lara, Diogo Rizzato; Swanson, Raymond A; Souza, Diogo Onofre

    2003-05-16

    Guanosine (GUO) has been shown to stimulate glutamate uptake in primary astrocyte cultures. The purpose of this study was to determine the effect and specificity of guanine- or adenine-based purines on glutamate and GABA uptake in cultured astrocytes. Stimulatory effect on glutamate uptake was observed with GUO, GMP or GTP. Simultaneous exposure with these guanine-based purines did not show an additive effect. We also investigated a possible interconversion of guanine-based purines during incubation time. Action by GTP was excluded since the hydrolysis resistant GTP analog, GMP-PNP did not stimulate glutamate uptake. Addition of an ecto-5'-nucleotidase inhibitor abolished GMP-stimulatory effect on glutamate uptake, without affecting GUO action. Taken together, these results suggest that GUO is the guanine-based purines responsible for glutamate uptake activation. In addition, the stimulatory effect on glutamate uptake was not observed with adenine-based purines. Moreover, GABA uptake was not activated by GUO. These results point to specificity in the interaction between GUO and the astrocyte glutamate uptake system.

  15. Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions.

    PubMed

    Dal-Cim, Tharine; Ludka, Fabiana K; Martins, Wagner C; Reginato, Charlise; Parada, Esther; Egea, Javier; López, Manuela G; Tasca, Carla I

    2013-08-01

    Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.

  16. Switching direction in electric-signal-induced cell migration by cyclic guanosine monophosphate and phosphatidylinositol signaling.

    PubMed

    Sato, Masayuki J; Kuwayama, Hidekazu; van Egmond, Wouter N; Takayama, Airi L K; Takagi, Hiroaki; van Haastert, Peter J M; Yanagida, Toshio; Ueda, Masahiro

    2009-04-21

    Switching between attractive and repulsive migration in cell movement in response to extracellular guidance cues has been found in various cell types and is an important cellular function for translocation during cellular and developmental processes. Here we show that the preferential direction of migration during electrotaxis in Dictyostelium cells can be reversed by genetically modulating both guanylyl cyclases (GCases) and the cyclic guanosine monophosphate (cGMP)-binding protein C (GbpC) in combination with the inhibition of phosphatidylinositol-3-OH kinases (PI3Ks). The PI3K-dependent pathway is involved in cathode-directed migration under a direct-current electric field. The catalytic domains of soluble GCase (sGC) and GbpC also mediate cathode-directed signaling via cGMP, whereas the N-terminal domain of sGC mediates anode-directed signaling in conjunction with both the inhibition of PI3Ks and cGMP production. These observations provide an identification of the genes required for directional switching in electrotaxis and suggest that a parallel processing of electric signals, in which multiple-signaling pathways act to bias cell movement toward the cathode or anode, is used to determine the direction of migration.

  17. Alkylation by propylene oxide of deoxyribonucleic acid, adenine, guanosine and deoxyguanylic acid

    PubMed Central

    Lawley, P. D.; Jarman, M.

    1972-01-01

    1. Propylene oxide reacts with DNA in aqueous buffer solution at about neutral pH to yield two principal products, identified as 7-(2-hydroxypropyl)guanine and 3-(2-hydroxypropyl)adenine, which hydrolyse out of the alkylated DNA at neutral pH values at 37°C. 2. These products were obtained in quantity by reactions between propylene oxide and guanosine or adenine respectively. 3. The reactions between propylene oxide and adenine in acetic acid were parallel to those between dimethyl sulphate and adenine in neutral aqueous solution; the alkylated positions in adenine in order of decreasing reactivity were N-3, N-1 and N-9. A method for separating these alkyladenines is described. 4. Deoxyguanylic acid sodium salt was alkylated at N-7 by propylene oxide in neutral aqueous solution. 5. The nature of the side chain in the principal alkylation products was established by mass spectrometry, and the nature of the products is consistent with their formation by the bimolecular reaction mechanism. PMID:5073240

  18. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

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

  19. X-ray characterization of mesophases of human telomeric G-quadruplexes and other DNA analogues

    PubMed Central

    Yasar, Selcuk; Schimelman, Jacob B.; Aksoyoglu, M. Alphan; Steinmetz, Nicole F.; French, Roger H.; Parsegian, V. Adrian; Podgornik, Rudolf

    2016-01-01

    Observed in the folds of guanine-rich oligonucleotides, non-canonical G-quadruplex structures are based on G-quartets formed by hydrogen bonding and cation-coordination of guanosines. In dilute 5′-guanosine monophosphate (GMP) solutions, G-quartets form by the self-assembly of four GMP nucleotides. We use x-ray diffraction to characterize the columnar liquid-crystalline mesophases in concentrated solutions of various model G-quadruplexes. We then probe the transitions between mesophases by varying the PEG solution osmotic pressure, thus mimicking in vivo molecular crowding conditions. Using the GMP-quadruplex, built by the stacking of G-quartets with no covalent linking between them, as the baseline, we report the liquid-crystalline phase behaviors of two other related G-quadruplexes: (i) the intramolecular parallel-stranded G-quadruplex formed by the 22-mer four-repeat human telomeric sequence AG3(TTAG3)3 and (ii) the intermolecular parallel-stranded G-quadruplex formed by the TG4T oligonucleotides. Finally, we compare the mesophases of the G-quadruplexes, under PEG-induced crowding conditions, with the corresponding mesophases of the canonical duplex and triplex DNA analogues. PMID:27249961

  20. Structural basis of thiamine pyrophosphate analogues binding to the eukaryotic riboswitch.

    PubMed

    Thore, Stéphane; Frick, Christian; Ban, Nenad

    2008-07-02

    The thiamine pyrophosphate (TPP)-sensing riboswitch is the only riboswitch found in eukaryotes. In plants, TPP regulates its own production by binding to the 3' untranslated region of the mRNA encoding ThiC, a critical enzyme in thiamine biosynthesis, which promotes the formation of an unstable splicing variant. In order to better understand the molecular basis of TPP-analogue binding to the eukaryotic TPP-responsive riboswitch, we have determined the crystal structures of the Arabidopsis thaliana TPP-riboswitch in complex with oxythiamine pyrophosphate (OTPP) and with the antimicrobial compound pyrithiamine pyrophosphate (PTPP). The OTPP-riboswitch complex reveals that the pyrimidine ring of OTPP is stabilized in its enol form in order to retain key interactions with guanosine 28 of the riboswitch previously observed in the TPP complex. The structure of PTPP in complex with the riboswitch shows that the base moiety of guanosine 60 undergoes a conformational change to cradle the pyridine ring of the PTPP. Structural information from these complexes has implications for the design of novel antimicrobials targeting TPP-sensing riboswitches.

  1. X-ray characterization of mesophases of human telomeric G-quadruplexes and other DNA analogues

    NASA Astrophysics Data System (ADS)

    Yasar, Selcuk; Schimelman, Jacob B.; Aksoyoglu, M. Alphan; Steinmetz, Nicole F.; French, Roger H.; Parsegian, V. Adrian; Podgornik, Rudolf

    2016-06-01

    Observed in the folds of guanine-rich oligonucleotides, non-canonical G-quadruplex structures are based on G-quartets formed by hydrogen bonding and cation-coordination of guanosines. In dilute 5‧-guanosine monophosphate (GMP) solutions, G-quartets form by the self-assembly of four GMP nucleotides. We use x-ray diffraction to characterize the columnar liquid-crystalline mesophases in concentrated solutions of various model G-quadruplexes. We then probe the transitions between mesophases by varying the PEG solution osmotic pressure, thus mimicking in vivo molecular crowding conditions. Using the GMP-quadruplex, built by the stacking of G-quartets with no covalent linking between them, as the baseline, we report the liquid-crystalline phase behaviors of two other related G-quadruplexes: (i) the intramolecular parallel-stranded G-quadruplex formed by the 22-mer four-repeat human telomeric sequence AG3(TTAG3)3 and (ii) the intermolecular parallel-stranded G-quadruplex formed by the TG4T oligonucleotides. Finally, we compare the mesophases of the G-quadruplexes, under PEG-induced crowding conditions, with the corresponding mesophases of the canonical duplex and triplex DNA analogues.

  2. X-ray characterization of mesophases of human telomeric G-quadruplexes and other DNA analogues

    SciTech Connect

    Yasar, Selcuk; Schimelman, Jacob B.; Aksoyoglu, M. Alphan; Steinmetz, Nicole F.; French, Roger H.; Parsegian, V. Adrian; Podgornik, Rudolf

    2016-06-02

    We report that observed in the folds of guanine-rich oligonucleotides, non-canonical G-quadruplex structures are based on G-quartets formed by hydrogen bonding and cation-coordination of guanosines. In dilute 5'-guanosine monophosphate (GMP) solutions, G-quartets form by the self-assembly of four GMP nucleotides. We use x-ray diffraction to characterize the columnar liquid-crystalline mesophases in concentrated solutions of various model G-quadruplexes. We then probe the transitions between mesophases by varying the PEG solution osmotic pressure, thus mimicking in vivo molecular crowding conditions. Using the GMP-quadruplex, built by the stacking of G-quartets with no covalent linking between them, as the baseline, we report the liquid-crystalline phase behaviors of two other related G-quadruplexes: (i) the intramolecular parallel-stranded G-quadruplex formed by the 22-mer four-repeat human telomeric sequence AG3 (TTAG3)3 and (ii) the intermolecular parallel-stranded G-quadruplex formed by the TG(4)T oligonucleotides. Finally, we compare the mesophases of the G-quadruplexes, under PEG-induced crowding conditions, with the corresponding mesophases of the canonical duplex and triplex DNA analogues.

  3. X-ray characterization of mesophases of human telomeric G-quadruplexes and other DNA analogues

    DOE PAGES

    Yasar, Selcuk; Schimelman, Jacob B.; Aksoyoglu, M. Alphan; ...

    2016-06-02

    We report that observed in the folds of guanine-rich oligonucleotides, non-canonical G-quadruplex structures are based on G-quartets formed by hydrogen bonding and cation-coordination of guanosines. In dilute 5'-guanosine monophosphate (GMP) solutions, G-quartets form by the self-assembly of four GMP nucleotides. We use x-ray diffraction to characterize the columnar liquid-crystalline mesophases in concentrated solutions of various model G-quadruplexes. We then probe the transitions between mesophases by varying the PEG solution osmotic pressure, thus mimicking in vivo molecular crowding conditions. Using the GMP-quadruplex, built by the stacking of G-quartets with no covalent linking between them, as the baseline, we report the liquid-crystallinemore » phase behaviors of two other related G-quadruplexes: (i) the intramolecular parallel-stranded G-quadruplex formed by the 22-mer four-repeat human telomeric sequence AG3 (TTAG3)3 and (ii) the intermolecular parallel-stranded G-quadruplex formed by the TG(4)T oligonucleotides. Finally, we compare the mesophases of the G-quadruplexes, under PEG-induced crowding conditions, with the corresponding mesophases of the canonical duplex and triplex DNA analogues.« less

  4. Anabolism of amdoxovir: phosphorylation of dioxolane guanosine and its 5'-phosphates by mammalian phosphotransferases.

    PubMed

    Feng, Joy Y; Parker, William B; Krajewski, Megan L; Deville-Bonne, Dominique; Veron, Michel; Krishnan, Preethi; Cheng, Yung-Chi; Borroto-Esoda, Katyna

    2004-11-01

    Amdoxovir [(-)-beta-D-2,6-diaminopurine dioxolane, DAPD], the prodrug of dioxolane guanosine (DXG), is currently in Phase I/II clinical development for the treatment of HIV-1 infection. In this study, we examined the phosphorylation pathway of DXG using 15 purified enzymes from human (8), animal (6), and yeast (1) sources, including deoxyguanosine kinase (dGK), deoxycytidine kinase (dCK), high Km 5'-nucleotidase (5'-NT), guanylate (GMP) kinase, nucleoside monophosphate (NMP) kinase, adenylate (AMP) kinase, nucleoside diphosphate (NDP) kinase, 3-phosphoglycerate (3-PG) kinase, creatine kinase, and pyruvate kinase. In addition, the metabolism of 14C-labeled DXG was studied in CEM cells. DXG was not phosphorylated by human dCK, and was a poor substrate for human dGK with a high Km (7 mM). Human 5'-NT phosphorylated DXG with relatively high efficiency (4.2% of deoxyguanosine). DXG-MP was a substrate for porcine brain GMP kinase with a substrate specificity that was 1% of dGMP. DXG-DP was phosphorylated by all of the enzymes tested, including NDP kinase, 3-PG kinase, creatine kinase, and pyruvate kinase. The BB-isoform of human creatine kinase showed the highest relative substrate specificity (47% of dGDP) for DXG-DP. In CEM cells incubated with 5 microM DXG for 24 h, 0.015 pmole/10(6) cells (approximately 7.5 nM) of DXG-TP was detected as the primary metabolite. Our study demonstrated that 5'-nucleotidase, GMP kinase, creatine kinase, and NDP kinase could be responsible for the activation of DXG in vivo.

  5. Guanosine protects against reperfusion injury in rat brains after ischemic stroke.

    PubMed

    Connell, Barry J; Di Iorio, Patrizia; Sayeed, Iqbal; Ballerini, Patrizia; Saleh, Monique C; Giuliani, Patricia; Saleh, Tarek M; Rathbone, Michel P; Su, Caixin; Jiang, Shucui

    2013-02-01

    After ischemic stroke, early thrombolytic therapy to reestablish tissue perfusion improves outcome but triggers a cascade of deleterious cellular and molecular events. Using a collaborative approach, our groups examined the effects of guanosine (Guo) in response to ischemic reperfusion injury in vitro and in vivo. In a transient middle cerebral artery occlusion (MCAO) in rats, Guo significantly reduced infarct volume in a dose-dependent manner when given systemically either immediately before or 30 min, but not 60 min, after the onset of the 5.5-hr reperfusion period. In a separate experiment, Guo significantly reduced infarct volume after 24 hr of reperfusion when administered 5 min before reperfusion. Western blot analysis did not reveal any significant changes either in endoplasmic reticulum (ER) stress proteins (GRP 78 and 94) or HSP 70 or in levels of m-calpain. In vitro oxygen and glucose deprivation (OGD) significantly increased production of both reactive oxygen species (ROS) and interleukin-8 (IL-8) in the primary astrocytes. Guo did not alter ROS or IL-8 production when given to the astrocytes before OGD. However, Guo when added to the cells prior to or 30 min after reperfusion significantly reduced IL-8 release but not ROS formation. Our study revealed a dose- and time-dependent protective effect of Guo on reperfusion injury in vitro and vivo. The mechanisms by which Guo exerts its effect are independent of unfolded proteins in ER or the level of intracellular calcium or ROS formation. However, the effect may be induced, at least partially, by inhibiting IL-8, a marker of reperfusion-triggered proinflammatory events.

  6. Suppression of the biosynthesis of guanosine triphosphate by protein synthesis inhibitors

    SciTech Connect

    Volkin, E.; Boling, M.E.; Jones, M.H.; Lee, W.H.; Pike, L.M.

    1980-10-10

    In a prior report it was observed that CTP synthesis and concomitant incorporation of CMP into RNA and dCMP into DNA were markedly reduced in cells cultured in the presence of cycloheximide and puromycin. Experiments described here with Novikoff hepatoma cells reveal that the purine biosynthetic pathway is similarly affected. When the cells are subjected to cycloheximide (30 or 60 ..mu..g/ml) or puromycin (100 ..mu..g/ml), there is a substantial reduction in the bioconversion of hypoxanthine, adenosine, and deoxyadenosine into guanylate compared to untreated cultures. Whereas synthesis (counts per min/nmol) of pool ATP was 70 to 100% of controls, that of pool GTP was 20 to 35% of controls. Incorporation of AMP into RNA was 40 to 60% of controls, but that of GMP was only 10 to 25% of controls. Incorporation of dAMP into DNA averaged 10% of controls, but that of dGMP was only 4% of controls. Synthesis of guanylates from formate by the de novo pathway was similarly reduced, but incorporation of guanosine, which enters via kinase action alone, was not disproportionately lowered. These results suggest that protein synthesis inhibitors cause a severely reduced availability of newly synthesized GTP and CTP as well as their deoxy counterparts, dGTP and dCTP, the proximal precursors for the synthesis of RNA and DNA. However, the nanomolar levels of all nucleoside triphosphates remain high, probably as a result of recycling of nucleic acid breakdown products. Thus, reduced synthesis of these compounds may restrict nucleic acid synthesis only of some sort of compartmentation leads to a limitation of these precursors at the site(s) of nucleic acid synthesis.

  7. Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension.

    PubMed

    Lee, Keng Jin; Berkelhamer, Sara K; Kim, Gina A; Taylor, Joann M; O'Shea, Kelly M; Steinhorn, Robin H; Farrow, Kathryn N

    2014-02-01

    Pulmonary hypertension (PH) occurs in 25 to 35% of premature infants with significant bronchopulmonary dysplasia (BPD). Neonatal mice exposed to 14 days of hyperoxia develop BPD-like lung injury and PH. To determinne the impact of hyperoxia on pulmonary artery (PA) cyclic guanosine monophosphate (cGMP) signaling in a murine model of lung injury and PH, neonatal C57BL/6 mice were placed in room air, 75% O2 for 14 days (chronic hyperoxia [CH]) or 75% O2 for 24 hours, followed by 13 days of room air (acute hyperoxia with recovery [AHR]) with or without sildenafil. At 14 days, mean alveolar area, PA medial wall thickness (MWT), right ventricular hypertrophy (RVH), and vessel density were assessed. PA protein was analyzed for cGMP, soluble guanylate cyclase, and PDE5 activity. CH and AHR mice had RVH, but only CH mice had increased alveolar area and MWT and decreased vessel density. In CH and AHR PAs, soluble guanylate cyclase activity was decreased, and PDE5 activity was increased. In CH mice, sildenafil attenuated MWT and RVH but did not improve mean alveolar area or vessel density. In CH and AHR PAs, sildenafil decreased PDE5 activity and increased cGMP. Our results indicate that prolonged hyperoxia leads to lung injury, PH, RVH, and disrupted PA cGMP signaling. Furthermore, 24 hours of hyperoxia causes RVH and disrupted PA cGMP signaling that persists for 13 days. Sildenafil reduced RVH and restored vascular cGMP signaling but did not attenuate lung injury. Thus, hyperoxia can rapidly disrupt PA cGMP signaling in vivo with sustained effects, and concurrent sildenafil therapy can be protective.

  8. Involvement of Cyclic Guanosine Monophosphate-Dependent Protein Kinase I in Renal Antifibrotic Effects of Serelaxin

    PubMed Central

    Wetzl, Veronika; Schinner, Elisabeth; Kees, Frieder; Hofmann, Franz; Faerber, Lothar; Schlossmann, Jens

    2016-01-01

    Introduction: Kidney fibrosis has shown to be ameliorated through the involvement of cyclic guanosine monophosphate (cGMP) and its dependent protein kinase I (cGKI). Serelaxin, the recombinant form of human relaxin-II, increases cGMP levels and has shown beneficial effects on kidney function in acute heart failure patients. Antifibrotic properties of serelaxin are supposed to be mediated via relaxin family peptide receptor 1 and subsequently enhanced nitric oxide/cGMP to inhibit transforming growth factor-β (TGF-β) signaling. This study examines the involvement of cGKI in the antifibrotic signaling of serelaxin. Methods and Results: Kidney fibrosis was induced by unilateral ureteral obstruction in wildtype (WT) and cGKI knock-out (KO) mice. After 7 days, renal antifibrotic effects of serelaxin were assessed. Serelaxin treatment for 7 days significantly increased cGMP in the kidney of WT and cGKI-KO. In WT, renal fibrosis was reduced through decreased accumulation of collagen1A1, total collagen, and fibronectin. The profibrotic connective tissue growth factor as well as myofibroblast differentiation were reduced and matrix metalloproteinases-2 and -9 were positively modulated after treatment. Moreover, Smad2 as well as extracellular signal-regulated kinase 1 (ERK1) phosphorylation were decreased, whereas phosphodiesterase (PDE) 5a phosphorylation was increased. However, these effects were not observed in cGKI-KO. Conclusion: Antifibrotic renal effects of serelaxin are mediated via cGMP/cGKI to inhibit Smad2- and ERK1-dependent TGF-β signaling and increased PDE5a phosphorylation. PMID:27462268

  9. The cyclic guanosine monophosphate/B-type natriuretic peptide ratio and mortality in advanced heart failure

    PubMed Central

    Lourenço, Patrícia; Araújo, José Paulo; Azevedo, Ana; Ferreira, António; Bettencourt, Paulo

    2009-01-01

    Aims Attenuation of the effects of natriuretic peptides has been demonstrated in animal models but studies in humans are scarce, particularly concerning renal attenuation. We investigated the attenuation of B-type natriuretic peptide (BNP) in chronic advanced heart failure (HF). Methods and results We included 62 outpatients with HF and severe left ventricular systolic dysfunction. Cases had at least one hospital admission or emergency department visit for acute HF in the previous year and were in NYHA class III/IV despite optimized therapy. The individual age- and sex-matched controls were symptomatically controlled (NYHA I and II). We collected 24 h urine and a blood sample from all patients. Plasma BNP and plasma (pcGMP) and urine cyclic guanosine monophosphate (ucGMP) were measured. Patients were followed for 3 months for hospital admission or all-cause death. ucGMP to plasma BNP (ucGMP/BNP) ratio was attenuated in cases vs. controls [median (IQR): 8354 (4293–16 456) vs. 12 693 (6896–22 851)]. There were no differences in pcGMP to BNP (pcGMP/BNP) ratio or urine cGMP excretion. Patients with worse outcome had lower pcGMP/BNP [260 (86–344) vs. 381 (244–728) in patients without adverse outcome events] and lower ucGMP/BNP [4146 (2207–9363) vs. 10 922 (7495–19 971)]. Conclusion Renal NP’s second messenger production is attenuated in advanced HF. Patients with worse outcome have lower ucGMP/BNP and pcGMP/BNP ratios. PMID:19168517

  10. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

  11. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

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

  12. Functional characterization of exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GPPA) of Campylobacter jejuni.

    PubMed

    Malde, Anandkumar; Gangaiah, Dharanesh; Chandrashekhar, Kshipra; Pina-Mimbela, Ruby; Torrelles, Jordi B; Rajashekara, Gireesh

    2014-05-15

    The inorganic polyphosphate (poly-P) is a key regulator of stress responses and virulence in many bacterial pathogens including Campylobacter jejuni. The role of exopolyphosphatases/guanosine pentaphosphate (pppGpp) phosphohydrolases (PPX/GPPA) in poly-P homeostasis and C. jejuni pathobiology remains unexplored. Here, we analyzed deletion mutants (∆ppx1, ∆ppx2) and the double knockout mutant (dkppx), all ∆ppx mutants exhibited increased capacity to accumulate poly-P; however only ∆ppx1 and dkppx mutants showed decreased accumulation of ppGpp, an alarmone molecule that regulates stringent response in bacteria, suggesting potential dual role for PPX1/GPPA. Nutrient survival defect of ∆ppx mutants was rescued by the supplementation of specific amino acids implying that survival defect may be associated with decreased ppGpp and/ or increased poly-P in ∆ppx mutants. The ppk1 and spoT were upregulated in both ∆ppx1 and ∆ppx2 suggesting a compensatory role for SpoT and Ppk1 in poly-P and ppGpp homeostasis. The lack of ppx genes resulted in defects in motility, biofilm formation, nutrient stress survival, invasion and intracellular survival indicating that maintaining a certain level of poly-P is critical for ppx genes in C. jejuni pathophysiology. Both ppx1 and ppx2 mutants were resistant to human complement-mediated killing; however, the dkppx mutant was sensitive. The serum susceptibility did not occur in the presence of MgCl 2 and EGTA suggesting an involvement of the classical or lectin pathway of complement mediated killing. Interestingly, the chicken serum did not have any effect on the ∆ppx mutants' survival. The observed serum susceptibility was not related to C. jejuni surface capsule and lipooligosaccharide structures. Our study underscores the importance of PPX/GPPA proteins in poly-P and ppGpp homeostasis, two critical molecules that modulate environmental stress responses and virulence in C. jejuni.

  13. Functional characterization of exopolyphosphatase/guanosine pentaphosphate phosphohydrolase (PPX/GPPA) of Campylobacter jejuni

    PubMed Central

    Malde, Anandkumar; Gangaiah, Dharanesh; Chandrashekhar, Kshipra; Pina-Mimbela, Ruby; Torrelles, Jordi B; Rajashekara, Gireesh

    2014-01-01

    The inorganic polyphosphate (poly-P) is a key regulator of stress responses and virulence in many bacterial pathogens including Campylobacter jejuni. The role of exopolyphosphatases/guanosine pentaphosphate (pppGpp) phosphohydrolases (PPX/GPPA) in poly-P homeostasis and C. jejuni pathobiology remains unexplored. Here, we analyzed deletion mutants (∆ppx1, ∆ppx2) and the double knockout mutant (dkppx), all ∆ppx mutants exhibited increased capacity to accumulate poly-P; however only ∆ppx1 and dkppx mutants showed decreased accumulation of ppGpp, an alarmone molecule that regulates stringent response in bacteria, suggesting potential dual role for PPX1/GPPA. Nutrient survival defect of ∆ppx mutants was rescued by the supplementation of specific amino acids implying that survival defect may be associated with decreased ppGpp and/ or increased poly-P in ∆ppx mutants. The ppk1 and spoT were upregulated in both ∆ppx1 and ∆ppx2 suggesting a compensatory role for SpoT and Ppk1 in poly-P and ppGpp homeostasis. The lack of ppx genes resulted in defects in motility, biofilm formation, nutrient stress survival, invasion and intracellular survival indicating that maintaining a certain level of poly-P is critical for ppx genes in C. jejuni pathophysiology. Both ppx1 and ppx2 mutants were resistant to human complement-mediated killing; however, the dkppx mutant was sensitive. The serum susceptibility did not occur in the presence of MgCl2 and EGTA suggesting an involvement of the classical or lectin pathway of complement mediated killing. Interestingly, the chicken serum did not have any effect on the ∆ppx mutants’ survival. The observed serum susceptibility was not related to C. jejuni surface capsule and lipooligosaccharide structures. Our study underscores the importance of PPX/GPPA proteins in poly-P and ppGpp homeostasis, two critical molecules that modulate environmental stress responses and virulence in C. jejuni. PMID:24569519

  14. Trichomonas vaginalis NTPDase and ecto-5'-nucleotidase hydrolyze guanine nucleotides and increase extracellular guanosine levels under serum restriction.

    PubMed

    Menezes, Camila Braz; Durgante, Juliano; de Oliveira, Rafael Rodrigues; Dos Santos, Victor Hugo Jacks Mendes; Rodrigues, Luiz Frederico; Garcia, Solange Cristina; Dos Santos, Odelta; Tasca, Tiana

    2016-05-01

    Trichomonas vaginalis is the aethiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease in the world. The purinergic signaling pathway is mediated by extracellular nucleotides and nucleosides that are involved in many biological effects as neurotransmission, immunomodulation and inflammation. Extracellular nucleotides can be hydrolyzed by a family of enzymes known as ectonucleotidases including the ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) family which hydrolyses nucleosides triphosphate and diphosphate as preferential substrates and ecto-5'-nucleotidase which catalyzes the conversion of monophosphates into nucleosides. In T. vaginalis the E-NTPDase and ecto-5'-nucleotidase activities upon adenine nucleotides have already been characterized in intact trophozoites but little is known concerning guanine nucleotides and nucleoside. These enzymes may exert a crucial role on nucleoside generation, providing the purine sources for the synthesis de novo of these essential nutrients, sustaining parasite growth and survival. In this study, we investigated the hydrolysis profile of guanine-related nucleotides and nucleoside in intact trophozoites from long-term-grown and fresh clinical isolates of T. vaginalis. Knowing that guanine nucleotides are also substrates for T. vaginalis ectoenzymes, we evaluated the profile of nucleotides consumption and guanosine uptake in trophozoites submitted to a serum limitation condition. Results show that guanine nucleotides (GTP, GDP, GMP) were substrates for T. vaginalis ectonucleotidases, with expected kinetic parameters for this enzyme family. Different T. vaginalis isolates (two from the ATCC and nine fresh clinical isolates) presented a heterogeneous hydrolysis profile. The serum culture condition increased E-NTPDase and ecto-5'-nucleotidase activities with high consumption of extracellular GTP generating enhanced GDP, GMP and guanosine levels as demonstrated by HPLC, with final

  15. Adenosine-guanosine preferential photocleavage of DNA by azido-benzoyl- and diazocyclopenta-dienylcarbonyloxy derivatives of 9-aminoacridine.

    PubMed Central

    Nielsen, P E; Jeppesen, C; Egholm, M; Buchardt, O

    1988-01-01

    The photoreactions of 9-[6-(4-azidobenzamido)hexylamino]acridine (AHA) and 9-[6-(2-diazocyclopentadienylcarbonyloxy)hexylamino]acridine (DHA) with double stranded DNA result in formation of single strand nicks and alkali labile sites (adducts) with an efficiency of 6 x 10(-3) nicks per AHA and 3 x 10(-2) nicks per DHA molecule. The alkali dependent DNA cleavage by AHA shows a pronounced A+G preference whereas that by DHA is practically sequence independent. In the presence of diacridines, however, DHA exhibits a preference for cleavage at guanosines. These DNA photocleaving reagents could be useful for DNA photofootprinting and photosequencing. Images PMID:2836803

  16. Interaction of a novel fluorescent GTP analogue with the small G-protein K-Ras.

    PubMed

    Iwata, Seigo; Masuhara, Kaori; Umeki, Nobuhisa; Sako, Yasushi; Maruta, Shinsaku

    2016-01-01

    A novel fluorescent guanosine 5'-triphosphate (GTP) analogue, 2'(3')-O-{6-(N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl)amino) hexanoic}-GTP (NBD-GTP), was synthesized and utilized to monitor the effect of mutations in the functional region of mouse K-Ras. The effects of the G12S, A59T and G12S/A59T mutations on GTPase activity, nucleotide exchange rates were compared with normal Ras. Mutation at A59T resulted in reduction of the GTPase activity by 0.6-fold and enhancement of the nucleotide exchange rate by 2-fold compared with normal Ras. On the other hand, mutation at G12S only slightly affected the nucleotide exchange rate and did not affect the GTPase activity. We also used NBD-GTP to study the effect of these mutations on the interaction between Ras and SOS1, a guanine nucleotide exchange factor. The mutation at A59T abolished the interaction with SOS1. The results suggest that the fluorescent GTP analogue, NBD-GTP, is applicable to the kinetic studies for small G-proteins.

  17. Molecular mechanisms for the regulation of insulin-stimulated glucose uptake by small guanosine triphosphatases in skeletal muscle and adipocytes.

    PubMed

    Satoh, Takaya

    2014-10-16

    Insulin is a hormone that regulates the blood glucose level by stimulating various physiological responses in its target tissues. In skeletal muscle and adipose tissue, insulin promotes membrane trafficking of the glucose transporter GLUT4 from GLUT4 storage vesicles to the plasma membrane, thereby facilitating the uptake of glucose from the circulation. Detailed mechanisms underlying insulin-dependent intracellular signal transduction for glucose uptake remain largely unknown. In this article, I give an overview on the recently identified signaling network involving Rab, Ras, and Rho family small guanosine triphosphatases (GTPases) that regulates glucose uptake in insulin-responsive tissues. In particular, the regulatory mechanisms for these small GTPases and the cross-talk between protein kinase and small GTPase cascades are highlighted.

  18. An Unconventional Acid-Labile Nucleobase Protection Concept for Guanosine Phosphoramidites in RNA Solid-Phase Synthesis.

    PubMed

    Jud, Lukas; Micura, Ronald

    2017-03-08

    We present an innovative O(6) -tert-butyl/N(2) -tert-butyloxycarbonyl protection concept for guanosine (G) phosphoramidites. This concept is advantageous for 2'-modified G building blocks because of very efficient synthetic access when compared with existing routes that usually employ O(6) -(4-nitrophenyl)ethyl/N(2) -acyl protection or that start from 2-aminoadenosine involving enzymatic transformation into guanosine later on in the synthetic path. The new phosphoramidites are fully compatible with 2'-O-tBDMS or TOM phosphoramidites in standard RNA solid-phase synthesis and deprotection, and provide excellent quality of tailored RNAs for the growing range of applications in RNA biophysics, biochemistry, and biology.

  19. Borrelia burgdorferi rel Is Responsible for Generation of Guanosine-3′-Diphosphate-5′-Triphosphate and Growth Control

    PubMed Central

    Bugrysheva, Julia V.; Bryksin, Anton V.; Godfrey, Henry P.; Cabello, Felipe C.

    2005-01-01

    The global transcriptional regulator (p)ppGpp (guanosine-3′-diphosphate-5′-triphosphate and guanosine-3′,5′-bisphosphate, collectively) produced by the relA and spoT genes in Escherichia coli allows bacteria to adapt to different environmental stresses. The genome of Borrelia burgdorferi encodes a single chromosomal rel gene (BB0198) (B. burgdorferi rel [relBbu]) homologous to relA and spoT of E. coli. Its role in (p)ppGpp synthesis, bacterial growth, and modulation of gene expression has not been studied in detail. We constructed a relBbu deletion mutant in an infectious B. burgdorferi 297 strain and isolated an extrachromosomally complemented derivative of this mutant. The mutant did not synthesize relBbu mRNA, RelBbu protein, or (p)ppGpp. This synthesis was restored in the complemented derivative, confirming that relBbu is necessary and sufficient for (p)ppGpp synthesis and degradation in B. burgdorferi. The relBbu mutant grew well during log phase in complete BSK-H but reached lower cell concentrations in the stationary phase than the wild-type parent, suggesting that (p)ppGpp may be an important factor in the ability of B. burgdorferi to adapt to stationary phase. Deletion of relBbu did not eliminate the temperature-elicited OspC shift, nor did it alter bmp gene expression or B. burgdorferi antibiotic susceptibility. Although deletion of relBbu eliminated B. burgdorferi virulence for mice, which was not restored by complementation, we suggest that relBbu-dependent accumulation of (p)ppGpp may be important for in vivo survival of this pathogen. PMID:16041012

  20. The colorimetric determination of selectively cleaved adenosines and guanosines in DNA oligomers using bicinchoninic acid and copper.

    PubMed

    Thomas, Elizabeth M; Testa, Stephen M

    2017-01-01

    Colorimetric methods combined with color-changing chemical probes are widely used as simple yet effective tools for identifying and quantifying a wide variety of molecules in solution. For nucleic acids (DNA and RNA), perhaps the most commonly used colorimetric probe is potassium permanganate, which can be used to identify single-stranded pyrimidines (thymine and cytosine) in polymers. Unfortunately, permanganate is not an effective probe for identifying purines (adenine and guanine), especially in the presence of the more reactive pyrimidines. Therefore, robust methods for discriminating between the purines remain elusive, thereby creating a barrier toward developing more complex colorimetric applications. In this proof-of-principle study, we demonstrate that bicinchoninic acid (BCA) and copper, when combined with purine-specific chemical cleavage reactions, can be a colorimetric probe for the identification and quantification of adenosines and/or guanosines in single-stranded DNA oligomers, even in the presence of pyrimidines. Furthermore, the reactions are stoichiometric, which allows for the quantification of the number of adenosines and/or guanosines in these oligomers. Because the BCA/copper reagent detects the reducing sugar, 2-deoxyribose, that results from the chemical cleavage of a given nucleotide's N-glycosidic bond, these colorimetric assays are effectively detecting apurinic sites in DNA oligomers, which are known to occur via DNA damage in biological systems. We demonstrate that simple digital analysis of the color-changing chromophore (BCA/copper) is all that is necessary to obtain quantifiable and reproducible data, which indicates that these assays should be broadly accessible.

  1. Lipid peroxides as endogenous oxidants forming 8-oxo-guanosine and lipid-soluble antioxidants as suppressing agents

    PubMed Central

    Kanazawa, Kazuki; Sakamoto, Miku; Kanazawa, Ko; Ishigaki, Yoriko; Aihara, Yoshiko; Hashimoto, Takashi; Mizuno, Masashi

    2016-01-01

    The oxidation of guanosine to 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA is closely associated with induction of various diseases, but the endogenous oxidant species involved remains unclear. Hydrogen peroxides (H2O2) have been considered to be the oxidant, while lipid peroxides are another possible oxidant because generated easily in bio-membranes surrounding DNA. The oxidant potency was compared between lipid peroxides and H2O2. Linoleic acid hydroperoxides (LOOH) formed 8-oxo-dG at a higher level than H2O2 in guanosine or double-stranded DNA. In the presence of a physiological concentration of Fe2+ to produce hydroxyl radicals, LOOH was also a stronger oxidant. In a lipid micelle, LOOH markedly produced 8-oxo-dG at a concentration one-tenth of that of H2O2. Upon adding to rat hepatic mitochondria, phosphatidylcholine hydroperoxides produced 8-oxo-dG abundantly. Employing HepG2 cells after pretreated with glutathione peroxidase inhibitor, LOOH formed 8-oxo-dG more abundantly than H2O2. Then, antioxidants to suppress the 8-oxo-dG formation were examined, when the nuclei of pre-incubated HepG2 with antioxidants were exposed to LOOH. Water-soluble ascorbic acid, trolox, and N-acetyl cysteine showed no or weak antioxidant potency, while lipid-soluble 2,6-dipalmitoyl ascorbic acid, α-tocopherol, and lipid-soluble phytochemicals exhibited stronger potency. The present study shows preferential formation of 8-oxo-dG upon LOOH and the inhibition by lipid-soluble antioxidants. PMID:27499574

  2. The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase.

    PubMed

    Vestal, Deborah J; Jeyaratnam, Jonathan A

    2011-01-01

    Originally identified by their unusual ability to bind guanosine monophosphate (GMP) nucleotide agarose, the guanylate-binding proteins (GBPs) were used extensively to promote our understanding of interferon-induced gene transcription and as markers of interferon responsiveness. Structural and biochemical analyses of human GBP-1 subsequently demonstrated that the GBPs are a unique subfamily of guanosine triphosphatase (GTPases) that hydrolyze guanosine triphosphate (GTP) to both guanosine diphosphate (GDP) and GMP. As members of the larger dynamin superfamily of GTPases, GBPs exhibit such properties as nucleotide-dependent oligomerization and concentration-dependent GTPase activity. Recently, progress has been made in assigning functions to members of the GBP family. While many of these functions involve protection against intracellular pathogens, a growing number of them are not directly related to pathogen protection. It is currently unclear how the unusual properties of GBPs contribute to this growing list of functions. As future studies uncover the molecular mechanism(s) of action of the GBPs, we will gain a greater understanding of how individual GBPs can mediate what currently appears to be a divergent set of functions.

  3. Oxidatively damaged guanosine in white blood cells and in urine of welders: associations with exposure to welding fumes and body iron stores.

    PubMed

    Pesch, Beate; Lotz, Anne; Koch, Holger M; Marczynski, Boleslaw; Casjens, Swaantje; Käfferlein, Heiko U; Welge, Peter; Lehnert, Martin; Heinze, Evelyn; Van Gelder, Rainer; Hahn, Jens-Uwe; Behrens, Thomas; Raulf, Monika; Hartwig, Andrea; Weiss, Tobias; Brüning, Thomas

    2015-08-01

    The International Agency for Research on Cancer considers the carcinogenicity of welding fume of priority for re-evaluation. Genotoxic effects in experimental animals are still inconclusive. Here, we investigated the association of personal exposure to metals in respirable welding fumes during a working shift with oxidatively damaged guanosine in DNA of white blood cells (WBC) and in postshift urine samples from 238 welders. Medians of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were 2.35/10(6) dGuo in DNA of WBC and 4.33 µg/g creatinine in urine. The median of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) was 7.03 µg/g creatinine in urine. The extent of both urinary parameters was higher in welders applying techniques with high particle emission rates to stainless steel than in tungsten inert gas welders (8-oxodGuo: 9.96 vs. 4.49 µg/L, 8-oxoGuo: 15.7 vs. 7.7 µg/L), but this apparent difference diminished after creatinine adjustment. We applied random intercept models to estimate the influence of airborne and systemic exposure to metals on oxidatively damaged guanosine in WBC and urine together with covariates. We observed a highly significant nonlinear association of urinary 8-oxoGuo with serum ferritin (P < 0.0001) and higher 8-oxoGuo concentrations for respirable iron >1,000 µg/m(3) compared to ≤57 µg/m(3). Similar effects were found for manganese. Airborne chromium but not nickel was associated with all oxidatively modified guanosine measures, whereas urinary chromium as well as nickel showed associations with urinary modified guanosines. In summary, oxidatively damaged urinary guanosine was associated with airborne and systemic exposure to metals in welders and showed a strong relation to body iron stores.

  4. Neuronal Analogues of Conditioning Paradigms

    DTIC Science & Technology

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  5. Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca²+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake.

    PubMed

    Dal-Cim, T; Martins, W C; Santos, A R S; Tasca, C I

    2011-06-02

    Guanine derivatives (GD) have been implicated in many relevant brain extracellular roles, such as modulation of glutamate transmission and neuronal protection against excitotoxic damage. GD are spontaneously released to the extracellular space from cultured astrocytes and during oxygen/glucose deprivation (OGD). The aim of this study has been to evaluate the potassium channels and phosphatidilinositol-3 kinase (PI3K) pathway involvement in the mechanisms related to the neuroprotective role of guanosine in rat hippocampal slices subjected to OGD. The addition of guanosine (100 μM) to hippocampal slices subjected to 15 min of OGD and followed by 2 h of re-oxygenation is neuroprotective. The presence of K+ channel blockers, glibenclamide (20 μM) or apamin (300 nM), revealed that neuroprotective effect of guanosine was not dependent on ATP-sensitive K+ channels or small conductance Ca²+-activated K+ channels. The presence of charybdotoxin (100 nM), a large conductance Ca²+-activated K+ channel (BK) blocker, inhibited the neuroprotective effect of guanosine. Hippocampal slices subjected to OGD and re-oxygenation showed a significant reduction of glutamate uptake. Addition of guanosine in the re-oxygenation period has blocked the reduction of glutamate uptake. This guanosine effect was inhibited when hippocampal slices were pre-incubated with charybdotoxin or wortmanin (a PI3K inhibitor, 1 μM) in the re-oxygenation period. Guanosine promoted an increase in Akt protein phosphorylation. However, the presence of charybdotoxin blocked such effect. In conclusion, the neuroprotective effect of guanosine involves augmentation of glutamate uptake, which is modulated by BK channels and the activation of PI3K pathway. Moreover, neuroprotection caused by guanosine depends on the increased expression of phospho-Akt protein.

  6. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  7. Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways.

    PubMed

    Bettio, Luis E B; Cunha, Mauricio P; Budni, Josiane; Pazini, Francis L; Oliveira, Ágatha; Colla, André R; Rodrigues, Ana Lúcia S

    2012-10-01

    Guanosine is an extracellular signaling molecule implicated in the modulation of glutamatergic transmission and neuroprotection. The present study evaluated the antidepressant-like effect of guanosine in the forced swimming test (FST) and in the tail suspension test (TST) in mice. The contribution of NMDA receptors as well as l-arginine-NO-cGMP and PI3K-mTOR pathways to this effect was also investigated. Guanosine administered orally produced an antidepressant-like effect in the FST (0.5-5 mg/kg) and TST (0.05-0.5 mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1 pmol/site, i.c.v.), d-serine (30 μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10 μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1 μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1 mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001 mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01 mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. None of the treatments affected locomotor activity. Altogether, results firstly indicate that guanosine exerts an antidepressant-like effect that seems to be mediated through an interaction with NMDA receptors, l-arginine-NO-cGMP and PI3K-mTOR pathways.

  8. Guanosine may increase absence epileptic activity by means of A2A adenosine receptors in Wistar Albino Glaxo Rijswijk rats.

    PubMed

    Lakatos, Renáta Krisztina; Dobolyi, Árpád; Todorov, Mihail Ivilinov; Kékesi, Katalin A; Juhász, Gábor; Aleksza, Magdolna; Kovács, Zsolt

    2016-06-01

    The non-adenosine nucleoside guanosine (Guo) was demonstrated to decrease quinolinic acid(QA)-induced seizures, spontaneously emerged absence epileptic seizures and lipopolysaccharide(LPS)-evoked induction of absence epileptic seizures suggesting its antiepileptic potential. It was also described previously that intraperitoneal (i.p.) injection of 20 and 50mg/kg Guo decreased the number of spike-wave discharges (SWDs) in a well investigated model of human absence epilepsy, the Wistar Albino Glaxo Rijswijk (WAG/Rij) rats during 4th (20mg/kg Guo) and 3rd as well as 4th (50mg/kg Guo) measuring hours. Guanosine can potentially decrease SWD number by means of its putative receptors but absence epileptic activity changing effects of Guo by means of increased extracellular adenosine (Ado) cannot be excluded. An increase in the dose of i.p. injected Guo is limited by its low solubility in saline, therefore, we addressed in the present study whether higher doses of Guo, diluted in sodium hydroxide (NaOH) solution, have more potent antiepileptic effect in WAG/Rij rats. We confirmed that i.p. 50mg/kg Guo decreased but, surprisingly, i.p. 100mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5mg/kg) or a selective Ado A2A receptor (A2AR) antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) (1mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10mg/kg) with 100mg/kg Guo decreased the SWD number compared to i.p. 100mg/kg Guo alone. The results suggest that i.p. 100mg/kg Guo can increase SWD number by means of the adenosinergic system.

  9. Intranasal guanosine administration presents a wide therapeutic time window to reduce brain damage induced by permanent ischemia in rats.

    PubMed

    Ramos, Denise Barbosa; Muller, Gabriel Cardozo; Rocha, Guilherme Botter Maio; Dellavia, Gustavo Hirata; Almeida, Roberto Farina; Pettenuzzo, Leticia Ferreira; Loureiro, Samanta Oliveira; Hansel, Gisele; Horn, Ângelo Cássio Magalhães; Souza, Diogo Onofre; Ganzella, Marcelo

    2016-03-01

    In addition to its intracellular roles, the nucleoside guanosine (GUO) also has extracellular effects that identify it as a putative neuromodulator signaling molecule in the central nervous system. Indeed, GUO can modulate glutamatergic neurotransmission, and it can promote neuroprotective effects in animal models involving glutamate neurotoxicity, which is the case in brain ischemia. In the present study, we aimed to investigate a new in vivo GUO administration route (intranasal, IN) to determine putative improvement of GUO neuroprotective effects against an experimental model of permanent focal cerebral ischemia. Initially, we demonstrated that IN [(3)H] GUO administration reached the brain in a dose-dependent and saturable pattern in as few as 5 min, presenting a higher cerebrospinal GUO level compared with systemic administration. IN GUO treatment started immediately or even 3 h after ischemia onset prevented behavior impairment. The behavior recovery was not correlated to decreased brain infarct volume, but it was correlated to reduced mitochondrial dysfunction in the penumbra area. Therefore, we showed that the IN route is an efficient way to promptly deliver GUO to the CNS and that IN GUO treatment prevented behavioral and brain impairment caused by ischemia in a therapeutically wide time window.

  10. Synthesis of the coenzymes adenosine diphosphate glucose, guanosine diphosphate glucose, and cytidine diphosphoethanolamine under primitive Earth conditions

    NASA Technical Reports Server (NTRS)

    Mar, A.; Oro, J.

    1991-01-01

    The nonenzymatic synthesis of the coenzymes adenosine diphosphate glucose (ADPG), guanosine diphosphate glucose (GDPG), and cytidine diphosphoethanolamine (CDP-ethanolamine) has been carried out under conditions considered to have been prevalent on the early Earth. The production of these compounds was performed by allowing simple precursor molecules to react under aqueous solutions, at moderate temperatures and short periods of time, with mediation by cyanamide or urea. These two condensing agents are considered to have been present in significant amounts on the primitive Earth and have been previously used in the nonenzymatic synthesis of several other important biochemical compounds. In our experiments, ADPG was obtained by heating glucose-1-phosphate (G1P) and ATP in the presence of cyanamide for 24 h at 70 degrees C. The reaction of G1P and GTP under the same conditions yielded GDPG. The cyanamide-mediated production of CDP-ethanolamine was carried out by reacting a mixture of ethanolamine phosphate and CTP for 24 h at 70 degrees C. The separation and identification of the reaction products was carried out by paper chromatography, thin-layer chromatography, high performance thin-layer chromatography, high performance liquid chromatography, both normal and reverse-phase, UV spectroscopy, enzymatic assays, and acid hydrolysis. Due to the mild conditions employed, and to the relative ease of these reactions, these studies offer a simple attractive system for the nonenzymatic synthesis of phosphorylated high-energy metabolic intermediates under conditions considered to have been prevalent on the ancient Earth.

  11. Influence of tunable external stimuli on the self-assembly of guanosine supramolecular nanostructures studied by atomic force microscope.

    PubMed

    Li, Yinli; Dong, Mingdong; Otzen, Daniel E; Yao, Yuheng; Liu, Bo; Besenbacher, Flemming; Mamdouh, Wael

    2009-12-01

    The self-assembly of guanosine (G) molecules on solid surfaces is investigated by tapping-mode atomic force microscopy (AFM) upon controlling and introducing external factors (stimuli) to the G stock solution such as incubation time, presence/absence of metal cations, and mechanical shaking. Surprisingly, at different stages of incubation time at room temperature and in the absence of any metal cations in the G stock solution, which are known to be one of the governing factors in forming G-nanostructures, two assembly pathways resulting into two distinct supramolecular nanostructures were revealed. Astonishingly, by introducing a mechanical shaking of the tube containing the G stock solution, one-dimensional (1D) wires of G molecules are observed by AFM, and very interestingly, novel "branched" supramolecular nanostructures are formed. We have also observed that the later branched G nanostructures can grow further into a two-dimensional (2D) thin film by increasing the incubation time of the G stock solution at room temperature after it is exposed to the external mechanical stimuli. The self-assembled nanostructures of G molecules are changed significantly by tuning the assembly conditions, which show that it is indeed possible to grow complex 2D nanostructures from simple nucleoside molecules.

  12. Peroxynitrite-Dependent Zinc Release and Inactivation of Guanosine 5′-Triphosphate Cyclohydrolase 1 Instigate Its Ubiquitination in Diabetes

    PubMed Central

    Zhao, Yu; Wu, Jiliang; Zhu, Huaiping; Song, Ping; Zou, Ming-Hui

    2013-01-01

    Aberrant degradation of guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) with consequent deficiency of tetrahydrobiopterin is considered the primary cause for endothelial dysfunction in diabetes. How GTPCH1 becomes susceptible to the degradation remains unknown. We hypothesized that oxidation and release of the zinc ion by peroxynitrite (ONOO−), a potent oxidant generated by nitric oxide and superoxide anions, instigates GTPCH1 ubiquitination and degradation. Zinc contents, GTPCH1 ubiquitination, and GTPCH1 activity were assayed in purified GTPCH1, endothelial cells, and hearts from diabetic mice. Exogenous ONOO− dose-dependently released zinc, inhibited its activity, and increased the ubiquitin binding affinity of GTPCH1 in vitro and in endothelial cells. Consistently, high glucose (30 mmol/L) inhibited GTPCH1 activity with increased ubiquitination, which was inhibited by antioxidants. Furthermore, mutation of the zinc-binding cysteine (141) (C141R or C141A) significantly reduced GTPCH1 activity and reduced its half-life but increased GTPCH1 ubiquitination, indicating an essential role of the zinc ion in maintaining the catalytic activity and stability of GTPCH1. Finally, GTPCH1 ubiquitination and degradation markedly increased in parallel with decreased GTPCH1 activity in the aortas and hearts of diabetic mice, both of which were attenuated by the inhibitors of ONOO− in mice in vivo. Taken together, we conclude that ONOO− releases zinc and inhibits GTPCH1, resulting in its ubiquitination and degradation of the enzyme. PMID:23974923

  13. Gas-Phase Conformations and Energetics of Sodium Cationized 2^'-DEOXYGUANOSINE and Guanosine: Irmpd Action Spectroscopy and Theoretical Studies

    NASA Astrophysics Data System (ADS)

    Zhu, Yanlong; Hamlow, Lucas; He, Chenchen; Bao, Xun; Rodgers, M. T.; Gao, Juehan; Oomens, J.

    2015-06-01

    In living systems, the local structures of DNA and RNA are influenced by protonation, deprotonation and noncovalent binding interactions with cations. In order to determine the effects of Na+ cationization on the gas-phase structures of 2^'-deoxyguanosine, [dGuo+Na]+, and guanosine, [Guo+Na]+, infrared multiple photon dissociation (IRMPD) action spectra of these two sodium cationized DNA and RNA mononucleosides are measured over the range extending from ~500 to ~1850 cm-1 using the FELIX free electron laser. Complementary electronic structure calculations are performed to determine the stable low-energy conformations of these complexes. Geometry optimizations and frequency analyses of these species are performed at the B3LYP/6-31G* level of theory, whereas single-point energies are calculated at the B3LYP/6-311+G(2d,2p) level of theory to determine the relative stabilities of these conformations. Comparison of the measure IRMPD action spectra and computed linear IR spectra enable the conformations accessed in the experiments to be elucidated. In both cases, preferential binding of the Na+ cation to O6 and N7 positions of the nucleobase is observed. Present results for the sodium cationized nucleosides are compared to results for the analogous protonated forms of these nucleosides to elucidate the effects of multiple chelating interactions with the sodium cation to hydrogen bonding interactions in the protonated systems on the structures and stabilities of these nucleosides.

  14. Growth hormone deficiency in a dopa-responsive dystonia patient with a novel mutation of guanosine triphosphate cyclohydrolase 1 gene.

    PubMed

    Lin, Yu; Wang, Dan-Ni; Chen, Wan-Jin; Lin, Xiang; Lin, Min-Ting; Wang, Ning

    2015-05-01

    Dopa-responsive dystonia is a rare hereditary movement disorder caused by mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene. This disease typically manifests in dystonia, with marked diurnal fluctuation and a dramatic response to levodopa. However, growth retardation in dopa-responsive dystonia has rarely been reported, and the etiology of short stature is not clarified. Here, we report a 14-year-old patient with extremities dystonia and short stature. Treatment with levodopa relieved his symptoms and resulted in a height increase. We also investigated the mutation in GCH1 and the etiology of short stature in this case. Sequence analysis of GCH1 revealed a novel mutation (c.695G>T). Laboratory examinations and imaging confirmed the diagnosis of growth hormone deficiency. We conclude that our case reveals a rare feature for dopa-responsive dystonia and suggests a possible pathogenic link between growth hormone deficiency and dopa-responsive dystonia. We recommend levodopa as the first choice for treating dopa-responsive dystonia in children with growth hormone deficiency.

  15. Peroxynitrite-dependent zinc release and inactivation of guanosine 5'-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes.

    PubMed

    Zhao, Yu; Wu, Jiliang; Zhu, Huaiping; Song, Ping; Zou, Ming-Hui

    2013-12-01

    Aberrant degradation of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) with consequent deficiency of tetrahydrobiopterin is considered the primary cause for endothelial dysfunction in diabetes. How GTPCH1 becomes susceptible to the degradation remains unknown. We hypothesized that oxidation and release of the zinc ion by peroxynitrite (ONOO(-)), a potent oxidant generated by nitric oxide and superoxide anions, instigates GTPCH1 ubiquitination and degradation. Zinc contents, GTPCH1 ubiquitination, and GTPCH1 activity were assayed in purified GTPCH1, endothelial cells, and hearts from diabetic mice. Exogenous ONOO(-) dose-dependently released zinc, inhibited its activity, and increased the ubiquitin binding affinity of GTPCH1 in vitro and in endothelial cells. Consistently, high glucose (30 mmol/L) inhibited GTPCH1 activity with increased ubiquitination, which was inhibited by antioxidants. Furthermore, mutation of the zinc-binding cysteine (141) (C141R or C141A) significantly reduced GTPCH1 activity and reduced its half-life but increased GTPCH1 ubiquitination, indicating an essential role of the zinc ion in maintaining the catalytic activity and stability of GTPCH1. Finally, GTPCH1 ubiquitination and degradation markedly increased in parallel with decreased GTPCH1 activity in the aortas and hearts of diabetic mice, both of which were attenuated by the inhibitors of ONOO(-) in mice in vivo. Taken together, we conclude that ONOO(-) releases zinc and inhibits GTPCH1, resulting in its ubiquitination and degradation of the enzyme.

  16. Small elevations of glucose concentration redirect and amplify the synthesis of guanosine 5'-triphosphate in rat islets.

    PubMed Central

    Metz, S A; Meredith, M; Rabaglia, M E; Kowluru, A

    1993-01-01

    Recent studies suggest a permissive requirement for guanosine 5'-triphosphate (GTP) in insulin release, based on the use of GTP synthesis inhibitors (such as myocophenolic acid) acting at inosine monophosphate (IMP) dehydrogenase; herein, we examine the glucose dependency of GTP synthesis. Mycophenolic acid inhibited insulin secretion equally well after islet culture at 7.8 or 11.1 mM glucose (51% inhibition) but its effect was dramatically attenuated when provided at < or = 6.4 mM glucose (13% inhibition; P < 0.001). These observations were explicable by a stimulation of islet GTP synthesis derived from IMP since, at high glucose: (a) total GTP content was augmented; (b) a greater decrement in GTP (1.75 vs. 1.05 pmol/islet) was induced by mycophenolic acid; and (c) a smaller "pool" of residual GTP persisted after drug treatment. Glucose also accelerated GTP synthesis from exogenous guanine ("salvage" pathway) and increased content of a pyrimidine, uridine 5'-triphosphate (UTP), suggesting that glucose augments production of a common regulatory intermediate (probably 5-phosphoribosyl-1-pyrophosphate). Pathway-specific radiolabeling studies confirmed that glucose tripled both salvage and de novo synthesis of nucleotides. We conclude that steep changes in the biosynthesis of cytosolic pools of GTP occur at modest changes in glucose concentrations, a finding which may have relevance to the adaptive (patho) physiologic responses of islets to changes in ambient glucose levels. PMID:8349822

  17. Metabolic engineering of Escherichia coli to produce 2'-fucosyllactose via salvage pathway of guanosine 5'-diphosphate (GDP)-l-fucose.

    PubMed

    Chin, Young-Wook; Seo, Nari; Kim, Jae-Han; Seo, Jin-Ho

    2016-11-01

    2'-Fucosyllactose (2-FL) is one of the key oligosaccharides in human milk. In the present study, the salvage guanosine 5'-diphosphate (GDP)-l-fucose biosynthetic pathway from fucose was employed in engineered Escherichia coli BL21star(DE3) for efficient production of 2-FL. Introduction of the fkp gene coding for fucokinase/GDP-l-fucose pyrophosphorylase (Fkp) from Bacteroides fragilis and the fucT2 gene encoding α-1,2-fucosyltransferase from Helicobacter pylori allows the engineered E. coli to produce 2-FL from fucose, lactose and glycerol. To enhance the lactose flux to 2-FL production, the attenuated, and deleted mutants of β-galactosidase were employed. Moreover, the 2-FL yield and productivity were further improved by deletion of the fucI-fucK gene cluster coding for fucose isomerase (FucI) and fuculose kinase (FucK). Finally, fed-batch fermentation of engineered E. coli BL21star(DE3) deleting lacZ and fucI-fucK, and expressing fkp and fucT2 resulted in 23.1 g/L of extracellular concentration of 2-FL and 0.39 g/L/h productivity. Biotechnol. Bioeng. 2016;113: 2443-2452. © 2016 Wiley Periodicals, Inc.

  18. Theoretical vibrational spectroscopy of intermediates and the reaction mechanism of the guanosine triphosphate hydrolysis by the protein complex Ras-GAP

    NASA Astrophysics Data System (ADS)

    Khrenova, Maria G.; Grigorenko, Bella L.; Nemukhin, Alexander V.

    2016-09-01

    The structures and vibrational spectra of the reacting species upon guanosine triphosphate (GTP) hydrolysis to guanosine diphosphate and inorganic phosphate (Pi) trapped inside the protein complex Ras-GAP were analyzed following the results of QM/MM simulations. The frequencies of the phosphate vibrations referring to the reactants and to Pi were compared to those observed in the experimental FTIR studies. A good correlation between the theoretical and experimental vibrational data provides a strong support to the reaction mechanism of GTP hydrolysis by the Ras-GAP enzyme system revealed by the recent QM/MM modeling. Evolution of the vibrational bands associated with the inorganic phosphate Pi during the elementary stages of GTP hydrolysis is predicted.

  19. Photo-electrochemical Bioanalysis of Guanosine Monophosphate Using Coupled Enzymatic Reactions at a CdS/ZnS Quantum Dot Electrode.

    PubMed

    Sabir, Nadeem; Khan, Nazimuddin; Völkner, Johannes; Widdascheck, Felix; del Pino, Pablo; Witte, Gregor; Riedel, Marc; Lisdat, Fred; Konrad, Manfred; Parak, Wolfgang J

    2015-11-18

    A photo-electrochemical sensor for the specific detection of guanosine monophosphate (GMP) is demonstrated, based on three enzymes combined in a coupled reaction assay. The first reaction involves the adenosine triphosphate (ATP)-dependent conversion of GMP to guanosine diphosphate (GDP) by guanylate kinase, which warrants substrate specificity. The reaction products ADP and GDPare co-substrates for the enzymatic conversion of phosphoenolpyruvate to pyruvate in a second reaction mediated by pyruvate kinase. Pyruvate in turn is the co-substrate for lactate dehydrogenase that generates lactate via oxidation of nicotinamide adenine dinucleotide (reduced form) NADH to NAD(+). This third enzymatic reaction is electrochemically detected. For this purpose a CdS/ZnS quantum dot (QD) electrode is illuminated and the photocurrent response under fixed potential conditions is evaluated. The sequential enzyme reactions are first evaluated in solution. Subsequently, a sensor for GMP is constructed using polyelectrolytes for enzyme immobilization.

  20. Lower urinary tract symptoms/benign prostatic hypertrophy and vascular function: Role of the nitric oxide-phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate pathway.

    PubMed

    Higashi, Yukihito

    2017-03-22

    It is well known that there is an association of lower urinary tract symptoms/benign prostatic hypertrophy with cardiovascular disease, suggesting that lower urinary tract symptoms/benign prostatic hypertrophy is a risk factor for cardiovascular events. Vascular function, including endothelial function and vascular smooth muscle function, is involved in the pathogenesis, maintenance and development of atherosclerosis, leading to cardiovascular events. Vascular dysfunction per se should also contribute to lower urinary tract symptoms/benign prostatic hypertrophy. Both lower urinary tract symptoms/benign prostatic hypertrophy and vascular dysfunction have cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes mellitus, aging, obesity and smoking. Inactivation of the phosphodiesterase type 5-cyclic guanosine 3',5'-monophosphate-nitric oxide pathway causes lower urinary tract symptoms/benign prostatic hypertrophy through an enhancement of sympathetic nervous activity, endothelial dysfunction, increase in Rho-associated kinase activity and vasoconstriction, and decrease in blood flow of pelvic viscera. Both endogenous nitric oxide and exogenous nitric oxide act as vasodilators on vascular smooth muscle cells through an increase in the content of cyclic guanosine 3',5'-monophosphate, which is inactivated by phosphodiesterase type 5. In a clinical setting, phosphodiesterase type 5 inhibitors are widely used in patients with lower urinary tract symptoms/benign prostatic hypertrophy. Phosphodiesterase type 5 inhibitors might have beneficial effects on vascular function through not only inhibition of cyclic guanosine 3',5'-monophosphate degradation, but also increases in testosterone levels and nitric oxide bioavailability, increase in the number and improvement of the function of endothelial progenitor cells, and decrease in insulin resistance. In the present review, the relationships between lower urinary tract symptoms/benign prostatic hypertrophy, the

  1. Guanosine-based hydrogen-bonded 2D scaffolds: metal-free formation of G-quartet and G-ribbon architectures at the solid/liquid interface.

    PubMed

    El Garah, Mohamed; Perone, Rosaria C; Bonilla, Alejandro Santana; Haar, Sébastien; Campitiello, Marilena; Gutierrez, Rafael; Cuniberti, Gianaurelio; Masiero, Stefano; Ciesielski, Artur; Samorì, Paolo

    2015-07-25

    We report on the synthesis and self-assembly of three novel lipophilic guanosine derivatives exposing a ferrocene moiety in the C(5') position of the sugar unit. Their self-association in solution, and at the solid/liquid interface, can be tuned by varying the size and nature of the C(8)-substituent, leading to the generation of either G-ribbons, lamellar G-dimer based arrays or the G4 cation-free architectures.

  2. Ecstasy analogues found in cacti.

    PubMed

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

    2008-06-01

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

  3. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  4. Template polymerization of nucleotide analogues

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.

    1991-01-01

    Recent work on the template-directed reactions of the natural D-nucleotides has made it clear that l-nucleotides and nucleotide-like derivatives of other sugars would strongly inhibit the formation of long oligonucleotides. Consequently, attention is focusing on molecules simpler than nucleotides that might have acted as monomers of an information transfer system. We have begun a general exploration of the template directed reactions of diverse peptide analogues. I will present work by Dr. Taifeng Wu on oxidative oligomerization of phosphorothioates and of Dr. Mary Tohidi on the cyclic polymerization of nucleoside and related cyclic pyrophosphates.

  5. Choline Analogues in Malaria Chemotherapy

    PubMed Central

    Peyrottes, Suzanne; Caldarelli, Sergio; Wein, Sharon; Périgaud, Christian; Pellet, Alain; Vial, Henri

    2012-01-01

    Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches. PMID:22607139

  6. Electrostatic evaluation of isosteric analogues

    NASA Astrophysics Data System (ADS)

    Sayle, Roger; Nicholls, Anthony

    2006-04-01

    A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on␣seven model systems; dihydrofolate reductase, Lck␣kinase, ribosome inactivating protein, l-arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.

  7. The Valles natural analogue project

    SciTech Connect

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

    1994-12-01

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

  8. Heteroatom-Containing Porphyrin Analogues.

    PubMed

    Chatterjee, Tamal; Shetti, Vijayendra S; Sharma, Ritambhara; Ravikanth, Mangalampalli

    2017-02-22

    The heteroatom-containing porphyrin analogues or core-modified porphyrins that resulted from the replacement of one or two pyrrole rings with other five-membered heterocycles such as furan, thiophene, selenophene, tellurophene, indene, phosphole, and silole are highly promising macrocycles and exhibit quite different physicochemical properties compared to regular azaporphyrins. The properties of heteroporphyrins depend on the nature and number of different heterocycle(s) present in place of pyrrole ring(s). The heteroporphyrins provide unique and unprecedented coordination environments for metals. Unlike regular porphyrins, the monoheteroporphyrins are known to stabilize metals in unusual oxidation states such as Cu and Ni in +1 oxidation states. The diheteroporphyrins, which are neutral macrocycles without ionizable protons, also showed interesting coordination chemistry. Thus, significant progress has been made in last few decades on core-modified porphyrins in terms of their synthesis, their use in building multiporphyrin arrays for light-harvesting applications, their use as ligands to form interesting metal complexes, and also their use for several other studies. The synthetic methods available in the literature allow one to prepare mono- and diheteroporphyrins and their functionalized derivatives, which were used extensively to prepare several covalent and noncovalent heteroporphyrin-based multiporphyrin arrays. The methods are also developed to synthesize different hetero analogues of porphyrin derivatives such as heterocorroles, heterochlorins, heterocarbaporphyrinoids, heteroatom-substituted confused porphyrins, and so on. This Review summarizes the key developments that have occurred in heteroporphyrin chemistry over the last four decades.

  9. Crystallographic study of Glu58Ala RNase T1 x 2'-guanosine monophosphate at 1.9-A resolution.

    PubMed

    Pletinckx, J; Steyaert, J; Zegers, I; Choe, H W; Heinemann, U; Wyns, L

    1994-02-22

    Glu58 is known to participate in phosphodiester transesterification catalyzed by the enzyme RNase T1. For Glu58 RNase T1, an altered mechanism has been proposed in which His40 replaces Glu58 as the base catalyst [Steyaert, J., Hallenga, K., Wyns, L., & Stanssens, P. (1990) Biochemistry 29, 9064-9072]. Glu58Ala Rnase T1 has been cocrystallized with guanosine 2'-monophosphate (2'-GMP). The crystals are of space group P2(1), with one molecule per asymmetric unit (a = 32.44 A, b = 49.64 A, c = 26.09 A, beta = 99.17 degrees). The three-dimensional structure of the enzyme was determined to a nominal resolution of 1.9 A, yielding a crystallographic R factor of 0.178 for all X-ray data. Comparison of this structure with wild-type structures leads to the following conclusions. The minor changes apparent in the tertiary structure can be explained by either the mutation of Glu58 or by the change in the space group. In the active site, the extra space available through the mutation of Glu58 is occupied by the phosphate group (after a reorientation) and by a solvent molecule replacing a carboxylate oxygen of Glu58. This solvent molecule is a candidate for participation in the altered mechanism of this mutant enzyme. Following up on a study of conserved water sites in RNase T1 crystallized in space group P2(1)2(1)2(1) [Malin, R., Zielenkiewicz, P., & Saenger, W. (1991) J. Mol. Biol. 266, 4848-4852], we investigated the hydration structure for four different packing modes of RNase T1.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Structure of radicals from X-irradiated guanine derivatives: an experimental and computational study of sodium guanosine dihydrate single crystals.

    PubMed

    Jayatilaka, Nayana; Nelson, William H

    2007-02-01

    In sodium guanosine dihydrate single crystals, the guanine moiety is deprotonated at N1 due to growth from high-pH (>12) solutions. Electron paramagnetic resonance (EPR) and electron-nuclear double resonance (ENDOR) studies of crystals X-irradiated at 10 K detected evidence for three radical forms. Radical R1, characterized by two proton and two nitrogen hyperfine interactions, was identified as the product of net hydrogenation at N7 of the N1-deprotonated guanine unit. R1 exhibited an unusually distorted structure leading to net positive isotropic components of the hydrogen alpha-couplings. Radical R2, characterized by one proton and one nitrogen hyperfine coupling, was identified as the primary electron-loss product. This product is equivalent to that of deprotonation at N1 by the guanine cation and represents the first ENDOR characterization of that product. Radical R3, characterized by a single hydrogen hyperfine coupling, was identified as the product of net dehydrogenation at C1' of the ribose moiety. The identification of radicals R1-R3 was supported by density functional theory (DFT) calculations on several possible structures using the B3LYP/6-311G(2df,p)//6-31G(d,p) approach. Radical R4, detected after warming the crystals to room temperature, was identified as the well-known product of net hydrogenation of C8 of the (N1-deprotonated) guanine component. Radical R1, evidently formed by protonation of the primary electron addition product, was present as roughly 60% of the total radicals detected at 10 K. Radical R2 was present as roughly 27% of the total yield, and the concentration of R3 contributed the remaining 13%. R3 is evidently the product of one-electron oxidation followed by deprotonation; thus, the balance of oxidation and reduction products is approximately equal within experimental uncertainty.

  11. Nitric oxide/cyclic guanosine monophosphate signaling in the central complex of the grasshopper brain inhibits singing behavior.

    PubMed

    Wenzel, Beate; Kunst, Michael; Günther, Cornelia; Ganter, Geoffrey K; Lakes-Harlan, Reinhard; Elsner, Norbert; Heinrich, Ralf

    2005-07-25

    Grasshopper sound production, in the context of mate finding, courtship, and rivalry, is controlled by the central body complex in the protocerebrum. Stimulation of muscarinic acetylcholine receptors in the central complex has been demonstrated to stimulate specific singing in various grasshoppers including the species Chorthippus biguttulus. Sound production elicited by stimulation of muscarinic acetylcholine receptors in the central complex is inhibited by co-applications of various drugs activating the nitric oxide/cyclic guanosine monophosphate (cGMP) signaling pathway. The nitric oxide-donor sodium nitroprusside caused a reversible suppression of muscarine-stimulated sound production that could be blocked by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxaline-1-one (ODQ), which prevents the formation of cGMP by specifically inhibiting soluble guanylyl cyclase. Furthermore, injections of both the membrane-permeable cGMP analog 8-Br-cGMP and the specific inhibitor of the cGMP-degrading phosphodiesterase Zaprinast reversibly inhibited singing. To identify putative sources of nitric oxide, brains of Ch. biguttulus were subjected to both nitric oxide synthase immunocytochemistry and NADPH-diaphorase staining. Among other areas known to express nitric oxide synthase, both procedures consistently labeled peripheral layers in the upper division of the central body complex, suggesting that neurons supplying this neuropil contain nitric oxide synthase and may generate nitric oxide upon activation. Exposure of dissected brains to nitric oxide and 3-(5'hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) induced cGMP-associated immunoreactivity in both the upper and lower division. Therefore, both the morphological and pharmacological data presented in this study strongly suggest a contribution of the nitric oxide/cGMP signaling pathway to the central control of grasshopper sound production.

  12. Guanosine-5'-O-(3-thiotriphosphate) modifies kinetics of voltage-dependent calcium current in chick sensory neurons.

    PubMed Central

    Marchetti, C; Robello, M

    1989-01-01

    Internal perfusion with the G-protein activator guanosine-5'-O-(3-thiotriphosphate) (GTP-gamma S) mimics the effect of noradrenaline and dopamine on the voltage-dependent calcium current in chick dorsal root ganglion (DRG) cells. With 100 microM GTP-gamma S in the pipette, the current at +10 mV was depressed by approximately 50%, with a 10-fold increase of its time to peak. The activation time course of the control calcium current could be approximated with a single exponential curve, whereas with GTP-gamma S the activation time course was double exponential, with time constants tau 1 and tau 2. 2 mM Mg-ATP in the pipette prevented the GTP-gamma S-induced current decrease in 70% of the cells, but the time course of the current was always double exponential. From -50 mV, the current at +10 mV was best fitted with tau 1 = 1.7 +/- 0.5 and tau 2 = 25.6 +/- 5.5 in seven cells. Both time constants decreased with increasing depolarizations. In the first 2 min of recording, the current changed with time. However, both tau 1 and tau 2 were constant, whereas the relative contribution of the slow component increased from 10 to 70%. In addition, the effect was independent of the holding potential in the range from -100 to -30 mV. These results suggest that the activation of a G-protein causes a fraction of the high-threshold calcium channels to switch to a new closed state, with slower opening kinetics. PMID:2558735

  13. Diversity in guanosine 3',5'-bisdiphosphate (ppGpp) sensitivity among guanylate kinases of bacteria and plants.

    PubMed

    Nomura, Yuhta; Izumi, Atsushi; Fukunaga, Yoshinori; Kusumi, Kensuke; Iba, Koh; Watanabe, Seiya; Nakahira, Yoichi; Weber, Andreas P M; Nozawa, Akira; Tozawa, Yuzuru

    2014-05-30

    The guanosine 3',5'-bisdiphosphate (ppGpp) signaling system is shared by bacteria and plant chloroplasts, but its role in plants has remained unclear. Here we show that guanylate kinase (GK), a key enzyme in guanine nucleotide biosynthesis that catalyzes the conversion of GMP to GDP, is a target of regulation by ppGpp in chloroplasts of rice, pea, and Arabidopsis. Plants have two distinct types of GK that are localized to organelles (GKpm) or to the cytosol (GKc), with both enzymes being essential for growth and development. We found that the activity of rice GKpm in vitro was inhibited by ppGpp with a Ki of 2.8 μM relative to the substrate GMP, whereas the Km of this enzyme for GMP was 73 μM. The IC50 of ppGpp for GKpm was ∼10 μM. In contrast, the activity of rice GKc was insensitive to ppGpp, as was that of GK from bakers' yeast, which is also a cytosolic enzyme. These observations suggest that ppGpp plays a pivotal role in the regulation of GTP biosynthesis in chloroplasts through specific inhibition of GKpm activity, with the regulation of GTP biosynthesis in chloroplasts thus being independent of that in the cytosol. We also found that GKs of Escherichia coli and Synechococcus elongatus PCC 7942 are insensitive to ppGpp, in contrast to the ppGpp sensitivity of the Bacillus subtilis enzyme. Our biochemical characterization of GK enzymes has thus revealed a novel target of ppGpp in chloroplasts and has uncovered diversity among bacterial GKs with regard to regulation by ppGpp.

  14. Electron attachment to hydrated oligonucleotide dimers: guanylyl-3',5'-cytidine and cytidylyl-3',5'-guanosine.

    PubMed

    Gu, Jiande; Xie, Yaoming; Schaefer, Henry F

    2010-05-03

    The dinucleoside phosphate deoxycytidylyl-3',5'-deoxyguanosine (dCpdG) and deoxyguanylyl-3',5'-deoxycytidine (dGpdC) systems are among the largest to be studied by reliable theoretical methods. Exploring electron attachment to these subunits of DNA single strands provides significant progress toward definitive predictions of the electron affinities of DNA single strands. The adiabatic electron affinities of the oligonucleotides are found to be sequence dependent. Deoxycytidine (dC) on the 5' end, dCpdG, has larger adiabatic electron affinity (AEA, 0.90 eV) than dC on the 3' end of the oligomer (dGpdC, 0.66 eV). The geometric features, molecular orbital analyses, and charge distribution studies for the radical anions of the cytidine-containing oligonucleotides demonstrate that the excess electron in these anionic systems is dominantly located on the cytosine nucleobase moiety. The pi-stacking interaction between nucleobases G and C seems unlikely to improve the electron-capturing ability of the oligonucleotide dimers. The influence of the neighboring base on the electron-capturing ability of cytosine should be attributed to the intensified proton accepting-donating interaction between the bases. The present investigation demonstrates that the vertical detachment energies (VDEs) of the radical anions of the oligonucleotides dGpdC and dCpdG are significantly larger than those of the corresponding nucleotides. Consequently, reactions with low activation barriers, such as those for O-C sigma bond and N-glycosidic bond breakage, might be expected for the radical anions of the guanosine-cytosine mixed oligonucleotides.

  15. Ag(I)-mediated homo and hetero pairs of guanosine and cytidine: Monitoring by circular dichroism spectroscopy

    NASA Astrophysics Data System (ADS)

    Goncharova, Iryna

    2014-01-01

    Ag(I)-containing compounds are attractive as antibacterial and antifungal agents. The renewed interest in the application of silver(I) compounds has led to the need for detailed knowledge of the mechanism of their action. One of the possible ways is the coordination of Ag(I) to G-C pairs of DNA, where Ag+ ions form Ag(I)-mediated base pairs and inhibit the transcription. Herein, a systematic chiroptical study on silver(I)-mediated homo and mixed pairs of the C-G complementary-base derivatives cytidine(C) and 5‧-guanosine monophosphate(G) in water is presented. Ag(I)-mediated homo and hetero pairs of G and C and their self-assembled species were studied under two pH levels (7.0 and 10.0) by vibrational (VCD) and electronic circular dichroism(ECD). VCD was used for the first time in this field and showed itself to be a powerful method for obtaining specific structural information in solution. Based on results of the VCD experiments, the different geometries of the homo pairs were proposed under pH 7.0 and 10.0. ECD was used as a diagnostic tool to characterize the studied systems and as a contact point between the previously defined structures of the metal or proton mediated pairs of nucleobases and the systems studied here. On the basis of the obtained data, the formation of the self-assembled species of cytidine with a structure similar to the i-motif structure in DNA was proposed at pH 10.0.

  16. Formation of 8-hydroxy(deoxy)guanosine and generation of strand breaks at guanine residues in DNA by singlet oxygen

    SciTech Connect

    Devasagayam, T.P.A.; Obendorf, M.S.W.; Schulz, W.A.; Sies, H. ); Steenken, S. )

    1991-06-25

    Singlet molecular oxygen ({sup 1}O{sub 2}) was generated in aqueous solution (H{sub 2}O or D{sub 2}O) at 37 C by the thermal dissociation of the endoperoxide of 3,3'-(1,4-naphthylidene) dipropionate (NDPO{sub 2}). Guanosine and deoxyguanosine quench {sup 1}O{sub 2} with overall quenching rate constants of 6.2 {times} 10{sup 6} M{sup {minus}1} s{sup {minus}1} and 5.2 {times} 10{sup 6} M{sup {minus}1} s{sup {minus}1}, respectively. Reaction with {sup 1}O{sub 2} results in the formation of 8-hydroxyguanosine (8-OH-Guo) and 8-hydroxydeoxyguanosine (8-OH-dGuo), respectively, with a yield of 1.5% at 1 mM substrate with an NDPO{sub 2} concentration of 40 mM; a corresponding 8-hydroxy derivative is not formed from deoxyadenosine. in D{sub 2}O the yield of 8-OH-Guo is 1.5-fold that in H{sub 2}O. Sodium azide suppresses 8-OH-Guo and 8-OH-dGuo production. in contrast, the hydroxyl radical scavengers, tert-butanol, 2-propanol, or sodium formate, do not decrease the production of the 8-OH derivatives. The formation of 8-OH derivatives is significantly increased (2-5-fold) by thiols such as dithiothreitol, glutathione, cysteine, and cysteamine. With use of a plasmid containing a fragment of the mouse metallothionein 1 promoter (pMTP3') and a novel end-labeling technique, the position of {sup 1}O{sub 2}-induced single-strand breaks in DNA was examined. Strand breaks occur selectively at dGuo; no major differences (hot spots) were observed between individual guanines.

  17. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

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

  18. Macrolactam analogues of macrolide natural products.

    PubMed

    Hügel, Helmut M; Smith, Andrew T; Rizzacasa, Mark A

    2016-12-07

    The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.

  19. The future of somatostatin analogue therapy.

    PubMed

    Stewart, P M; James, R A

    1999-10-01

    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  20. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  1. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-03

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  2. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  3. Ricin A-chain structural determinant for binding substrate analogues: a molecular dynamics simulation analysis.

    PubMed

    Olson, M A

    1997-01-01

    Ricin A-chain is a cytotoxic protein that attacks ribosomes by hydrolyzing a specific adenine base from a highly conserved, single-stranded rRNA hairpin containing the tetraloop sequence GAGA. Molecular-dynamics simulation methods are used to analyze the structural determinant for three substrate analogues bound to the ricin A-chain molecule. Simulations were applied to the binding of the dinucleotide adenyl-3',5'-guanosine employing the x-ray crystal structure of the ricin complex and a modeled CGAGAG hexanucleotide loop taken from the NMR solution structure of a 29-mer oligonucleotide hairpin. A third simulation model is also presented describing a conformational search of the docked 29-mer structure by using a simulated-annealing method. Analysis of the structural interaction energies for each model shows the overall binding dominated by nonspecific interactions, which are mediated by specific arginine contracts from the highly basic region on the protein surface. The tetraloop conformation of the 29-mer was found to make specific interactions with conserved protein residues, in a manner that favored the GAGA sequence. A comparison of the two docked loop conformations with the NMR structure revealed significant positional deviations, suggesting that ricin may use an induced fit mechanism to recognize and bind the rRNA substrate. The conserved Tyr-80 may play an important conformational entropic role in the binding and release of the target adenine in the active site.

  4. Elevated nitric oxide and 3’,5’ cyclic guanosine monophosphate levels in patients with alcoholic cirrhosis

    PubMed Central

    Siqueira, Cíntia; de Moura, Miguel Carneiro; Pedro, Ana Julia; Rocha, Paula

    2008-01-01

    AIM: To evaluate whether serum levels of nitric oxide (NO•) and plasma levels of cyclic guanosine monophosphate (cGMP) and total glutathione (GSH) are altered in patients with alcoholic cirrhosis and to examine their correlation with the severity of liver disease. METHODS: Twenty-six patients with alcoholic liver cirrhosis were studied. Serum levels of NO• and plasma levels of cGMP and GSH were measured in 7 patients with compensated alcoholic cirrhosis (Child-Pugh A) and 19 patients with advanced cirrhosis (Child-Pugh B and C). The model for end-stage liver disease (MELD) score was evaluated. Sixteen healthy volunteers served as controls. Liver enzymes and creatinine levels were also tested. RESULTS: NO• and cGMP levels were higher in patients with Child-Pugh B and C cirrhosis than in Child-Pugh A cirrhosis or controls (NO•: 21.70 ± 8.07 vs 11.70 ± 2.74; 21.70 ± 8.07 vs 7.26 ± 2.47 μmol/L, respectively; P < 0.001) and (cGMP: 20.12 ± 6.62 vs 10.14 ± 2.78; 20.12 ± 6.62 vs 4.95 ± 1.21 pmol/L, respectively; P < 0.001). Total glutathione levels were lower in patients with Child-Pugh B and C cirrhosis than in patients with Child-Pugh A cirrhosis or controls (16.04 ± 6.06 vs 23.01 ± 4.38 or 16.04 ± 6.06 vs 66.57 ± 26.23 μmol/L, respectively; P < 0.001). There was a significant correlation between NO• and cGMP levels in all patients with alcoholic cirrhosis. A significant negative correlation between reduced glutathione/glutathione disulfide and the MELD score was found in all cirrhotic patients. CONCLUSION: Our results suggest a role for oxidative stress in alcoholic liver cirrhosis, which is more significant in decompensated patients with higher levels of NO• and cGMP and lower GSH levels than in compensated and control patients. Altered mediator levels in decompensated patients may influence the hemodynamic changes in and progression of liver disease. PMID:18186561

  5. Type II cyclic guanosine monophosphate-dependent protein kinase inhibits Rac1 activation in gastric cancer cells

    PubMed Central

    WANG, YING; CHEN, YONGCHANG; WU, MIN; LAN, TING; WU, YAN; LI, YUEYING; QIAN, HAI

    2015-01-01

    Enhanced motility of cancer cells is a critical step in promoting tumor metastasis, which remains the major cause of gastric cancer-associated mortality. The small GTPase Rac1 is a key signaling component in the regulation of cell migration. Previous studies have demonstrated that Rac1 activity may be regulated by protein kinase G (PKG); however, the underlying mechanism is not yet clear. The current study aimed to investigate the effect of type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) on Rac1 activity. The human gastric cancer cell line AGS was infected with adenoviral constructs encoding PKG II to increase the expression of this enzyme, and treated with a cGMP analog (8-pCPT-cGMP) to induce its activation. A Transwell assay was employed to measure cell migration, and the activity of Rac1 was assessed using a pull-down assay. Immunoprecipitation was used to isolate the Rac1 protein. Phosphorylation of phosphatidylinositol 4,5 bisphosphate 3 kinase (PI3K) and its downstream effecter protein kinase B (Akt) are associated with lysophosphatidic acid (LPA)-induced motility/migration of cancer cells. Extracellular signal regulated kinase (ERK) is the major signaling molecule of the Mitogen activated protein kinase (MAPK) mediated signaling pathway. ERK and its upstream activator MAPK kinase (MEK) are also involved in LPA-induced motility/migration of cancer cells. Phosphorylation of PI3K/Akt, MEK/ERK and enriched Rac1 were detected by western blotting. The results revealed that blocking the activation of Rac1 by ectopically expressing an inactive Rac1 mutant (T17N) impeded LPA-induced cell migration. Increased PKG II activity inhibited LPA-induced migration and LPA-induced activation of Rac1; however, it had no effect on the phosphorylation of Rac1. PKG II also inhibited the activation of PI3K/Akt and MEK/ERK mediated signaling, which is important for LPA-induced Rac1 activation. These results suggest that PKG II affects LPA

  6. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

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

    2014-01-01

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

  7. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

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

  8. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  9. Space analogue studies in Antarctica.

    PubMed

    Lugg, D; Shepanek, M

    1999-01-01

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

  10. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

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

  11. Incorporation of a fluorescent guanosine analog into oligonucleotides and its application to a real time assay for the HIV-1 integrase 3'-processing reaction.

    PubMed Central

    Hawkins, M E; Pfleiderer, W; Mazumder, A; Pommier, Y G; Balis, F M

    1995-01-01

    We have synthesized a highly fluorescent (quantum yield 0.88) guanosine analog, (3-methyl-8-(2-deoxy-beta-D-ribofuranosyl) isoxanthopterin (3-Mi) in a dimethoxytrityl, phosphoramidite protected form, which can be site-specifically inserted into oligonucleotides through a 3',5'-phosphodiester linkage using an automated DNA synthesizer. Fluorescence is partially quenched within an oligonucleotide and the degree of quench is a function of the fluorophore's proximity to purines and its position in the oligonucleotide. As an example of the potential utility of this class of fluorophores, we developed a continuous assay for HIV-1 integrase 3'-processing reaction by incorporating 3-MI at the cleavage site in a double-stranded oligonucleotide identical to the U5 terminal sequence of the HIV genome. Integrase cleaves the 3'-terminal dinucleotide containing the fluorophore, resulting in an increase in fluorescence which can be monitored on a spectrofluorometer. Substitution of the fluorophore for guanosine at the cleavage site does not inhibit integrase activity. This assay is specific for the 3'-processing reaction. The change in fluorescence intensity is linear over time and proportional to the rate of the reaction. This assay demonstrates the potential utility of this new class of fluorophore for continuous monitoring of protein/DNA interactions. PMID:7659509

  12. Two-Step, One-Pot Synthesis of Inosine, Guanosine, and 2′-Deoxyguanosine O6-Ethers via Intermediate O6-(Benzotriazoly-1-yl) Derivatives

    PubMed Central

    Kokatla, Hari Prasad; Lakshman, Mahesh K.

    2013-01-01

    A simple method for the etherification at the O6-position of silyl-protected inosine, guanosine, and 2′-deoxyguanosine is described. Typically, a THF solution of the silylated nucleoside is treated with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs2CO3, under a nitrogen atmosphere. Conversion to the O6-(benzotriazol-1-yl) ethers occurs within about 10 minutes for inosine, and within about 60 minutes for guanosine and 2′-deoxyguanosine. Then, for reaction with alcohols, the reaction mixture is evaporated and the O6-(benzotriazol-1-yl) ether is treated with Cs2CO3 and an appropriate alcohol, at room temperature. On the other hand, for reaction with phenols, Cs2CO3 and the appropriate phenol are added to the reaction mixture without evaporation, and the reaction is carried out at 70°C. Subsequently, workup, isolation, and purification lead to the requisite O6-alkyl or -aryl ethers in good to excellent yields. PMID:22700333

  13. Kinetics of the template-directed oligomerization of guanosine 5'-phosphate-2-methylimidazolide: Effect of temperature on individual steps of reactionion

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.; Bernasconi, C. F.; Alberas, D. J.

    1991-01-01

    Non-enzymatic, template-directed reactions have been proposed as models for prebiological polynucleotide synthesis. Chemically activated mononucleotides react in the presence of a polynucleotide, acting as the template in a Watson-Crick base-pairing fashing, and form the complementary daughter polynucleotide. Phosphoimidazolide-activated nucleotides have been used successfully as substrates in these reactions. The kinetics of the guanosine 5'-monophosphate-2-methylimidazolide (2-MelmpG) reaction in aqueous pH 8.0 solutions in the presence and in the absence of polycytidylate (poly(C)) were studied, acting as the template at 6, 23, and 37 C. In the absence of the template, the major reaction pathway of 2-MelmpG is hydrolysis of the P-N bond to form the unreactive guanosine 5'-monophosphate (5'-GMP) and 2-methylimidazole. Concentrated solution of 2-MelmpG (greater than 0.02 M) in the absence of the template form only a small amount dinucleotide, (pG)2, but in the presence of poly(C), oligoguanylates, (pG)n with 2 less than or = n less than or = 40, can be detected. We were able to determine the rate constants for individual steps of this reaction. A summary of the conclusions is presented.

  14. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

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

  15. On the mechanical analogue of DNA.

    PubMed

    Yakushevich, Ludmila

    2017-03-01

    The creation of mechanical analogues of biological systems is known as a useful instrument that helps to understand better the dynamical mechanisms of the functioning of living organisms. Mechanical analogues of biomolecules are usually constructed for imitation of their internal mobility, which is one of the most important properties of the molecules. Among the different types of internal motions, angular oscillations of nitrous bases are of special interest because they make a substantial contribution to the base pairs opening that in turn is an important element of the process of the DNA-protein recognition. In this paper, we investigate the possibility to construct a mechanical analogue for imitation of angular oscillations of nitrous bases in inhomogeneous DNA. It is shown that the analogue has the form of a mechanical chain of non-identical pendulums that oscillate in the gravitational field of the Earth and coupled by identical springs. The masses and lengths of pendulums, as well as the distances between neighboring pendulums and the rigidity of springs are calculated. To illustrate the approach, we present the result of construction of the mechanical analogue of the fragment of the sequence of bacteriophage T7D.

  16. Analogue Downscaling of Seasonal Rainfall Forecasts

    NASA Astrophysics Data System (ADS)

    Charles, A. N.; Timbal, B.; Hendon, H.

    2010-12-01

    We have taken an existing statistical downscaling model (SDM), based on meteorological analogues that was developed for downscaling climate change projections (Timbal et al 2009), and applied it in the seasonal forecasting context to produce downscaled rainfall hindcasts from a coupled model seasonal forecast system (POAMA). Downscaling of POAMA forecasts is required to provide seasonal climate information at local scales of interest. Analogue downscaling is a simple technique to generate rainfall forecasts appropriate to the local scale by conditioning on the large scale predicted GCM circulation and the local topography and climate. Analogue methods are flexible and have been shown to produce good results when downscaling 20th century South Eastern Australian rainfall output from climate models. A set of re-forecasts for three month rainfall at 170 observing stations in the South Murray Darling region of Australia were generated using predictors from the POAMA re-forecasts as input for the analogue SDM. The predictors were optimised over a number of different GCMS in previous climate change downscaling studies. Downscaling with the analogue SDM results in predicted rainfall with realistic variance while maintaining the modest predictive skill of the dynamical model. Evaluation of the consistency between the large scale mean of downscaled and direct GCM output precipitation is encouraging.

  17. GABAA Receptor Modulation by Etomidate Analogues

    PubMed Central

    Pejo, Ervin; Santer, Peter; Wang, Lei; Dershwitz, Philip; Husain, S. Shaukat; Raines, Douglas E.

    2015-01-01

    Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. We characterized the GABAA receptor and hypnotic potencies of etomidate analogues. We then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogues to their structures in order to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage-clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1(L264T)) that enhances anesthetic sensitivity (n = 36 – 60 measurements per concentration-response curve). The hypnotic potencies of etomidate analogues were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 – 21 measurements per dose-response curve). Three-dimensional quantitative structure-activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogues ranged by 91-fold and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated and a pharmacophore model was built that revealed both the structural elements in etomidate analogues associated with high potency and the interactions that these elements make with the etomidate binding site. Conclusion There are multiple specific structural elements in etomidate and etomidate analogues that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more. PMID:26691905

  18. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  19. Insulin analogues: action profiles beyond glycaemic control.

    PubMed

    Eckardt, Kristin; Eckel, Jürgen

    2008-02-01

    A variety of studies have documented significant improvements in the treatment of type 1 and 2 diabetes after the introduction of artificial insulins. This review gives an overview of insulin analogues which are currently approved for therapeutical use. Clinical data regarding the efficiency to control blood glucose level as well as improving HbA1c level in comparison to conventional insulin preparations in type 1 and 2 diabetic patients are summarized. Furthermore, special features of insulin analogues regarding their signalling properties are discussed with focus on the proliferative effects of insulin glargine as well as some recent data of insulin detemir.

  20. Crystal Structure of the Thermus thermophilus 16 S rRNA Methyltransferase RsmC in Complex with Cofactor and Substrate Guanosine

    SciTech Connect

    Demirci, H.; Gregory, S; Dahlberg, A; Jogl, G

    2008-01-01

    Post-transcriptional modification is a ubiquitous feature of ribosomal RNA in all kingdoms of life. Modified nucleotides are generally clustered in functionally important regions of the ribosome, but the functional contribution to protein synthesis is not well understood. Here we describe high resolution crystal structures for the N{sup 2}-guanine methyltransferase RsmC that modifies residue G1207 in 16 S rRNA near the decoding site of the 30 S ribosomal subunit. RsmC is a class I S-adenosyl-l-methionine-dependent methyltransferase composed of two methyltransferase domains. However, only one S-adenosyl-l-methionine molecule and one substrate molecule, guanosine, bind in the ternary complex. The N-terminal domain does not bind any cofactor. Two structures with bound S-adenosyl-l-methionine and S-adenosyl-l-homocysteine confirm that the cofactor binding mode is highly similar to other class I methyltransferases. Secondary structure elements of the N-terminal domain contribute to cofactor-binding interactions and restrict access to the cofactor-binding site. The orientation of guanosine in the active site reveals that G1207 has to disengage from its Watson-Crick base pairing interaction with C1051 in the 16 S rRNA and flip out into the active site prior to its modification. Inspection of the 30 S crystal structure indicates that access to G1207 by RsmC is incompatible with the native subunit structure, consistent with previous suggestions that this enzyme recognizes a subunit assembly intermediate.

  1. Solution structure of an RNA fragment with the P7/P9.0 region and the 3'-terminal guanosine of the tetrahymena group I intron.

    PubMed Central

    Kitamura, Aya; Muto, Yutaka; Watanabe, Satoru; Kim, Insil; Ito, Takuhiro; Nishiya, Yoichi; Sakamoto, Kensaku; Ohtsuki, Takashi; Kawai, Gota; Watanabe, Kimitsuna; Hosono, Kazumi; Takaku, Hiroshi; Katoh, Etsuko; Yamazaki, Toshimasa; Inoue, Tan; Yokoyama, Shigeyuki

    2002-01-01

    In the second step of the two consecutive transesterifications of the self-splicing reaction of the group I intron, the conserved guanosine at the 3' terminus of the intron (omegaG) binds to the guanosine-binding site (GBS) in the intron. In the present study, we designed a 22-nt model RNA (GBS/omegaG) including the GBS and omegaG from the Tetrahymena group I intron, and determined the solution structure by NMR methods. In this structure, omegaG is recognized by the formation of a base triple with the G264 x C311 base pair, and this recognition is stabilized by the stacking interaction between omegaG and C262. The bulged structure at A263 causes a large helical twist angle (40 +/- 80) between the G264 x C311 and C262 x G312 base pairs. We named this type of binding pocket with a bulge and a large twist, formed on the major groove, a "Bulge-and-Twist" (BT) pocket. With another twist angle between the C262 x G312 and G413 x C313 base pairs (45 +/- 100), the axis of GBS/omegaG is kinked at the GBS region. This kinked axis superimposes well on that of the corresponding region in the structure model built on a 5.0 A resolution electron density map (Golden et al., Science, 1998, 282:345-358). This compact structure of the GBS is also consistent with previous biochemical studies on group I introns. The BT pockets are also found in the arginine-binding site of the HIV-TAR RNA, and within the 16S rRNA and the 23S rRNA. PMID:11991639

  2. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  3. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-03-01

    Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

  4. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  5. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  6. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    PubMed

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  7. Optimization of propafenone analogues as antimalarial leads.

    PubMed

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  8. Enzymatic synthesis of lipid II and analogues.

    PubMed

    Huang, Lin-Ya; Huang, Shih-Hsien; Chang, Ya-Chih; Cheng, Wei-Chieh; Cheng, Ting-Jen R; Wong, Chi-Huey

    2014-07-28

    The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.

  9. Polyamine analogues targeting epigenetic gene regulation.

    PubMed

    Huang, Yi; Marton, Laurence J; Woster, Patrick M; Casero, Robert A

    2009-11-04

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of

  10. Benchmarking analogue models of brittle thrust wedges

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido; Buiter, Susanne J. H.; Boutelier, Jennifer; Burberry, Caroline; Callot, Jean-Paul; Cavozzi, Cristian; Cerca, Mariano; Chen, Jian-Hong; Cristallini, Ernesto; Cruden, Alexander R.; Cruz, Leonardo; Daniel, Jean-Marc; Da Poian, Gabriela; Garcia, Victor H.; Gomes, Caroline J. S.; Grall, Céline; Guillot, Yannick; Guzmán, Cecilia; Hidayah, Triyani Nur; Hilley, George; Klinkmüller, Matthias; Koyi, Hemin A.; Lu, Chia-Yu; Maillot, Bertrand; Meriaux, Catherine; Nilfouroushan, Faramarz; Pan, Chang-Chih; Pillot, Daniel; Portillo, Rodrigo; Rosenau, Matthias; Schellart, Wouter P.; Schlische, Roy W.; Take, Andy; Vendeville, Bruno; Vergnaud, Marine; Vettori, Matteo; Wang, Shih-Hsien; Withjack, Martha O.; Yagupsky, Daniel; Yamada, Yasuhiro

    2016-11-01

    We performed a quantitative comparison of brittle thrust wedge experiments to evaluate the variability among analogue models and to appraise the reproducibility and limits of model interpretation. Fifteen analogue modeling laboratories participated in this benchmark initiative. Each laboratory received a shipment of the same type of quartz and corundum sand and all laboratories adhered to a stringent model building protocol and used the same type of foil to cover base and sidewalls of the sandbox. Sieve structure, sifting height, filling rate, and details on off-scraping of excess sand followed prescribed procedures. Our analogue benchmark shows that even for simple plane-strain experiments with prescribed stringent model construction techniques, quantitative model results show variability, most notably for surface slope, thrust spacing and number of forward and backthrusts. One of the sources of the variability in model results is related to slight variations in how sand is deposited in the sandbox. Small changes in sifting height, sifting rate, and scraping will result in slightly heterogeneous material bulk densities, which will affect the mechanical properties of the sand, and will result in lateral and vertical differences in peak and boundary friction angles, as well as cohesion values once the model is constructed. Initial variations in basal friction are inferred to play the most important role in causing model variability. Our comparison shows that the human factor plays a decisive role, and even when one modeler repeats the same experiment, quantitative model results still show variability. Our observations highlight the limits of up-scaling quantitative analogue model results to nature or for making comparisons with numerical models. The frictional behavior of sand is highly sensitive to small variations in material state or experimental set-up, and hence, it will remain difficult to scale quantitative results such as number of thrusts, thrust spacing

  11. Antitumoral cyclic peptide analogues of chlamydocin.

    PubMed

    Bernardi, E; Fauchere, J L; Atassi, G; Viallefont, P; Lazaro, R

    1993-01-01

    A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

  12. Synthesis of constrained analogues of tryptophan

    PubMed Central

    Negrato, Marco; Abbiati, Giorgio; Dell’Acqua, Monica

    2015-01-01

    Summary A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues. PMID:26664620

  13. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  14. Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of bis selenide in the mouse tail suspension test.

    PubMed

    Jesse, Cristiano R; Wilhelm, Ethel A; Bortolatto, Cristiani F; Rocha, João B T; Nogueira, Cristina W

    2010-06-10

    The present study investigated a possible antidepressant-like effect of bis selenide by using the forced swimming and the tail suspension tests. The involvement of the l-arginine-nitric oxide-cyclic guanosine monophosphate signaling pathway in the antidepressant-like action of bis selenide was investigated. Bis selenide, given by oral route at doses of 0.5-5mg/kg, decreased the immobility time in the forced swimming and tail suspension tests. Pretreatment with l-arginine (750mg/kg, intraperitoneal, i.p., a nitric oxide precursor), sildenafil (5mg/kg, i.p., a phosphodiesterase 5 inhibitor) or S-nitroso-N-acetyl-penicillamine (25microg/site, intracerebroventricular, i.c.v., a nitric oxide donor) reversed the reduction in the immobility time elicited by bis selenide (1mg/kg, p.o.) in the tail suspension test. Bis selenide (0.1mg/kg, p.o., a subeffective dose) produced a synergistic antidepressant-like effect with N(G)-nitro-L-arginine (0.3mg/kg, i.p., an inhibitor of nitric oxide synthase) or 7-nitroindazole (25mg/kg, i.p., a specific neuronal nitric oxide synthase inhibitor) in the tail suspension test. Pretreatment of animals with methylene blue (10mg/kg, i.p., an inhibitor of nitric oxide synthase and soluble guanylate cyclase) or 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (30pmol, i.c.v., a specific inhibitor of soluble guanylate cyclase), at subeffective doses, caused a synergistic effect with bis selenide in the tail suspension test. Bis selenide (1mg/kg, p.o.), at an effective dose in the forced swimming and tail suspension tests, caused a significant decrease in the mouse cerebral nitrate/nitrite levels. The antidepressant-like effect of bis selenide in the tail suspension test is dependent on the inhibition of the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway.

  15. Thymidine analogues for tracking DNA synthesis.

    PubMed

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

    2011-09-15

    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.

  16. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

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

    2016-01-01

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

  17. Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway

    PubMed Central

    Angmo, Stanzin; Tripathi, Neha; Abbat, Sheenu; Sharma, Shailesh; Singh, Shelley Sardul; Halder, Avishek; Yadav, Kamalendra; Shukla, Geeta; Sandhir, Rajat; Rishi, Vikas; Bharatam, Prasad V.; Yadav, Hariom; Singhal, Nitin Kumar

    2017-01-01

    Hepcidin, a peptide hormone, is a key regulator in mammalian iron homeostasis. Increased level of hepcidin due to inflammatory conditions stimulates the ferroportin (FPN) transporter internalization, impairing the iron absorption; clinically manifested as anemia of inflammation (AI). Inhibiting hepcidin-mediated FPN degradation is proposed as an important strategy to combat AI. A systematic approach involving in silico, in vitro, ex vivo and in vivo studies is employed to identify hepcidin-binding agents. The virtual screening of 68,752 natural compounds via molecular docking resulted into identification of guanosine 5′-diphosphate (GDP) as a promising hepcidin-binding agent. The molecular dynamics simulations helped to identify the important hepcidin residues involved in stabilization of hepcidin-GDP complex. The results gave a preliminary indication that GDP may possibly inhibit the hepcidin-FPN interactions. The in vitro studies revealed that GDP caused FPN stabilization (FPN-GFP cell lines) and increased the FPN-mediated cellular iron efflux (HepG2 and Caco-2 cells). Interestingly, the co-administration of GDP and ferrous sulphate (FeSO4) ameliorated the turpentine-induced AI in mice (indicated by increased haemoglobin level, serum iron, FPN expression and decreased ferritin level). These results suggest that GDP a promising natural small-molecule inhibitor that targets Hepcidin-FPN complex may be incorporated with iron supplement regimens to ameliorate AI. PMID:28054602

  18. Identification of Guanosine 5‧-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway

    NASA Astrophysics Data System (ADS)

    Angmo, Stanzin; Tripathi, Neha; Abbat, Sheenu; Sharma, Shailesh; Singh, Shelley Sardul; Halder, Avishek; Yadav, Kamalendra; Shukla, Geeta; Sandhir, Rajat; Rishi, Vikas; Bharatam, Prasad V.; Yadav, Hariom; Singhal, Nitin Kumar

    2017-01-01

    Hepcidin, a peptide hormone, is a key regulator in mammalian iron homeostasis. Increased level of hepcidin due to inflammatory conditions stimulates the ferroportin (FPN) transporter internalization, impairing the iron absorption; clinically manifested as anemia of inflammation (AI). Inhibiting hepcidin-mediated FPN degradation is proposed as an important strategy to combat AI. A systematic approach involving in silico, in vitro, ex vivo and in vivo studies is employed to identify hepcidin-binding agents. The virtual screening of 68,752 natural compounds via molecular docking resulted into identification of guanosine 5‧-diphosphate (GDP) as a promising hepcidin-binding agent. The molecular dynamics simulations helped to identify the important hepcidin residues involved in stabilization of hepcidin-GDP complex. The results gave a preliminary indication that GDP may possibly inhibit the hepcidin-FPN interactions. The in vitro studies revealed that GDP caused FPN stabilization (FPN-GFP cell lines) and increased the FPN-mediated cellular iron efflux (HepG2 and Caco-2 cells). Interestingly, the co-administration of GDP and ferrous sulphate (FeSO4) ameliorated the turpentine-induced AI in mice (indicated by increased haemoglobin level, serum iron, FPN expression and decreased ferritin level). These results suggest that GDP a promising natural small-molecule inhibitor that targets Hepcidin-FPN complex may be incorporated with iron supplement regimens to ameliorate AI.

  19. Live-cell imaging in Caenorhabditis elegans reveals the distinct roles of dynamin self-assembly and guanosine triphosphate hydrolysis in the removal of apoptotic cells.

    PubMed

    He, Bin; Yu, Xiaomeng; Margolis, Moran; Liu, Xianghua; Leng, Xiaohong; Etzion, Yael; Zheng, Fei; Lu, Nan; Quiocho, Florante A; Danino, Dganit; Zhou, Zheng

    2010-02-15

    Dynamins are large GTPases that oligomerize along membranes. Dynamin's membrane fission activity is believed to underlie many of its physiological functions in membrane trafficking. Previously, we reported that DYN-1 (Caenorhabditis elegans dynamin) drove the engulfment and degradation of apoptotic cells through promoting the recruitment and fusion of intracellular vesicles to phagocytic cups and phagosomes, an activity distinct from dynamin's well-known membrane fission activity. Here, we have detected the oligomerization of DYN-1 in living C. elegans embryos and identified DYN-1 mutations that abolish DYN-1's oligomerization or GTPase activities. Specifically, abolishing self-assembly destroys DYN-1's association with the surfaces of extending pseudopods and maturing phagosomes, whereas inactivating guanosine triphosphate (GTP) binding blocks the dissociation of DYN-1 from these membranes. Abolishing the self-assembly or GTPase activities of DYN-1 leads to common as well as differential phagosomal maturation defects. Whereas both types of mutations cause delays in the transient enrichment of the RAB-5 GTPase to phagosomal surfaces, only the self-assembly mutation but not GTP binding mutation causes failure in recruiting the RAB-7 GTPase to phagosomal surfaces. We propose that during cell corpse removal, dynamin's self-assembly and GTP hydrolysis activities establish a precise dynamic control of DYN-1's transient association to its target membranes and that this control mechanism underlies the dynamic recruitment of downstream effectors to target membranes.

  20. Increased cyclic guanosine monophosphate production and endothelial nitric oxide synthase level in mononuclear cells from sildenafil citrate-treated patients with erectile dysfunction.

    PubMed

    García-Cardoso, J; Vela, R; Mahillo, E; Mateos-Cáceres, P J; Modrego, J; Macaya, C; López-Farré, A J

    2010-01-01

    Mononuclear cells express enzymes involved in the NO/cyclic guanosine monophosphate (cGMP) generating system, as well as PDE5. The objective of the study was to determine the effect of sildenafil citrate administration on the level of proteins involved in the NO/cGMP generating system in mononuclear cells from patients with ED. Twenty-one patients with ED (International Index of Erectile Function-Erectile Function Domain (IIEF-EFD) 17.9+/-0.8) were enrolled and 100 mg sildenafil citrate on-demand was administered during 12 weeks. All patients showed cardiovascular risk factors. After sildenafil citrate administration, IIEF-EFD score was improved (26+/-1.2 P<0.05). In the mononuclear cells, the protein level of endothelial NO synthase (eNOS) was higher after sildenafil citrate treatment. It was accompanied by reduction in the circulating plasma levels of both high-sensitive C-reactive protein and soluble intercellular adhesive molecule-1. The protein level of soluble guanylate cyclase and PDE5 did not change in the mononuclear cells after sildenafil citrate treatment. However, in the mononuclear cells exogenous NO induced a higher cGMP production after 12-weeks sildenafil citrate administration. In conclusion, in mononuclear cells from patients with ED sildenafil citrate administration increased the level of eNOS protein and increased cGMP production in response to NO. Moreover, sildenafil citrate administration reduced the plasma circulating levels of two biomarkers associated with inflammation.

  1. Structure and potential mutagenicity of new hydantoin products from guanosine and 8-oxo-7,8-dihydroguanine oxidation by transition metals.

    PubMed

    Burrows, Cynthia J; Muller, James G; Kornyushyna, Olga; Luo, Wenchen; Duarte, Victor; Leipold, Michael D; David, Sheila S

    2002-10-01

    In vitro work in this laboratory has identified new DNA lesions resulting from further oxidation of a common biomarker of oxidative damage, 8-oxo-7,8-dihydroguanine (OG). The major product of oxidation of OG in a nucleoside, nucleotide, or single-stranded oligodeoxynucleotide using metal ions that act as one-electron oxidants is the new nucleoside derivative spiroiminodihydantoin (Sp). In duplex DNA an equilibrating mixture of two isomeric products, guanidinohydantoin (Gh) and iminoallantoin (Ia), is produced. These products are also formed by the overall four-electron oxidation of guanosine by photochemical processes involving O(2). DNA template strands containing either Sp or Gh/Ia generally acted as a block to DNA synthesis with the Klenow exo(-) fragment of pol I. However, when nucleotide insertion did occur opposite the lesions, only 2'-deoxyadenosine 5-triphosphate and 2'-deoxyguanine 5-triphosphate were used for primer extension. The Escherichia coli DNA repair enzyme Fpg was able to remove the Sp and Gh/Ia lesions from duplex DNA substrates, although the efficiency was depended on the base opposite the lesion.

  2. DNA 3' pp 5' G de-capping activity of aprataxin: effect of cap nucleoside analogs and structural basis for guanosine recognition

    DOE PAGES

    Chauleau, Mathieu; Jacewicz, Agata; Shuman, Stewart

    2015-05-24

    DNA3' pp 5'G caps synthesized by the 3'-PO4/5'-OH ligase RtcB have a strong impact on enzymatic reactions at DNA 3'-OH ends. Aprataxin, an enzyme that repairs A5'pp5'DNA ends formed during abortive ligation by classic 3'-OH/5'-PO4 ligases, is also a DNA 3' de-capping enzyme, converting DNAppG to DNA3'p and GMP. By taking advantage of RtcB's ability to utilize certain GTP analogs to synthesize DNAppN caps, we show that aprataxin hydrolyzes inosine and 6-O-methylguanosine caps, but is not adept at removing a deoxyguanosine cap. We report a 1.5 Å crystal structure of aprataxin in a complex with GMP, which reveals that: (i)more » GMP binds at the same position and in the same anti nucleoside conformation as AMP; and (ii) aprataxin makes more extensive nucleobase contacts with guanine than with adenine, via a hydrogen bonding network to the guanine O6, N1, N2 base edge. Alanine mutations of catalytic residues His147 and His149 abolish DNAppG de-capping activity, suggesting that the 3' de-guanylylation and 5' de-adenylylation reactions follow the same pathway of nucleotidyl transfer through a covalent aprataxin-(His147)–NMP intermediate. Alanine mutation of Asp63, which coordinates the guanosine ribose hydroxyls, impairs DNAppG de-capping.« less

  3. Intradermal cytosine-phosphate-guanosine treatment reduces lung inflammation but induces IFN-γ-mediated airway hyperreactivity in a murine model of natural rubber latex allergy.

    PubMed

    Haapakoski, Rita; Karisola, Piia; Fyhrquist, Nanna; Savinko, Terhi; Wolff, Henrik; Turjanmaa, Kristiina; Palosuo, Timo; Reunala, Timo; Lauerma, Antti; Alenius, Harri

    2011-05-01

    Asthma and other allergic diseases are continuously increasing, causing considerable economic and sociologic burden to society. The hygiene hypothesis proposes that lack of microbial T helper (Th) 1-like stimulation during early childhood leads to increased Th2-driven allergic disorders later in life. Immunostimulatory cytosine-phosphate-guanosine (CpG)-oligodeoxynucleotide motifs are candidate molecules for immunotherapeutic studies, as they have been shown to shift the Th2 response toward the Th1 direction and reduce allergic symptoms. Using natural rubber latex (NRL)-induced murine model of asthma, we demonstrated that intradermal CpG administration with allergen reduced pulmonary eosinophilia, mucus production, and Th2-type cytokines, but unexpectedly induced airway hyperreactivity (AHR) to inhaled methacholine, one of the hallmarks of asthma. We found that induction in AHR was dependent on STAT4, but independent of STAT6 signaling. CpG treatment increased production of IFN-γ in the airways and shifted the ratio of CD4(+):CD8(+) T cells toward CD8(+) dominance. By blocking soluble IFN-γ with neutralizing antibody, AHR diminished and the CD4(+):CD8(+) ratio returned to CD4(+) dominance. These results indicate that increased production of IFN-γ in the lungs may lead to severe side effects, such as enhancement of bronchial hyperreactivity to inhaled allergen. This finding should be taken into consideration when planning prophylaxis treatment of asthma with intradermal CpG injections.

  4. Guanosine tetra- and pentaphosphate synthase activity in chloroplasts of a higher plant: association with 70S ribosomes and inhibition by tetracycline

    PubMed Central

    Kasai, Koji; Kanno, Takuya; Endo, Yaeta; Wakasa, Kyo; Tozawa, Yuzuru

    2004-01-01

    Chloroplasts possess bacterial-type systems for transcription and translation. On the basis of the identification of a Chlamydomonas reinhardtii gene encoding a RelA-SpoT homolog (RSH) that catalyzes the synthesis of guanosine tetra- or pentaphosphate [(p)ppGpp], we have previously suggested the operation of stringent control in the chloroplast genetic system. Although RSH genes have also been identified in several higher plants, the activities of the encoded enzymes and their mode of action in chloroplasts have remained uncharacterized. We have now characterized the intrinsic (p)ppGpp synthase activity of chloroplast extracts prepared from pea (Pisum sativum). Fractionation by ultracentrifugation suggested that the (p)ppGpp synthase activity of a translationally active chloroplast stromal extract was associated with 70S ribosomes. Furthermore, this enzymatic activity was inhibited by tetracycline, as was the peptide elongation activity of the extract. Structural comparisons between rRNA molecules of Escherichia coli and pea chloroplasts revealed the conservation of putative tetracycline-binding sites. These observations demonstrate the presence of a ribosome-associated (p)ppGpp synthase activity in the chloroplasts of a higher plant, further implicating (p)ppGpp in a genetic system of chloroplasts similar to that operative in bacteria. PMID:15507686

  5. Effect of guanosine 5'-diphosphate 3'-diphosphate and related nucleoside polyphosphates on induction of tryptophanase and beta-galactosidase in permeabilized cells of Escherichia coli.

    PubMed

    Yoshimoto, A; Oki, T; Inui, T

    1978-10-04

    Exogenous addition of guanosine and adenosine 5'-(mono, di and tri) phosphate 3'-diphosphates (pppGpp, ppGpp, pGpp, pppApp, ppApp and pApp) stimulated the synthesis of tryptophanase and beta-galactosidase in permeabilized cells of Escherichia coli. From the results obtained with ppGpp and pppApp, this effect appeared to be at a transcriptional level and depended greatly on the growth condition; the largest effect was observed in cells under shiftdown or grown on poor enrgy source. ppGpp and pppApp, unlike cyclic AMP, did not act to overcome the inhibition of enzyme induction by glucose, but in combination with cyclic AMP caused a synergistic stimulation effect. In the shiftdown cells, ppGpp and pppApp gave 30% or more stimulation effect on tryptophanase induction while cyclic AMP did not stimulate induction. There was therefore a pronounced difference between cyclic AMP and ppGpp or pppApp in stimulatory function.

  6. Structural Basis of Differential Ligand Recognition by Two Classes of bis-(3-5)-cyclic Dimeric Guanosine Monophosphate-binding Riboswitches

    SciTech Connect

    K Smith; C Shanahan; E Moore; A Simon; S Strobel

    2011-12-31

    The bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) signaling pathway regulates biofilm formation, virulence, and other processes in many bacterial species and is critical for their survival. Two classes of c-di-GMP-binding riboswitches have been discovered that bind this second messenger with high affinity and regulate diverse downstream genes, underscoring the importance of RNA receptors in this pathway. We have solved the structure of a c-di-GMP-II riboswitch, which reveals that the ligand is bound as part of a triplex formed with a pseudoknot. The structure also shows that the guanine bases of c-di-GMP are recognized through noncanonical pairings and that the phosphodiester backbone is not contacted by the RNA. Recognition is quite different from that observed in the c-di-GMP-I riboswitch, demonstrating that at least two independent solutions for RNA second messenger binding have evolved. We exploited these differences to design a c-di-GMP analog that selectively binds the c-di-GMP-II aptamer over the c-di-GMP-I RNA. There are several bacterial species that contain both types of riboswitches, and this approach holds promise as an important tool for targeting one riboswitch, and thus one gene, over another in a selective fashion.

  7. An Interplay among FIS, H-NS, and Guanosine Tetraphosphate Modulates Transcription of the Escherichia coli cspA Gene under Physiological Growth Conditions

    PubMed Central

    Brandi, Anna; Giangrossi, Mara; Giuliodori, Anna M.; Falconi, Maurizio

    2016-01-01

    CspA, the most characterized member of the csp gene family of Escherichia coli, is highly expressed not only in response to cold stress, but also during the early phase of growth at 37°C. Here, we investigate at molecular level the antagonistic role played by the nucleoid proteins FIS and H-NS in the regulation of cspA expression under non-stress conditions. By means of both probing experiments and immunological detection, we demonstrate in vitro the existence of binding sites for these proteins on the cspA regulatory region, in which FIS and H-NS bind simultaneously to form composite DNA-protein complexes. While the in vitro promoter activity of cspA is stimulated by FIS and repressed by H-NS, a compensatory effect is observed when both proteins are added in the transcription assay. Consistently with these findings, inactivation of fis and hns genes reversely affect the in vivo amount of cspA mRNA. In addition, by means of strains expressing a high level of the alarmone guanosine tetraphosphate ((p)ppGpp) and in vitro transcription assays, we show that the cspA promoter is sensitive to (p)ppGpp inhibition. The (p)ppGpp-mediated expression of fis and hns genes is also analyzed, thus clarifying some aspects of the regulatory loop governing cspA transcription. PMID:27252944

  8. (15)N Double-labeled guanosine from inosine through ring-opening-ring-closing and one-pot Pd-catalyzed C-O and C-N cross-coupling reactions.

    PubMed

    Caner, Joaquim; Vilarrasa, Jaume

    2010-07-16

    [N,1-(15)N(2)]-Guanosine, or [1,NH(2)-(15)N(2)]-guanosine, and derivatives were prepared from tri-O-acetylinosine, via N-nitration and reaction with (15)NH(2)OH, followed by conversion of the (15)N-labeled 1-hydroxyinosine to the corresponding 2,6-dichloropurine riboside. The sequential one-pot C-O and C-N key couplings of this dichloro derivative with PhCH(2)OH and PhCO(15)NH(2) or (i)PrCO(15)NH(2) was achieved in good overall yields, with Pd(0)-Xantphos as the best choice of five different catalytic systems examined.

  9. Polyamine analogues bind human serum albumin.

    PubMed

    Beauchemin, R; N'soukpoé-Kossi, C N; Thomas, T J; Thomas, T; Carpentier, R; Tajmir-Riahi, H A

    2007-10-01

    Polyamine analogues show antitumor activity in experimental models, and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues, such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333), in aqueous solution at physiological conditions using a constant protein concentration and various polyamine contents (microM to mM). FTIR, UV-visible, and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind nonspecifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 x 10(3) M(-1), KBE-333 = 5.63 x 10(2) M(-1), and KBE-3333 = 3.66 x 10(2) M(-1). The protein secondary structure showed major alterations with a reduction of alpha-helix from 55% (free protein) to 43-50% and an increase of beta-sheet from 17% (free protein) to 29-36% in the 333, BE-333, and BE-3333 complexes, indicating partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues compared to those of the biogenic polyamines.

  10. New synthetic approaches towards analogues of bedaquiline.

    PubMed

    Priebbenow, Daniel L; Barbaro, Lisa; Baell, Jonathan B

    2016-10-12

    Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

  11. The Lehmer Matrix and Its Recursive Analogue

    DTIC Science & Technology

    2010-01-01

    for failing to comply with a collection of information if it does not display a currently valid OMB control number . 1. REPORT DATE 2010 2. REPORT...TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE The Lehmer matrix and its recursive analogue 5a. CONTRACT NUMBER 5b...GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND

  12. U.S. Nuclear Regulatory Commission natural analogue research program

    SciTech Connect

    Kovach, L.A.; Ott, W.R.

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  13. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Cordatos, Harry

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  14. Synthesis of a cyanopeptide-analogue with trypsin activating properties.

    PubMed

    Radau, G; Rauh, D

    2000-04-17

    An efficient synthesis of a peptidic analogue of cyanobacterial metabolites with proposed serine protease inhibitory activity has been developed. Surprisingly, one trypsin activating compound was obtained.

  15. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  16. Self-Powered Analogue Smart Skin.

    PubMed

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity.

  17. Protection of Nrf2 against arsenite-induced oxidative damage is regulated by the cyclic guanosine monophosphate-protein kinase G signaling pathway.

    PubMed

    Chen, Chengzhi; Jiang, Xuejun; Gu, Shiyan; Lai, Yanhao; Liu, Yuan; Zhang, Zunzhen

    2016-10-24

    Arsenite has been shown to induce a variety of oxidative damage in mammalian cells. However, the mechanisms underlying cellular responses to its adverse effects remain unknown. We previously showed that the level of Nrf2, a nuclear transcription factor significantly increased in arsenite-treated human bronchial epithelial (HBE) cells suggesting that Nrf2 is involved in responding to arsenite-induced oxidative damage. To explore how Nrf2 can impact arsenite-induced oxidative damage, in this study, we examined Nrf2 activation and its regulation upon cellular arsenite exposure as well as its effects on arsenite-induced oxidative damage in HBE cells. We found that Nrf2 mRNA and protein levels were significantly increased by arsenite in a dose- and time-dependent manner. Furthermore, we showed that over-expression of Nrf2 significantly reduced the level of arsenite-induced oxidative damage in HBE cells including DNA damage, chromosomal breakage, lipid peroxidation and depletion of antioxidants. This indicates a protective role of Nrf2 against arsenite toxicity. This was further supported by the fact that activation of Nrf2 by its agonists, tertiary butylhydroquinone (t-BHQ) and sulforaphane (SFN) resulted in the same protective effects against arsenite toxicity. Moreover, we demonstrated that arsenite-induced activation of Nrf2 was mediated by the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway. This is the first evidence showing that Nrf2 protects against arsenite-induced oxidative damage through the cGMP-PKG pathway. Our study suggests that activation of Nrf2 through the cGMP-PKG signaling pathway in HBE cells may be developed as a new strategy for prevention of arsenite toxicity. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.

  18. Association of blood lead levels with urinary F₂-8α isoprostane and 8-hydroxy-2-deoxy-guanosine concentrations in first-grade Uruguayan children.

    PubMed

    Roy, Aditi; Queirolo, Elena; Peregalli, Fabiana; Mañay, Nelly; Martínez, Gabriela; Kordas, Katarzyna

    2015-07-01

    Oxidative stress (OS) is a potential molecular mechanism for lead-induced toxicities, yet, we have limited understanding of the relation between low-level lead (Pb) exposure and OS, especially in children. This cross-sectional study examines the association between blood lead level (BLL) and two OS markers-urinary F2-8α isoprostane or isoprostane (a marker of lipid peroxidation) and 8-hydroxy-2-deoxy-Guanosine or 8-OH-dG (a marker of DNA damage) in 211 children, aged 5-8 years, from Montevideo, Uruguay. The role of dietary intakes of vitamin C and zinc in modifying the relation between BLL and OS was also examined. The mean (SD) BLL of the study children was 4.7 (2.2) µg/dL, with 30.2% children having BLL ≥5 µg/dL, the current reference level set by the US Centre for Disease Control for identifying, monitoring and management of children with elevated BLL. In covariate-adjusted analysis, there was a weak positive association between BLL and urinary isoprostane (adjusted for specific gravity) [β=0.09, p<0.1]. No association was found between children's BLL and urinary 8-OH-dG. Interactions between dietary intakes of vitamin C or zinc and BLL on OS biomarkers were not consistent. However, when BLL and vitamin C or BLL and zinc were modeled together, BLL was independently associated with isoprostane concentration [β=0.10, p<0.05] but vitamin C or zinc intake was not. These findings suggest that there may be a potential adverse effect of BLL on OS in children with low-level Pb exposure. There is a need to study the effects of Pb on other OS measures, as well as the role of OS in mediating low-level Pb toxicity on functional outcomes.

  19. Evidence that insulin and guanosine triphosphate regulate dephosphorylation of the beta-subunit of the insulin receptor in sarcolemma membranes isolated from skeletal muscle.

    PubMed Central

    Horn, R S; Lystad, E; Adler, A; Walaas, O

    1986-01-01

    When sarcolemma membranes isolated from rat skeletal muscle were incubated with [gamma-32P]ATP, a membrane protein of apparent Mr 95,000 was rapidly phosphorylated, with the 32P content reaching a maximum within 2 s. On the basis of immunoprecipitation with anti-insulin-receptor antiserum, phosphoamino acid analysis and Mr, this protein probably represents the beta-subunit of the insulin receptor. Similarly, on incubation of the membrane with adenosine 5'-[gamma-[35S]thio] triphosphate the 95 kDa protein was thiophosphorylated, indicating thiophosphorylation of the beta-subunit of the insulin receptor on the basis of immunoprecipitation studies. The effect of insulin on the phosphorylation of this protein in the membrane was studied. Insulin induced a 20% decrease in the 32P labelling of the protein when the membranes were phosphorylated for 10 s. This insulin effect was dose-dependent, with half-maximal effect obtained at 2-3 nM-insulin. Addition of GTP, but not GDP or guanosine 5'-[beta, gamma-imido]triphosphate, enhanced the effect to 35% inhibition, with half-maximal effect of GTP obtained at 0.5 microM. GTP had no effect on the phosphorylation of the protein in the absence of insulin. Analysis of this insulin effect showed that insulin increased the rate of dephosphorylation of the 95 kDa protein in the membrane. In contrast, insulin had no effect on thiophosphorylation of the 95 kDa membrane protein after incubation with adenosine 5'-[gamma-[35S]thio]triphosphate. Since thiophosphorylated proteins are less sensitive to phosphatase action, these investigations suggest that insulin stimulated a protein phosphatase activity in a GTP-dependent manner. The possibility that GTP-regulatory proteins are involved in the action of insulin on the phosphorylation of the insulin receptor and other membrane proteins is discussed. Images Fig. 1. Fig. 3. PMID:3521589

  20. Involvement of nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tropisetron and ondansetron in mice forced swimming test and tail suspension test.

    PubMed

    Haj-Mirzaian, Arya; Kordjazy, Nastaran; Amiri, Shayan; Haj-Mirzaian, Arvin; Amini-Khoei, Hossien; Ostadhadi, Sattar; Dehpour, AhmadReza

    2016-06-05

    Antidepressant-like effects of 5-hydroxytryptamine subtype 3 (5-HT3) antagonists including tropisetron and ondansetron have been previously demonstrated in the literature. It was reported that stimulation of 5-HT3 receptors activate the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, which is involved in regulation of behavioral and emotional functions. In our study, treating animals with tropisetron (5, 10, and 30mg/kg) and ondansetron (0.01 and 0.1µg/kg) significantly decreased the immobility time in forced swimming test (FST) and tail-suspension test (TST). Co-administration of subeffective doses of tropisetron (1mg/kg) and ondansetron (0.001µg/kg) with subeffective dose of l-NAME (10mg/kg, nonselective NO synthase (NOS) inhibitor) and 7-nitroindazole (25mg/kg, neural NOS inhibitor) exerted antidepressant-like effect in FST and TST, while aminoguanidine (50mg/kg, inducible NOS inhibitor) did not enhance the antidepressant-like effect of 5-HT3 antagonists. Besides, l-arginine (750mg/kg, NO precursor) and sildenafil (5mg/kg, phosphodiesterase inhibitor) suppressed the anti-immobility effect of 5-HT3 antagonists. None of the treatments altered the locomotor behavior of mice in open-field test. Also, hippocampal (but not cortical) nitrite level was significantly lower in tropisetron and ondansetron-treated mice compared with saline-injected mice. Also, co-administration of 7-nitroindazole with tropisetron or ondansetron caused a significant decrease in hippocampal nitrite levels. In conclusion, we suggest that antidepressant-like effect of tropisetron and ondansetron are partially mediated by modulation of NO-cGMP pathway.

  1. Effect of some cyclooxygenase inhibitors on the increase in guanosine 3′:5′-cyclic monophosphate induced by NO-donors in human whole platelets

    PubMed Central

    Failli, Paola; Cecchi, Enrica; Tosti-Guerra, Cristina; Mugelli, Alessandro; Laffi, Giacomo; Zilletti, Lucilla; Giotti, Alberto

    1998-01-01

    The effect of the NSAIDs indomethacin, indoprofen, diclofenac and acetylsalicylic acid on the increase in guanosine 3′:5′-cyclic monophosphate (cyclic GMP) induced by nitric oxide-donor agents was tested in human whole platelets and in platelet crude homogenate.In whole platelets, indomethacin reduced the increase in cyclic GMP induced by the nitric oxide-donors (NO-donors) sodium nitroprusside (NaNP) and S-nitroso-N-acetylpenicillamine (SNAP) in a dose-dependent way, its IC50 being 13.7 μM and 15.8 μM, respectively.Of the other cyclooxygenase inhibitors tested, only indoprofen reduced the increase in cyclic GMP induced by both NO-donors in a dose-dependent way (IC50=32.7 μM, NaNP and 25.0 μM, SNAP), while acetylsalicylic acid (up to 1000 μM) and diclofenac (up to 100 μM) were ineffective.However, in platelet crude homogenate neither indomethacin nor indoprofen reduced the cyclic GMP production.Indomethacin (10 μM), indoprofen (30 μM), diclofenac (100 μM) and acetylsalicylic acid (1000 μM) showed a comparable efficacy in inhibiting platelet thromboxane B2 (TXB2) production, suggesting that the inhibitory effect of indomethacin and indoprofen on the increase in cyclic GMP induced by both NO-donors was not mediated by inhibition of cyclooxygenase.In vitro, the NSAIDs analysed did not interfere with nitrite production of SNAP.The unhomogeneous behaviour of NSAIDs on the increase in cyclic GMP induced by NO-donors in whole platelets may contribute to the different pharmacological and toxicological characteristics of the drugs, providing new knowledge on the effect of indomethacin and indoprofen. PMID:9579743

  2. DNA 3' pp 5' G de-capping activity of aprataxin: effect of cap nucleoside analogs and structural basis for guanosine recognition

    SciTech Connect

    Chauleau, Mathieu; Jacewicz, Agata; Shuman, Stewart

    2015-05-24

    DNA3' pp 5'G caps synthesized by the 3'-PO4/5'-OH ligase RtcB have a strong impact on enzymatic reactions at DNA 3'-OH ends. Aprataxin, an enzyme that repairs A5'pp5'DNA ends formed during abortive ligation by classic 3'-OH/5'-PO4 ligases, is also a DNA 3' de-capping enzyme, converting DNAppG to DNA3'p and GMP. By taking advantage of RtcB's ability to utilize certain GTP analogs to synthesize DNAppN caps, we show that aprataxin hydrolyzes inosine and 6-O-methylguanosine caps, but is not adept at removing a deoxyguanosine cap. We report a 1.5 Å crystal structure of aprataxin in a complex with GMP, which reveals that: (i) GMP binds at the same position and in the same anti nucleoside conformation as AMP; and (ii) aprataxin makes more extensive nucleobase contacts with guanine than with adenine, via a hydrogen bonding network to the guanine O6, N1, N2 base edge. Alanine mutations of catalytic residues His147 and His149 abolish DNAppG de-capping activity, suggesting that the 3' de-guanylylation and 5' de-adenylylation reactions follow the same pathway of nucleotidyl transfer through a covalent aprataxin-(His147)–NMP intermediate. Alanine mutation of Asp63, which coordinates the guanosine ribose hydroxyls, impairs DNAppG de-capping.

  3. Visualization of drug-nucleic acid interactions at atomic resolution. IX. Structures of two N,N-dimethylproflavine: 5-iodocytidylyl (3'-5') guanosine crystalline complexes

    SciTech Connect

    Bhandary, K.K.; Sakore, T.D.; Sobell, H.M.; King, D.; Gabbay, E.J.

    1984-01-01

    This paper describes two complexes containing N,N-dimethylproflavine and the dinucleoside monophosphate, 5-iodocytidylyl(3'-5')guanosine (iodoCpG). The first complex is triclinic, space group P1, with unit cell dimensions a = 11.78 A, b = 14.55 A, c = 15.50 A, ..cap alpha.. = 89.2/sup 0/, ..beta.. 86.2/sup 0/, ..gamma.. = 96.4/sup 0/. The second complex is monoclinic, space group P2/sub 1/, with a = 14.20 A, b = 19.00 A, c = 20.73 A, ..beta.. = 103.6/sup 0/. Both structures have been solved to atomic resolution and refined by Fourier and least squares methods. The first structure has been refined anisotropically to a residual of 0.09 on 5025 observed reflections using block diagonal least squares, while the second structure has been refined isotropically to a residual of 0.13 on 2888 reflections with full matrix least squares. The asymmetric unit in both structures contains two dimethylproflavine molecules and two iodoCpG molecules; the first structure has 16 water molecules (a total of 134 non-hydrogen atoms), while the second structure has 18 water molecules (a total of 136 non-hydrogen atoms). Both structures demonstrate intercalation of dimethylproflavine between base-paired iodoCpG dimers. In addition, dimethylproflavine molecules stack on either side of the intercalated duplex, being related by a unit cell translation along b and a axes, respectively. 16 references, 13 figures, 5 tables.

  4. Mode-specific vibrational relaxation of photoexcited guanosine 5'-monophosphate and its acid form: a femtosecond broadband mid-IR transient absorption and theoretical study.

    PubMed

    Zhang, Yuyuan; Improta, Roberto; Kohler, Bern

    2014-01-28

    UV-pump/broadband-mid-IR-probe transient absorption (TA) experiments and ab initio quantum mechanical (QM) calculations were used to investigate the photophysics in heavy water of the neutral and acid forms of guanosine 5'-monophosphate (GMP and GMPD(+), respectively). Excited GMP undergoes ultrafast internal conversion (IC) and returns to the electronic ground state in less than one picosecond with a large amount of excess vibrational energy. The spectroscopic signals are dominated by vibrational cooling - a process in which the solute dissipates vibrational energy to the solvent. For neutral GMP, cooling proceeds with a time constant of 3 ps. Following IC, at least some medium-frequency modes such as the carbonyl stretch and an in-plane ring vibration are excited, suggesting that the vibrational energy distribution is non-statistical. This is consistent with predicted structural changes upon passage through the S1/S0 conical intersection. GMPD(+) differs from GMP by a single deuteron at the N7 position, but has a dramatically longer lifetime of 200 ps. Vibrational cooling of the S1 state of GMPD(+) was monitored via several medium-frequency modes that were assigned using QM calculations. These medium-frequency modes are also vibrationally excited in a non-statistical fashion. Excitation of these modes is in line with the change in geometry at the S1 minimum of GMPD(+) predicted by QM calculations. Furthermore, these modes relax at different rates, fully consistent with QM calculations, which predict that excited vibrational states of the carbonyl stretch couple strongly to the D2O solvent and thus deactivate via intermolecular energy transfer (IET). In contrast, the ring stretch couples strongly to other ring modes of the guanine chromophore and appears to decay via intramolecular vibrational energy redistribution (IVR).

  5. Neuroprotection Promoted by Guanosine Depends on Glutamine Synthetase and Glutamate Transporters Activity in Hippocampal Slices Subjected to Oxygen/Glucose Deprivation.

    PubMed

    Dal-Cim, Tharine; Martins, Wagner C; Thomaz, Daniel T; Coelho, Victor; Poluceno, Gabriela Godoy; Lanznaster, Débora; Vandresen-Filho, Samuel; Tasca, Carla I

    2016-05-01

    Guanosine (GUO) has been shown to act as a neuroprotective agent against glutamatergic excitotoxicity by increasing glutamate uptake and decreasing its release. In this study, a putative effect of GUO action on glutamate transporters activity modulation was assessed in hippocampal slices subjected to oxygen and glucose deprivation (OGD), an in vitro model of brain ischemia. Slices subjected to OGD showed increased excitatory amino acids release (measured by D-[(3)H]aspartate release) that was prevented in the presence of GUO (100 µM). The glutamate transporter blockers, DL-TBOA (10 µM), DHK (100 µM, selective inhibitor of GLT-1), and sulfasalazine (SAS, 250 µM, Xc(-) system inhibitor) decreased OGD-induced D-aspartate release. Interestingly, DHK or DL-TBOA blocked the decrease in glutamate release induced by GUO, whereas SAS did not modify the GUO effect. GUO protected hippocampal slices from cellular damage by modulation of glutamate transporters, however selective blockade of GLT-1 or Xc- system only did not affect this protective action of GUO. OGD decreased hippocampal glutamine synthetase (GS) activity and GUO recovered GS activity to control levels without altering the kinetic parameters of GS activity, thus suggesting GUO does not directly interact with GS. Additionally, the pharmacological inhibition of GS activity with methionine sulfoximine abolished the effect of GUO in reducing D-aspartate release and cellular damage evoked by OGD. Altogether, results in hippocampal slices subjected to OGD show that GUO counteracts the release of excitatory amino acids, stimulates the activity of GS, and decreases the cellular damage by modulation of glutamate transporters activity.

  6. Association of blood lead levels with urinary F2-8α Isoprostane and 8-hydroxy-2-deoxy-Guanosine concentrations in first-grade Uruguayan children

    PubMed Central

    Roy, Aditi; Queirolo, Elena; Peregalli, Fabiana; Mañay, Nelly; Martínez, Gabriela; Kordas, Katarzyna

    2015-01-01

    Oxidative stress (OS) is a potential molecular mechanism for lead-induced toxicities, yet, we have limited understanding of the relation between low-level lead (Pb) exposure and OS, especially in children. This cross-sectional study examines the association between blood lead level (BLL) and two OS markers—urinary F2-8α isoprostane or isoprostane (a marker of lipid peroxidation) and 8-hydroxy-2-deoxy-Guanosine or 8-OH-dG (a marker of DNA damage) in 211 children, aged 5–8 years, from Montevideo, Uruguay. The role of dietary intakes of vitamin C and zinc in modifying the relation between BLL and OS was also examined. The mean (SD) BLL of the study children was 4.7 (2.2) μg/dL, with 30.2% children having BLL ≥5 μg/dL, the current reference level set by the US Centre for Disease Control for identifying, monitoring and management of children with elevated BLL. In covariate-adjusted analysis, there was a weak positive association between BLL and urinary isoprostane (adjusted for specific gravity) [β = 0.09, p< 0.1]. No association was found between children’s BLL and urinary 8-OH-dG. Interactions between dietary intakes of vitamin C or zinc and BLL on OS biomarkers were not consistent. However, when BLL and vitamin C or BLL and zinc were modeled together, BLL was independently associated with isoprostane concentration [β = 0.10, p< 0.05] but vitamin C or zinc intake was not. These findings suggest that there may be a potential adverse effect of BLL on OS in children with low-level Pb exposure. There is a need to study the effects of Pb on other OS measures, as well as the role of OS in mediating low-level Pb toxicity on functional outcomes. PMID:25863186

  7. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  8. A nonlinear dynamic analogue model of substorms

    NASA Astrophysics Data System (ADS)

    Klimas, A. J.; Baker, D. N.; Roberts, D. A.; Fairfield, D. H.; Büchner, J.

    Linear prediction filter studies have shown that the magnetospheric response to energy transfer from the solar wind contains both directly driven and unloading components. These studies have also shown that the magnetospheric response is significantly nonlinear and, thus, the linear prediction filtering technique and other correlative techniques which assume a linear magnetospheric response cannot give a complete deacription of that response. Here, the solar wind-magnetosphere interaction is discussed within the framework of deterministic nonlinear dynamics. An earlier dripping faucet mechanical analogue to the magnetosphere is first reviewed and then the plasma physical counterpart to the mechanical model is constructed. A Faraday loop in the magnetotail is considered and the relationship of electric potentials on the loop to changes in the magnetic flux threading the loop is developed. This approach leads to a model of geomagnetic activity which is similar to the earlier mechanical model but described in terms of the geometry and plasma contents of the magnetotail. This Faraday loop response model contains analogues to both the directly driven and the storage-release magnetospheric responses and it includes, in a fundamental way, the inherent nonlinearity of the solar wind-magnetosphere system. It can be chancterized as a nonlinear, damped harmonic oscillator that is driven by the loading-unloading substorm cycle. The model is able to explain many of the features of the linear prediction filter results. In particular, at low geomagnetic activity levels the model exbibits the "regular dripping" response which provides an explanation for the unloading component at 1 hour lag in the linear prediction filters. Further, the model suggests that the disappearance of the unloading component in the linear prediction filters at high geomagnetic activity levels is due to a chaotic transition beyond which the loading-unloading mechanism becomes aperiodic. The model predicts

  9. Tren-based analogues of bacillibactin: structure and stability.

    PubMed

    Dertz, Emily A; Xu, Jide; Raymond, Kenneth N

    2006-07-10

    Synthetic analogues were designed to highlight the effect of the glycine moiety of bacillibactin on the overall stability of the ferric complex as compared to synthetic analogues of enterobactin. Insertion of a variety of amino acids to catecholamide analogues based on a Tren (tris(2-aminoethyl)amine) backbone increased the overall acidity of the ligands, causing an enhancement of the stability of the resulting ferric complex as compared to TRENCAM. Solution thermodynamic behavior of these siderophores and their synthetic analogues was investigated through potentiometric and spectrophotometric titrations. X-ray crystallography, circular dichroism, and molecular modeling were used to determine the chirality and geometry of the ferric complexes of bacillibactin and its analogues. In contrast to the Tren scaffold, addition of a glycine to the catechol chelating arms causes an inversion of the trilactone backbone, resulting in opposite chiralities of the two siderophores and a destabilization of the ferric complex of bacillibactin compared to ferric enterobactin.

  10. Analogue Divider by Averaging a Triangular Wave

    NASA Astrophysics Data System (ADS)

    Selvam, Krishnagiri Chinnathambi

    2017-03-01

    A new analogue divider circuit by averaging a triangular wave using operational amplifiers is explained in this paper. The triangle wave averaging analog divider using operational amplifiers is explained here. The reference triangular waveform is shifted from zero voltage level up towards positive power supply voltage level. Its positive portion is obtained by a positive rectifier and its average value is obtained by a low pass filter. The same triangular waveform is shifted from zero voltage level to down towards negative power supply voltage level. Its negative portion is obtained by a negative rectifier and its average value is obtained by another low pass filter. Both the averaged voltages are combined in a summing amplifier and the summed voltage is given to an op-amp as negative input. This op-amp is configured to work in a negative closed environment. The op-amp output is the divider output.

  11. Naturalness in an emergent analogue spacetime.

    PubMed

    Liberati, Stefano; Visser, Matt; Weinfurtner, Silke

    2006-04-21

    Effective field theories (EFTs) have been widely used as a framework in order to place constraints on the Planck suppressed Lorentz violations predicted by various models of quantum gravity. There are, however, technical problems in the EFT framework when it comes to ensuring that small Lorentz violations remain small--this is the essence of the "naturalness" problem. Herein we present an "emergent" spacetime model, based on the "analogue gravity" program, by investigating a specific condensed-matter system. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore, our model explicitly avoids the naturalness problem, and makes specific suggestions regarding how to construct a physically reasonable quantum gravity phenomenology.

  12. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

    PubMed Central

    Oueis, Emilia; Adamson, Catherine; Mann, Greg; Ludewig, Hannes; Redpath, Philip; Migaud, Marie

    2015-01-01

    Abstract Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID:26507241

  13. A simple analogue of lung mechanics.

    PubMed

    Sherman, T F

    1993-12-01

    A model of the chest and lungs can be easily constructed from a bottle of water, a balloon, a syringe, a rubber stopper, glass and rubber tubing, and clamps. The model is a more exact analogue of the body than the classic apparatus of Hering in two respects: 1) the pleurae and intrapleural fluid are represented by water rather than air, and 2) the subatmospheric "intrapleural" pressure is created by the elasticity of the "lung" (balloon) rather than by a vacuum pump. With this model, students can readily see how the lung is inflated and deflated by movements of the "diaphragm and chest" (syringe plunger) and how intrapleural pressures change as this is accomplished.

  14. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  15. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  16. Terrestrial analogues for lunar impact melt flows

    NASA Astrophysics Data System (ADS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2017-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pāhoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pāhoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  17. Current european regulatory perspectives on insulin analogues

    PubMed Central

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  18. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    PubMed

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  19. Effects of wortmannin, sodium nitroprusside, insulin, genistein, and guanosine triphosphate on chemotaxis and cell growth of Entodinium caudatum, Epidinium caudatum, and mixed ruminal protozoa.

    PubMed

    Diaz, H L; Knapp, J R; Karnati, S K R; Dehority, B A; Firkins, J L

    2014-01-01

    The mechanisms by which ruminal protozoa sense and migrate toward nutrients are not fully understood. Chemotaxis by many diverse eukaryotic cells is mediated by phosphatidylinositol-3-kinase, which is highly conserved in receptor tyrosine kinase (RTK) signaling pathways and consistently inhibited by wortmannin. In experiment 1a, increasing the concentration of wortmannin inhibited cell growth nonlinearly at 24h of a culture of the rumen protozoan Entodinium caudatum, but high variability prevented growth inhibition of Epidinium caudatum from reaching significance. In experiment 1b, increasing the insulin concentration recovered 24-h cell counts for both cultures, depending on wortmannin concentration. In experiment 2, addition of sodium nitroprusside (Snp; activator of protein kinase G for cilial beat reversal in nonrumen ciliate models) at 500µM or wortmannin at 200µM in beakers containing rumen fluid decreased random swimming by mixed entodiniomorphids into capillary tubes (inserted into beakers) containing saline. Both Snp and wortmannin increased chemotaxis into tubes containing glucose compared with the beaker control. For isotrichids, beaker treatments had no response. Glucose increased chemotaxis, but peptides decreased chemotaxis even when combined with glucose. In experiment 3, we assessed preincubation of genistein (a purported RTK blocker in nonrumen ciliate models) at 40 or 400µM in beakers and guanosine triphosphate (GTP; a universal chemorepellent in nonrumen ciliate models, perhaps mediated through an RTK) at 10 or 100µM combined with glucose in capillary tubes. Neither genistein nor GTP affected chemotaxis toward glucose for entodiniomorphids. However, GTP at 100µM reduced chemotaxis toward glucose for isotrichids. After the animal is fed, isotrichids that are depleted in glycogen migrate to the dorsal area of the rumen, and the rapid uptake of sugars is enhanced through strong chemotaxis but can be reversed by peptides or GTP. In contrast

  20. Effects of dietary administration of guanosine monophosphate on the growth, digestibility, innate immune responses and stress resistance of juvenile red sea bream, Pagrus major.

    PubMed

    Hossain, Md Sakhawat; Koshio, Shunsuke; Ishikawa, Manabu; Yokoyama, Saichiro; Sony, Nadia Mahjabin

    2016-10-01

    The present study explored the dietary administration effects of guanosine monophosphate (GMP) on growth, digestibility, innate immune responses and stress resistance of juvenile red sea bream, Pagrus major. A semi-purified basal diet supplemented with 0% (Control), 0.1% (GMP-0.1), 0.2% (GMP-0.2), 0.4% (GMP-0.4) and 0.8% (GMP-0.8) purified GMP to formulate five experimental diets. Each diet was randomly allocated to triplicate groups of fish (mean initial weight 3.4 g) for 56 days. The obtained results clearly indicated that, growth performance of red sea bream enhanced by dietary GMP supplementation compared to control and significantly higher final weight was found in fish fed diet group GMP-0.4. Specific growth rate (SGR) and percent weight gain (%WG) also significantly higher in diet group GMP-0.4 in compared to control and it was not differed (P > 0.05) with diet group GMP-0.8. Feed intake significantly increased with the supplementation of GMP. Feed conversion efficiency (FCE) and protein efficiency ratio (PER) also improved (P < 0.05) when fish fed the diets containing GMP and diet group GMP-0.4 showed the significantly higher value in compared to control. The Apparent digestibility coefficients (dry matter, protein and lipid) also improved by GMP supplementation and the significantly higher protein digestibility was observed in fish fed diet groups GMP-0.2, GMP-0.4 and GMP-0.8. Among the measured non specific immune parameters peroxidase activity (PA), respiratory burst activity (NBT), Bactericidal activity (BA) were significantly affected by dietary supplementation and highest value obtained in diet group GMP-0.4. Total serum protein, lysozyme activity (LA), and agglutination antibody titer also increased (P > 0.05) by GMP supplementation. In contrast, catalase activity decreased with GMP supplementation. In terms of oxidative stress GMP-0.2 showed best condition with low oxidative stress and high antioxidant level. Moreover, the fish fed GMP

  1. Genetic regulation of glycogen biosynthesis in Escherichia coli: in vitro effects of cyclic AMP and guanosine 5'-diphosphate 3'-diphosphate and analysis of in vivo transcripts.

    PubMed Central

    Romeo, T; Preiss, J

    1989-01-01

    Glycogen accumulation in Escherichia coli is inversely related to the growth rate and occurs most actively when cells enter the stationary phase. The levels of the three biosynthetic enzymes undergo corresponding changes under these conditions, suggesting that genetic control of enzyme biosynthesis may account for at least part of the regulation (J. Preiss, Annu. Rev. Microbiol. 38:419-458, 1984). We have begun to explore the molecular basis of this control by identifying factors which affect the expression of the glycogen genes and by determining the 5'-flanking regions required to mediate the regulatory effects. The in vitro coupled transcription-translation of two of the biosynthetic genes, glgC (ADPglucose pyrophosphorylase) and glgA (glycogen synthase), was enhanced up to 26- and 10-fold, respectively, by cyclic AMP (cAMP) and cAMP receptor protein (CRP). Guanosine 5'-diphosphate 3'-diphosphate stimulated the expression of these genes 3.6- and 1.8-fold, respectively. The expression of glgB (glycogen branching enzyme) was affected weakly or negligibly by the above-mentioned compounds. Assays which measured the in vitro formation of the first dipeptide of glgC showed that a restriction fragment which contained 0.5 kilobases of DNA upstream from the initiation codon supported cAMP-CRP-activated expression. Sequence-specific binding of cAMP-CRP to a 243-base-pair restriction fragment from the region upstream from glgC was observed by virtue of the altered electrophoretic mobility of the bound DNA. S1 nuclease protection analysis identified 5' termini of four in vivo transcripts within 0.5 kilobases of the glgC coding region. The relative concentrations of transcripts were higher in the early stationary phase than in the exponential phase. Two mutants which overproduced the biosynthesis enzymes accumulated elevated levels of specific transcripts. The 5' termini of three of the transcripts were mapped to a high resolution. Their upstream sequences showed weak

  2. Design of multi-epitope, analogue-based cancer vaccines.

    PubMed

    Fikes, John D; Sette, Alessandro

    2003-09-01

    The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.

  3. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  4. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    PubMed Central

    Verlee, Arno; Heugebaert, Thomas; van der Meer, Tom; Kerchev, Pavel I; Van Breusegem, Frank

    2017-01-01

    For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl)benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues. PMID:28326139

  5. Mars on Earth: soil analogues for future Mars missions

    NASA Astrophysics Data System (ADS)

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

    2008-04-01

    Preparations for missions to Mars are a major concern for scientists. Predicting how equipment and experiments will perform on the planet is difficult because tests are restricted to Earth. Mars soil analogues are being used to solve this problem. These terrestrial materials are chemically and physically similar to martian soils and, because they contain unusual minerals and trace amounts of organic matter, are scientifically interesting in their own right. However, no current analogue is appropriate for all necessary tests. Here we describe Mars soil analogues, identify limitations and suggest the need for new Mars simulants.

  6. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    PubMed

    Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Di Cesare Mannelli, Lorenzo; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; De Palma, Annalisa; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

    2016-10-04

    Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

  7. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    PubMed

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  8. Fluorescent polyene ceramide analogues as membrane probes.

    PubMed

    Nieves, Ingrid; Artetxe, Ibai; Abad, José Luis; Alonso, Alicia; Busto, Jon V; Fajarí, Lluís; Montes, L Ruth; Sot, Jesús; Delgado, Antonio; Goñi, Félix M

    2015-03-03

    Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.

  9. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  10. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

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

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

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

  12. Cell-cycle analyses using thymidine analogues in fission yeast.

    PubMed

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

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

  13. Weather and event generators based on analogues of atmospheric circulation

    NASA Astrophysics Data System (ADS)

    Yiou, Pascal

    2015-04-01

    Analogues of atmospheric circulation have had numerous applications on weather prediction, climate reconstructions and detection/attribution analyses. A stochastic weather generator based on circulation analogues was recently proposed by Yiou (2014) to simulate sequences of European temperatures. One of the features of this weather generator is that it preserves the spatial and temporal structures of the climate variables to be simulated. This method is flexible enough to be combined efficiently with a storm detection algorithm in order to generate large catalogues of high impact extra-tropical storms that hit Europe. I will present the gist of the method of circulation analogues and some performances. Two promising applications for weather generators based on this method (ensemble climate prediction and extra-tropical storms) will be tested. References Yiou, P.: AnaWEGE: a weather generator based on analogues of atmospheric circulation, Geosci. Model Dev., 7, 531-543, doi:10.5194/gmd-7-531-2014, 2014.

  14. Effect of glutamate analogues on brain tumor cell lines.

    PubMed

    Campbell, G L; Bartel, R; Freidman, H S; Bigner, D D

    1985-10-01

    Glutamate analogues have been used in many different experimental approaches in neurobiology. A small number of these analogues have been classified as gliotoxic. We have examined the effect of seven glutamate analogues (five gliotoxic and two neurotoxic) on the growth and viability of four human glioma cell lines, one human medulloblastoma cell line, and one human sarcoma cell line. Aminoadipic acid and homocysteic acid predominantly affected the growth of two glioma cell lines in the presence of 4 mM glutamine. Phosphonobutyric acid predominantly affected the other two glioma cell lines and the medulloblastoma cell line in the presence of 4 mM glutamine. In medium containing no glutamine, all three analogues had marked effects on all the cell lines except the sarcoma cell line. These effects were dose dependent. We postulate that these results can in part be explained on the basis of metabolic compartmentalization.

  15. A Non-Verbal Analogue to the Verbal Transformation Effect

    ERIC Educational Resources Information Center

    Lass, Norman J.; And Others

    1973-01-01

    Investigates the effectiveness of non-speech auditory stimuli in eliciting transformations analogous to those reported for speech stimuli to determine if a non-verbal analogue to the verbal transformation effect exists. (DD)

  16. Kinetic preference for the 3'-5'-linked dimer in the reaction of guanosine 5'-phosphorylmorpholinamide with deoxyguanosine 5'-phosphoryl-2-methylimidazolide as a function of poly(C) concentration

    NASA Technical Reports Server (NTRS)

    Kanavarioti, A.

    1998-01-01

    The formation of the internucleotide bond in diguanylate synthesis was studied in aqueous solution at pH 8 and 0.2 M Mg2+ in the presence and absence of polycytidylate, poly(C). The investigation was simplified by using guanosine 5'-phosphorylmorpholinamide, mor-pG, which can act only as a nucleophile, and deoxyguanosine 5'-phosphoryl-2-methylimidazolide, 2-MeImpdG, which can act only as an electrophile. The time-dependent product distribution was monitored by high-performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC/MS). In the absence of poly(C) the reaction between mor-pG and 2-MeImpdG yielded small amounts of the dimer mor-pGpdG with a regioselectivity of 2'-5':3'-5' = 3.5. In the presence of poly(C) dimer yields increased and a reversal in regioselectivity occurred; both effects were in proportion to the concentration of the polymer. The results can be quantitatively explained with the proposition that poly(C), acting as the template, catalyzes the reaction between template-bound monomers by about a factor of 4-5 over the reaction in solution and yields dimers with a regioselectivity of 2'-5':3'-5' approximately 0.33. These findings illustrate the intrinsic preference of guanosine monomers to correctly self-assemble on the appropriate template.

  17. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

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

  18. Adjuvant properties of a simplified C32 monomycolyl glycerol analogue.

    PubMed

    Bhowruth, Veemal; Minnikin, David E; Agger, Else Marie; Andersen, Peter; Bramwell, Vincent W; Perrie, Yvonne; Besra, Gurdyal S

    2009-04-01

    A simplified C(32) monomycolyl glycerol (MMG) analogue demonstrated enhanced immunostimulatory activity in a dioctadecyl ammonium bromide (DDA)/Ag85B-ESAT-6 formulation. Elevated levels of IFN-gamma and IL-6 were produced in spleen cells from mice immunised with a C(32) MMG analogue comparable activity to the potent Th1 adjuvant, trehalose 6,6'-di-behenate (TDB).

  19. Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

    PubMed

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

    2014-01-15

    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.

  20. Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

    PubMed

    Singh, Vijay P; Poon, Jia-fei; Engman, Lars

    2013-12-20

    In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

  1. Analogue and digital linear modulation techniques for mobile satellite

    NASA Technical Reports Server (NTRS)

    Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

    1990-01-01

    The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

  2. The relevance of analogue studies for understanding obsessions and compulsions.

    PubMed

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

    2014-04-01

    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.

  3. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  4. Analogue gravitational phenomena in Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2012-08-01

    Analogue gravity is based on the simple observation that perturbations propagating in several physical systems can be described by a quantum field theory in a curved spacetime. While phenomena like Hawking radiation are hardly detectable in astrophysical black holes, these effects may be experimentally tested in analogue systems. In this Thesis, focusing on Bose-Einstein condensates, we present our recent results about analogue models of gravity from three main perspectives: as laboratory tests of quantum field theory in curved spacetime, for the techniques that they provide to address various issues in general relativity, and as toy models of quantum gravity. The robustness of Hawking-like particle creation is investigated in flows with a single black hole horizon. Furthermore, we find that condensates with two (white and black) horizons develop a dynamical instability known in general relativity as black hole laser effect. Using techniques borrowed from analogue gravity, we also show that warp drives, which are general relativistic spacetimes allowing faster-than-light travel, are unstable. Finally, the cosmological constant issue is investigated from an analogue gravity perspective and relativistic Bose-Einstein condensates are proposed as new analogue systems with novel interesting properties.

  5. Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

    PubMed

    Satishkumar, Sakilam; Vuram, Prasanna K; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J; Montemayor, Michelle M Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K

    2015-10-09

    Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  6. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers.

    PubMed

    Liu, Yun; Lehn, Jean-Marie; Hirsch, Anna K H

    2017-02-21

    Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular

  7. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers

    PubMed Central

    2017-01-01

    Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition

  8. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  9. Terrestrial research in Mars analogue environments

    NASA Astrophysics Data System (ADS)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  10. Review of Insulin and its Analogues in Diabetes Mellitus

    PubMed Central

    Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

    2012-01-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  11. Fluorescent analogues of methotrexate: characterization and interaction with dihydrofolate reductase.

    PubMed

    Kumar, A A; Kempton, R J; Anstead, G M; Freisheim, J H

    1983-01-18

    The dansylated derivatives of lysine and ornithine analogues of methotrexate exhibit fluorescence properties characteristic of the dansyl moiety with an excitation at 328 nm and an emission maximum at 580 nm in aqueous media. As in the case of dansyl amino acids, the fluorescence emission is dependent upon the polarity of the medium. In solvents of low dielectric constant there is an enhancement of the dansyl fluorescence intensity as well as a shift to shorter wavelengths. The dansylated analogues show a reduction in the quantum yields as compared to N epsilon-dansyl-L-lysine and 5-(N,N-dimethylamino)-1-naphthalenesulfonic acid. The absorption spectra of the two dansyl analogues are similar to the spectra of the parent basic amino acid precursors but with reduced molar extinction values. The two fluorescent analogues of methotrexate were found to be potent inhibitors of purified dihydrofolate reductases from Lactobacillus casei and from chicken liver. The binding of these fluorescent analogues to either dihydrofolate reductase resulted in 10-15-nm blue shift of the ligand emission maxima and a 2-5-fold enhancement of the emission. These fluorescent properties of the bound ligands indicate a possible interaction of the dansyl moiety with a region on the enzyme molecule which is more hydrophobic relative to the surrounding solvent.

  12. Theoretical study on absorption and emission spectra of adenine analogues.

    PubMed

    Liu, Hongxia; Song, Qixia; Yang, Yan; Li, Yan; Wang, Haijun

    2014-04-01

    Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of four adenine analogues (termed as A1, A2, A3, and A4), and also consider the effects of aqueous solution and base pairing. The results show that the fluorescent adenine analogues can pair with thymine to form stable H-bonded WC base pairs. The excited geometries of both adenine analogues and WC base pairs are similar to the ground geometries. The absorption and emission maxima of adenine analogues are greatly red shifted compared with nature adenine, the oscillator strengths of A1 and A2 are stronger than A3 and A4 in both absorption and emission spectra. The calculated low-energy peaks in the absorption spectra are in good agreement with the experimental data. In general, the aqueous solution and base pairing can slightly red-shift both the absorption and emission maxima, and can increase the oscillator strengths of absorption spectra, but significantly decrease the oscillator strengths of A3 in emission spectra.

  13. Bioluminescent properties of obelin and aequorin with novel coelenterazine analogues.

    PubMed

    Gealageas, Ronan; Malikova, Natalia P; Picaud, Sandrine; Borgdorff, Aren J; Burakova, Ludmila P; Brûlet, Philippe; Vysotski, Eugene S; Dodd, Robert H

    2014-04-01

    The main analytical use of Ca(2+)-regulated photoproteins from luminous coelenterates is for real-time non-invasive visualization of intracellular calcium concentration ([Ca(2+)]i) dynamics in cells and whole organisms. A limitation of this approach for in vivo deep tissue imaging is the fact that blue light emitted by the photoprotein is highly absorbed by tissue. Seven novel coelenterazine analogues were synthesized and their effects on the bioluminescent properties of recombinant obelin from Obelia longissima and aequorin from Aequorea victoria were evaluated. Only analogues having electron-donating groups (m-OCH3 and m-OH) on the C6 phenol moiety or an extended resonance system at the C8 position (1-naphthyl and α-styryl analogues) showed a significant red shift of light emission. Of these, only the α-styryl analogue displayed a sufficiently high light intensity to allow eventual tissue penetration. The possible suitability of this compound for in vivo assays was corroborated by studies with aequorin which allowed the monitoring of [Ca(2+)]i dynamics in cultured CHO cells and in hippocampal brain slices. Thus, the α-styryl coelenterazine analogue might be potentially useful for non-invasive, in vivo bioluminescence imaging in deep tissues of small animals.

  14. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    PubMed

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

  15. Analogue peptides for the immunotherapy of human acute myeloid leukemia.

    PubMed

    Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R; Guinn, Barbara-Ann

    2015-11-01

    The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies.

  16. Synthesis and antioxidant activity of a procyanidin B3 analogue.

    PubMed

    Mizuno, Mirei; Nakanishi, Ikuo; Matsubayashi, Satoko; Imai, Kohei; Arai, Takuya; Matsumoto, Ken-Ichiro; Fukuhara, Kiyoshi

    2017-02-15

    Proanthocyanidin, an oligomer of catechin, is a natural antioxidant and a potent inhibitor of lectin-like oxidized LDL receptor-1, which is involved in the pathogenesis of arteriosclerosis. We synthesized proanthocyanidin analogue 1, in which the geometry of one catechin molecule in procyanidin B3, a dimer of (+)-catechin, is constrained to be planar. The antioxidant activities of the compounds were evaluated in terms of their capacities to scavenge galvinoxyl radicals, and results demonstrate that while procyanidin was 3.8 times more potent than (+)-catechin, the radical scavenging activity of proanthocyanidin analogue 1 was further increased to 1.9 times that of procyanidin B3. This newly designed proanthocyanidin analogue 1 may be a promising lead compound for the treatment of arteriosclerosis and related cerebrovascular diseases.

  17. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

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

  18. Design of novel CSA analogues as potential safeners and fungicides.

    PubMed

    Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

    2015-02-15

    Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues.

  19. Conception, synthesis, and biological evaluation of original discodermolide analogues.

    PubMed

    de Lemos, Elsa; Agouridas, Evangelos; Sorin, Geoffroy; Guerreiro, Antonio; Commerçon, Alain; Pancrazi, Ange; Betzer, Jean-François; Lannou, Marie-Isabelle; Ardisson, Janick

    2011-08-29

    Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.

  20. Migrastatin analogues target fascin to block tumour metastasis.

    PubMed

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

    2010-04-15

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

  1. Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue.

    PubMed

    Almaliti, Jehad; Al-Hamashi, Ayad A; Negmeldin, Ahmed T; Hanigan, Christin L; Perera, Lalith; Pflum, Mary Kay H; Casero, Robert A; Tillekeratne, L M Viranga

    2016-12-08

    A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp(3) to sp(2) at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

  2. Synthesis of daidzin analogues as potential agents for alcohol abuse.

    PubMed

    Gao, Guang-Yao; Li, Dian-Jun; Keung, Wing Ming

    2003-09-01

    Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.

  3. The Object-analogue approach for probabilistic forecasting

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

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

  4. The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test.

    PubMed

    Sakhaee, Ehsan; Ostadhadi, Sattar; Khan, Muhammad Imran; Yousefi, Farbod; Norouzi-Javidan, Abbas; Akbarian, Reyhaneh; Chamanara, Mohsen; Zolfaghari, Samira; Dehpour, Ahmad-Reza

    2017-01-01

    Depression is a devastating disorder which has a high impact on the wellbeing of overall society. As such, need for innovative therapeutic agents are always there. Most of the researchers focused on N-methyl-d-aspartate receptor to explore the antidepressant like activity of new therapeutic agents. Dextromethorphan is a cough suppressant agent with potential antidepressant activity reported in mouse force swimming test. Considering N-methyl-d-aspartate as a forefront in exploring antidepressant agents, here we focused to unpin the antidepressant mechanism of dextromethorphan targeting N-methyl-d-aspartate receptor induced nitric oxide-cyclic guanosine monophosphate signaling. Dextromethorphan administered at a dose of 10 and 30mg/kg i.p significantly reduced the immobility time. Interestingly, this effect of drug (30mg/kg) was inhibited when the animals were pretreated either with N-methyl-d-aspartate (75mg/kg), or l-arginine (750mg/kg) as a nitric oxide precursor and/or sildenafil (5mg/kg) as a phosphodiesterase 5 inhibitor. However, the antidepressant effect of Dextromethorphan subeffective dose (3mg/kg) was augmented when the animals were administered with either L-NG-Nitroarginine methyl ester (10mg/kg) non-specific nitric oxide synthase inhibitor, 7-Nitroindazole (30mg/kg) specific neural nitric oxide synthase inhibitor, MK-801 (0.05mg/kg) an N-methyl-d-aspartate receptor antagonist but not aminoguanidine (50mg/kg) which is specific inducible nitric oxide synthase inhibitor as compared to the drugs when administered alone. No remarkable effect on locomotor activity was observed during open field test when the drugs were administered at the above mentioned doses. Therefore, it is evident that the antidepressant like effect of Dextromethorphan is owed due to its inhibitory effect on N-methyl-d-aspartate receptor and NO- Cyclic guanosine monophosphate pathway.

  5. Antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a putative trace amine receptor ligand involves l-arginine-nitric oxide-cyclic guanosine monophosphate pathway.

    PubMed

    Dhir, Ashish; Kulkarni, S K

    2011-10-03

    1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol is a novel putative trace amine receptor modulator hypothesized to be useful for treatment-resistant depression. In our previous study, we have demonstrated the antidepressant-like effect of this molecule in mouse forced swim and tail suspension tests and shown to act via modulating the levels of norepinephrine, serotonin and dopamine. The present study attempts to explore the involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol in the mouse forced swim test. The antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (8 mg/kg, i.p) was reversed by pretreatment with L-arginine (750 mg/kg, i.p.), a nitric oxide precursor. In contrast, pretreatment with methylene blue (a soluble guanlyate cyclase inhibitor and nitric oxide synthase (NOS) inhibitor) or 7-nitroindazole (a specific neuronal NOS inhibitor) potentiated the antidepressant-like effect of sub-effective dose of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (2mg/kg, i.p.) in this test model. Furthermore, the antidepressant-like effect of this molecule (8 mg/kg, i.p.) was reversed by sildenafil (5mg/kg, i.p.), a phosphodiesterase inhibitor. In conclusion, the antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol involved L-arginine-nitric oxide-cyclic guanosine monophospate signaling pathway.

  6. On slow light as a black hole analogue

    NASA Astrophysics Data System (ADS)

    Unruh, W. G.; Schützhold, R.

    2003-07-01

    Although slow light (electromagnetically induced transparency) would seem an ideal medium in which to institute a “dumb hole” (black hole analogue), it suffers from a number of problems. We show that the high phase velocity in the slow light regime ensures that the system cannot be used as an analogue displaying Hawking radiation. Even though an appropriately designed slow-light setup may simulate classical features of black holes—such as horizon, mode mixing, “Bogoliubov” coefficients, etc.—it does not reproduce the related quantum effects.

  7. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  8. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

    PubMed Central

    Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  9. Retro-1 Analogues Differentially Affect Oligonucleotide Delivery and Toxin Trafficking.

    PubMed

    Yang, Bing; Ming, Xin; Abdelkafi, Hajer; Pons, Valerie; Michau, Aurelien; Gillet, Daniel; Cintrat, Jean-Christophe; Barbier, Julien; Juliano, Rudy

    2016-11-21

    Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both. This indicates that the molecular target(s) involved in the two processes are distinct.

  10. Synthesis and evaluation of heterocyclic analogues of bromoxynil.

    PubMed

    Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

    2014-01-15

    One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential

  11. Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

    PubMed

    Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

    2013-03-01

    A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work.

  12. Synthesis and antihistamine evaluations of novel loratadine analogues.

    PubMed

    Wang, Yue; Wang, Juan; Lin, Yan; Si-Ma, Li-Feng; Wang, Dong-hua; Chen, Li-Gong; Liu, Deng-Ke

    2011-08-01

    A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H(1) antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.

  13. Fluorescent diethylcarbamazine analogues: sites of accumulation in Brugia malayi.

    PubMed

    Junnila, Amy; Bohle, D Scott; Prichard, Roger; Perepichka, Inna; Spina, Carla

    2007-01-01

    New fluorescein and rhodamine B-labeled antifilarial drug DEC analogues for use in drug localization studies with confocal microscopy have been prepared by a high-yield three-step synthesis. The resulting beta-amine-substituted DEC analogue has a single ethyl substituent which is beta-aminated to accommodate the fluorophore of either fluorescein isothiocyananate or rhodamine B. Confocal microscopy is used to show that the drug accumulates in the adult filarial worms in the pharynx, esophagus, and near the nerve ring of all adults, as well as in the uteri and vulva and the testes of the females and males.

  14. Missions to Mars: Characterisation of Mars analogue rocks for the International Space Analogue Rockstore (ISAR)

    NASA Astrophysics Data System (ADS)

    Bost, Nicolas; Westall, Frances; Ramboz, Claire; Foucher, Frédéric; Pullan, Derek; Meunier, Alain; Petit, Sabine; Fleischer, Iris; Klingelhöfer, Göstar; Vago, Jorge L.

    2013-07-01

    Instruments for surface missions to extraterrestrial bodies should be cross-calibrated using a common suite of relevant materials. Such work is necessary to improve instrument performance and aids in the interpretation of in-situ measurements. At the CNRS campus in Orléans, the Observatoire des Sciences de l'Univers en région Centre (OSUC) has created a collection of well-characterised rocks and minerals for testing and calibrating instruments to be flown in space missions. The characteristics of the analogue materials are documented in an accompanying online database. In view of the recent and upcoming rover missions to Mars (NASA's 2011 Mars Science Laboratory (MSL) and ESA/Roscosmos' 2018 ExoMars), we are concentrating initially on materials of direct relevance to the red planet. The initial collection consists of 15 well-studied rock and mineral samples, including a variety of basalts (ultramafic, weathered, silicified, primitive), sediments (volcanic sands, chert, and a banded iron formation -BIF-), and the phyllosilicate nontronite (a clay). All the samples were characterised petrographically, petrologically, and geochemically using the types of analyses likely to be performed during in-situ missions, in particular ExoMars: hand specimen description; optical microscopy; mineralogical analysis by XRD, Raman and IR spectrometry; iron phase analysis by Mössbauer spectroscopy (MBS), elemental analysis by Energy-Dispersive X-ray spectroscopy (EDX), microprobe, Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and Mass Spectrometry (ICP-MS); and reduced carbon analysis by Raman spectrometry.

  15. [Oxazaphosphorinane drugs. New analogues, metabolic studies, and therapeutic approaches].

    PubMed

    Misiura, Konrad

    2004-01-01

    Recent studies on oxazaphosphorinane drugs, with the main focus on those carried out in Poland, are briefly reviewed. Research leading to the introduction of the new antitumor drug (S)-(-)-bromofosfamide are presented. The utility of phosphorus nuclear magnetic resonance in studies of ifosfamide metabolism and an application of analogues of the final, active metabolite of this drug in gene therapy are shown.

  16. An Analysis of an Autoclitic Analogue in Pigeons

    ERIC Educational Resources Information Center

    Kuroda, Toshikazu; Lattal, Kennon A.; García-Penagos, Andrés

    2014-01-01

    Using a conditional discrimination procedure, pigeons were exposed to a nonverbal analogue of qualifying autoclitics such as "definitely" and "maybe." It has been suggested that these autoclitics are similar to tacts except that they are under the control of private discriminative stimuli. Instead of the conventional assumption…

  17. A Macroscopic Analogue of the Nuclear Pairing Potential

    ERIC Educational Resources Information Center

    Dunlap, Richard A.

    2013-01-01

    A macroscopic system involving permanent magnets is used as an analogue to nucleons in a nucleus to illustrate the significance of the pairing interaction. This illustrates that the view of the total nuclear energy based only on the nucleon occupancy of the energy levels can yield erroneous results and it is only when the pairing interaction is…

  18. Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes.

    PubMed

    Tsyganov, Dmitry V; Krayushkin, Mikhail M; Konyushkin, Leonid D; Strelenko, Yuri A; Semenova, Marina N; Semenov, Victor V

    2016-04-22

    Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

  19. A Laboratory Analogue for the Study of Peer Sexual Harassment

    ERIC Educational Resources Information Center

    Mitchell, Damon; Hirschman, Richard; Angelone, D. J.; Lilly, Roy S.

    2004-01-01

    The purpose of this study was to develop a laboratory analogue for the study of peer sexual harassment, and to examine person and situational factors associated with male on female peer sexual harassment. One hundred twenty-two male participants were given the opportunity to tell jokes to a female confederate from a joke list that included…

  20. Interaction of tRNA with antitumor polyamine analogues.

    PubMed

    N'soukpoé-Kossi, C N; Ahmed Ouameur, A; Thomas, T; Thomas, T J; Tajmir-Riahi, H A

    2009-08-01

    We studied the interaction between tRNA and three polyamine analogues (1,11-diamino-4,8-diazaundecane.4HCl (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333)) using FTIR, UV-visible, and CD spectroscopic methods. Spectroscopic evidence showed that polyamine analogues bound tRNA via guanine N7, adenine, uracil O2, and the backbone phosphate (PO2-) groups, while the most reactive sites for biogenic polyamines were guanine N7/O6, adenine N7, uracil O2, and sugar 2'-OH groups as well as the backbone phosphate group. The binding constants of polyamine analogue-tRNA recognition were lower than those of the biogenic polyamine-tRNA complexes, with K333 = 2.8 (+/-0.5) x 10(4), K(BE-333) = 3.7 (+/-0.7) x 10(4), K(BE-3333) = 4.0 (+/-0.9) x 10(4), K(spm) = 8.7 (+/-0.9) x 10(5), K(spd) = 6.1 (+/-0.7) x 10(5), and K(put) = 1.0 (+/-0.3) x 10(5) mol/L. tRNA remained in the A-family conformation; however, it aggregated at high polyamine analogue concentrations.

  1. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions.

  2. Fluorescence Studies Of A Cholesterol-Analogue Probe

    NASA Astrophysics Data System (ADS)

    Drew, Jacinta; Szabo, Arthur G.; Morand, Peter

    1988-06-01

    A novel cholesterol-analogue probe1,2 with a diene-(2-naphthyl) fluorophore in the sidechain (Figure 1), hereafter referred to as DN-Chol, has had its steady-state and time-resolved fluorescence properties characterized in solvents and in various viscosity mineral oils.

  3. A new analogue of fatty alcohol from Tamarix hampeana L.

    PubMed

    Aykac, Ahmet; Akgül, Yurdanur

    2010-01-01

    New analogues of a long-chain secondary alcohol (1) and laserine (2) were isolated from the flowers of Tamarix hampeana L. The isolated compounds were identified using 1D and 2D NMR, LCMS/APCI, and chemical methods. Laserine was isolated for the first time from T. hampeana L.

  4. Cyclization of nucleotide analogues as an obstacle to polymerization

    NASA Technical Reports Server (NTRS)

    Hill, A. R. Jr; Nord, L. D.; Orgel, L. E.; Robins, R. K.

    1988-01-01

    Cyclization of activated nucleotide analogues by intramolecular phosphodiester-bond formation is likely to compete very effectively with template-directed condensation except in the cases of ribo- and arabinonucleotides. This could have excluded derivatives of most sugars from growing polyribonucleotide chains and thus reduced chain-termination in prebiotic polynucleotide synthesis.

  5. Synthesis of (+)-crocacin D and simplified bioactive analogues.

    PubMed

    Pasqua, Adele E; Ferrari, Frank D; Crawford, James J; Whittingham, William G; Marquez, Rodolfo

    2015-03-01

    The total synthesis of (+)-crocacin D has been achieved in 15 steps (9 isolated intermediates) and 14% overall yield from commercially available starting materials and using (+)-crocacin C as a key intermediate. A number of simplified analogues and their biological activities are also reported.

  6. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  7. q-bosons and the q-analogue quantized field

    NASA Technical Reports Server (NTRS)

    Nelson, Charles A.

    1995-01-01

    The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

  8. Thymidine analogues to assess microperfusion in human tumors

    SciTech Connect

    Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C. . E-mail: a.begg@nki.nl

    2005-07-15

    Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation.

  9. Vitamin D analogues: Potential use in cancer treatment.

    PubMed

    Duffy, Michael J; Murray, Alyson; Synnott, Naoise C; O'Donovan, Norma; Crown, John

    2017-04-01

    The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)2D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.

  10. Synthesis of chlorins, bacteriochlorins and their tetraaza analogues

    NASA Astrophysics Data System (ADS)

    Dudkin, S. V.; Makarova, E. A.; Lukyanets, E. A.

    2016-07-01

    The currently known methods for the synthesis of hydrogenated derivatives of synthetic porphyrins — chlorins, bacteriochlorins, isobacteriochlorins and their tetraaza analogues — are considered. Reactions involving quasi-isolated double bonds including reduction, oxidative addition and cycloaddition are presented. Examples of direct synthesis of these macroheterocycles are given. The bibliography includes 168 references.

  11. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

  12. Non-robust numerical simulations of analogue extension experiments

    NASA Astrophysics Data System (ADS)

    Naliboff, John; Buiter, Susanne

    2016-04-01

    Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

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

    NASA Astrophysics Data System (ADS)

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

    2014-12-01

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

  14. Biological evaluation of a novel sorafenib analogue, t-CUPM.

    PubMed

    Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

    2015-01-01

    Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.

  15. Sulphamoylated 2-Methoxyestradiol Analogues Induce Apoptosis in Adenocarcinoma Cell Lines

    PubMed Central

    Visagie, Michelle; Theron, Anne; Mqoco, Thandi; Vieira, Warren; Prudent, Renaud; Martinez, Anne; Lafanechère, Laurence; Joubert, Annie

    2013-01-01

    2-Methoxyestradiol (2ME2) is a naturally occurring estradiol metabolite which possesses antiproliferative, antiangiogenic and antitumor properties. However, due to its limited biological accessibility, synthetic analogues have been synthesized and tested in attempt to develop drugs with improved oral bioavailability and efficacy. The aim of this study was to evaluate the antiproliferative effects of three novel in silico-designed sulphamoylated 2ME2 analogues on the HeLa cervical adenocarcinoma cell line and estrogen receptor-negative breast adenocarcinoma MDA-MB-231 cells. A dose-dependent study (0.1–25 μM) was conducted with an exposure time of 24 hours. Results obtained from crystal violet staining indicated that 0.5 μM of all 3 compounds reduced the number of cells to 50%. Lactate dehydrogenase assay was used to assess cytotoxicity, while the mitotracker mitochondrial assay and caspase-6 and -8 activity assays were used to investigate the possible occurrence of apoptosis. Tubulin polymerization assays were conducted to evaluate the influence of these sulphamoylated 2ME2 analogues on tubulin dynamics. Double immunofluorescence microscopy using labeled antibodies specific to tyrosinate and detyrosinated tubulin was conducted to assess the effect of the 2ME2 analogues on tubulin dynamics. An insignificant increase in the level of lactate dehydrogenase release was observed in the compounds-treated cells. These sulphamoylated compounds caused a reduction in mitochondrial membrane potential, cytochrome c release and caspase 3 activation indicating apoptosis induction by means of the intrinsic pathway in HeLa and MDA-MB-231 cells. Microtubule depolymerization was observed after exposure to these three sulphamoylated analogues. PMID:24039728

  16. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

    PubMed

    Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

    2017-01-01

    3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.

  17. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  18. Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues.

    PubMed

    Yamashita, Ayako; Norton, Emily; Petersen, Peter J; Rasmussen, Beth A; Singh, Guy; Yang, Youjin; Mansour, Tarek S; Ho, Douglas M

    2003-10-06

    A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

  19. Synthesis of Nucleoside Analogues with Potential Antiviral Activity against Negative Strand RNA Virus Targets

    DTIC Science & Technology

    1989-11-01

    standing overnight. Washing the filtered crystals with ether removed triethylamine hydrochloride and triphenyl phosphine, then recrystallisation from...pyridine to from an ester, DMF and pyridinium hydrochloride . The reaction of the Vilsmeier reagent with (E)-5-(2-carboxyvinyl)uridine and quenching...include 2-deoxy-2-glucose (28), D- glucosamine (29) and tunicamycin (30). Deoxyglucose is utilized instead of glucose in the formation of guanosine

  20. Synthesis and antioxidant activity of peptide-based ebselen analogues.

    PubMed

    Satheeshkumar, Kandhan; Mugesh, Govindasamy

    2011-04-18

    A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

  1. An analogue conceptual rainfall-runoff model for educational purposes

    NASA Astrophysics Data System (ADS)

    Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

    2016-04-01

    Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

  2. Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

    PubMed

    Liu, Tao; Nair, Somarajan J; Lescarbeau, André; Belani, Jitendra; Peluso, Stéphane; Conley, James; Tillotson, Bonnie; O'Hearn, Patrick; Smith, Sherri; Slocum, Kelly; West, Kip; Helble, Joseph; Douglas, Mark; Bahadoor, Adilah; Ali, Janid; McGovern, Karen; Fritz, Christian; Palombella, Vito J; Wylie, Andrew; Castro, Alfredo C; Tremblay, Martin R

    2012-10-25

    Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.

  3. Noncommutative analogue Aharonov-Bohm effect and superresonance

    NASA Astrophysics Data System (ADS)

    Anacleto, M. A.; Brito, F. A.; Passos, E.

    2013-06-01

    We consider the idea of modeling a rotating acoustic black hole by an idealized draining bathtub vortex which is a planar circulating flow phenomenon with a sink at the origin. We find the acoustic metric for this phenomenon from a noncommutative Abelian Higgs model. As such the acoustic metric not only describes a rotating acoustic black hole but also inherits the noncommutative characteristic of the spacetime. We address the issues of superresonance and analogue Aharonov-Bohm (AB) effect in this background. We mainly show that the scattering of planar waves by a draining bathtub vortex leads to a modified AB effect and due to spacetime noncommutativity, the phase shift persists even in the limit where the parameters associated with the circulation and draining vanish. Finally, we also find that the analogue AB effect and superresonance are competing phenomena at a noncommutative spacetime.

  4. Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition.

    PubMed

    Arrowsmith, Merle; Böhnke, Julian; Braunschweig, Holger; Celik, Mehmet Ali; Claes, Christina; Ewing, William C; Krummenacher, Ivo; Lubitz, Katharina; Schneider, Christoph

    2016-09-05

    Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaromatic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient conditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6 π-aromatic diborabenzene compound, a 2 π-aromatic triplet biradical 1,3-diborete, and a phosphine-stabilized 2 π-homoaromatic 1,3-dihydro-1,3-diborete. DFT calculations suggest that all three compounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6 H6 and C4 H4 (2+) , and homoaromatic C4 H5 (+) .

  5. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    SciTech Connect

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V. )

    1989-08-01

    Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

  6. All-dielectric metasurface analogue of electromagnetically induced transparency.

    PubMed

    Yang, Yuanmu; Kravchenko, Ivan I; Briggs, Dayrl P; Valentine, Jason

    2014-12-16

    Metasurface analogues of electromagnetically induced transparency (EIT) have been a focus of the nanophotonics field in recent years, due to their ability to produce high-quality factor (Q-factor) resonances. Such resonances are expected to be useful for applications such as low-loss slow-light devices and highly sensitive optical sensors. However, ohmic losses limit the achievable Q-factors in conventional plasmonic EIT metasurfaces to values <~10, significantly hampering device performance. Here we experimentally demonstrate a classical analogue of EIT using all-dielectric silicon-based metasurfaces. Due to extremely low absorption loss and coherent interaction of neighbouring meta-atoms, a Q-factor of 483 is observed, leading to a refractive index sensor with a figure-of-merit of 103. Furthermore, we show that the dielectric metasurfaces can be engineered to confine the optical field in either the silicon resonator or the environment, allowing one to tailor light-matter interaction at the nanoscale.

  7. New homoisoflavonoid analogues protect cells by regulating autophagy.

    PubMed

    Gan, Li-She; Zeng, Lin-Wei; Li, Xiang-Rong; Zhou, Chang-Xin; Li, Jie

    2017-03-15

    As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective compounds with representative structure diversities were then evaluated for their neuroprotective effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadaverine (MDC) fluorescence staining methods and molecular docking studies indicated the action mechanism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.

  8. New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine

    SciTech Connect

    Sadek, S.A.; Basmadjian, G.P.; Hsu, P.M.; Rieger, J.A.

    1983-07-01

    Selenium-75 labeled selenonium analogues of dopamine, (2-(3,4-dimethoxyphenyl)ethyl)dimethylselenonium iodide and its dihydroxy analogue, were prepared by reducing (/sup 75/Se)selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the /sup 75/Se-labeled selenonium agents intravenously demonstrated high initial heart uptake. Prolonged adrenal retention and high adrenal to blood ratio of compound 4 were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

  9. Geoscience in Support of a Mars Methane Analogue Mission

    NASA Astrophysics Data System (ADS)

    Boivin, Alexandre

    The Mars Methane Analogue Mission, funded by the Canadian Space Agency through its Analogue Missions program, simulates a Mars rover mission whose purpose is to detect, analyse, and determine the source of methane emissions on the planet's surface. As part of this project, both an electromagnetic induction sounder (EMIS) and a high-resolution triangulation-based 3D laser scanner were tested in the field to demonstrate the benefit of including these instruments on future rover missions. EMIS data was inverted in order to derive information on the conductivity and magnetic susceptibility of the near subsurface. 3D laser scanner data was processed with fracture detection as a goal in order to simplify the search for areas of potential methane seepage. Both instruments were found to be very valuable for future rover missions of this type.

  10. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  11. Optical analogue of relativistic Dirac solitons in binary waveguide arrays

    SciTech Connect

    Tran, Truong X.; Longhi, Stefano; Biancalana, Fabio

    2014-01-15

    We study analytically and numerically an optical analogue of Dirac solitons in binary waveguide arrays in the presence of Kerr nonlinearity. Pseudo-relativistic soliton solutions of the coupled-mode equations describing dynamics in the array are analytically derived. We demonstrate that with the found soliton solutions, the coupled mode equations can be converted into the nonlinear relativistic 1D Dirac equation. This paves the way for using binary waveguide arrays as a classical simulator of quantum nonlinear effects arising from the Dirac equation, something that is thought to be impossible to achieve in conventional (i.e. linear) quantum field theory. -- Highlights: •An optical analogue of Dirac solitons in nonlinear binary waveguide arrays is suggested. •Analytical solutions to pseudo-relativistic solitons are presented. •A correspondence of optical coupled-mode equations with the nonlinear relativistic Dirac equation is established.

  12. Isobaric Analogue States Studied in Mirrored Fragmentation and Knockout Reactions

    SciTech Connect

    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.

    2010-05-21

    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.

  13. Animal analogues for the study of dental and oral diseases.

    PubMed

    Levy, B M

    1980-01-01

    The usual laboratory animals, such as rats and hamsters, may not fit the criteria for an analogue of human periodontal disease, although they may be useful in the study of dental caries. Rats, hamsters, mice, guinea pigs and rabbits have been the animals of choice in studies relating nutritional deficiencies and excesses to the dental and oral tissues. Gerbils, dogs, cats, horses, cows and fowl are useful in the study of mineralized tissues of teeth and bones. Recently, primate analogues have been developed for the study of periodontal diseaes and dental caries, the two most important dental diseases afflicting man. The use of a wide variety of laboratory animals in basic dental research makes it timely to review some of the guidelines for the selection of specific animals for particular diseases.

  14. Analogue Transformations in Physics and their Application to Acoustics

    PubMed Central

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

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

    SciTech Connect

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

    1994-12-31

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

  16. Neurological Effects of Bisphenol A and its Analogues

    PubMed Central

    Inadera, Hidekuni

    2015-01-01

    The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

  17. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

    PubMed Central

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps. PMID:27966660

  18. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps.

    PubMed

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-12-14

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

  19. Synthesis of dehydroepiandrosterone analogues modified with phosphatidic acid moiety.

    PubMed

    Smuga, Damian A; Smuga, Małgorzata; Swizdor, Alina; Panek, Anna; Wawrzeńczyk, Czesław

    2010-12-12

    Dehydroepiandrosterone (DHEA) and its metabolite 7α-OH DHEA have many diverse physiological, biological and biochemical effects encompassing various cell types, tissues and organs. In in vitro studies, DHEA analogues have myriad biological actions, but in vivo, especially in oral administration, DHEA produces far more limited clinical effects. One of the possible solutions of this problem is conversion of DHEA to active analogues and/or its transformation into prodrug form. In this article, the studies on the conversion of DHEA and 7α-OH DHEA into their phosphatides by the phosphodiester approach are described. In this esterification, N,N-dicyclohexylcarbodiimide (DCC) was the most efficient coupling agent as well as p-toluenesulphonyl chloride (TsCl).

  20. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

    PubMed Central

    Cardenas-Salas, Jersy

    2016-01-01

    Summary In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. Learning points: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues. Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment. This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients. PMID:27933171

  1. OptZyme: Computational Enzyme Redesign Using Transition State Analogues

    PubMed Central

    Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.

    2013-01-01

    OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli β-glucuronidase as a benchmark system, we confirm that KM correlates (R2 = 0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- β, D-glucuronide substrate, kcat/KM correlates (R2 = 0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2 = 0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- β, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- β, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

  2. Synthesis of a platform to access bistramides and their analogues.

    PubMed

    Commandeur, Malgorzata; Commandeur, Claude; Cossy, Janine

    2011-11-18

    The platform C14-C40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%. Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the versatility of the synthesis of the C14-C40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.

  3. Effect of lipophilicity on the pharmacokinetics of radiolabeled spiperone analogues

    SciTech Connect

    Moerlein, S.M.; Laufer, P.; Stocklin, G.

    1985-05-01

    Several radiolabeled analogues of the butyrophenone neuroleptic spiperone exhibit in vivo localization in D/sub 2/ receptor-rich areas of the brain. A series of N-alkylated spiperone analogues and the corresponding p-brominated compounds were synthesized to ascertain the optimum structure for labeling with /sup 18/F or /sup 75/Br. In vivo studies indicated that all analogues had D/sub 2/ receptor-binding affinity within the same order of magnitude (IC/sub 50/=2.6 nM for SP and 3.9 nM for BPSP), whereas the lipophilicity varied greatly (log P=2.7 for SP and 5.2 for BPSP). In vivo studies in the rat using the radiobrominated analogues were done using compounds labeled with n.c.a. /sup 77/Br via in-situ oxidation by dichloramine-T or H/sub 2/O/sub 2//CH/sub 3/COOH. Alkylation of BSP was found to decrease the striatum-to-cerebellum concentration at 6 hr from 8.2 for BSP to 5.2 for BPSP. Unexpectedly, the cerebral uptake did not increase with log P, the striatal concentration dropping from 390% MBC for BSP to 85% MBC for BPSP. This contrasts with previous results for SP and MSP, where the brain uptake increases slightly with log P. Increasing lipophilicity increases blood faster than brain concentrations, and it is concluded that whereas N-alkylation may be beneficial for /sup 18/F-labeld neuroleptics, non-alkylated spiperone is the optimum labeling substrate for /sup 75/Br.

  4. Bis(vinylenedithio)tetrathiafulvalene analogues of BEDT-TTF

    PubMed Central

    Demirtas, İlknur; Ozturk, Turan

    2015-01-01

    Summary This review aims to give an overview of the current status of our research on the synthesis of π-electron donor bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF, ET) analogues prepared from 1,8-diketones via a ring forming reaction. The new synthesized π-electron donors have vinyl moieties producing extended π-electron delocalization over the substituent phenyl rings at the peripheries. PMID:25977714

  5. Dimerization and DNA recognition rules of mithramycin and its analogues

    PubMed Central

    Weidenbach, Stevi; Hou, Caixia; Chen, Jhong-Min; Tsodikov, Oleg V.; Rohr, Jürgen

    2016-01-01

    The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2+)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents. PMID:26760230

  6. Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

    PubMed Central

    Nasomjai, Pitak; Slawin, Alexandra M Z

    2009-01-01

    Summary The synthesis of phosphonate analogues of ribose-1-phosphate and 5-fluoro-5-deoxyribose-1-phosphate is described. Preparations of both the α- and β-phosphonate anomers are reported for the ribose and 5-fluoro-5-deoxyribose series and a synthesis of the corresponding cyclic phostones of each α-ribose is also reported. These compounds have been prepared as tools to probe the details of fluorometabolism in S. cattleya. PMID:19777136

  7. Novel ynamide structural analogues and their synthetic transformations

    PubMed Central

    Lu, Ting; Hsung, Richard P.

    2015-01-01

    This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses. PMID:26280027

  8. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    DTIC Science & Technology

    2011-07-01

    the effects of DHB analogues to ascertain if they are longer-acting compounds than the parent compound. Although obtaining the first and only drug ...useful in the treatment of PD. Body of Work The goal of this study is to fully assess and compare the potency of compounds that are structurally...SARA 313: Carcinogenicity Classification (components present at 0.1% or more): none, unless listed below TSCA (US Toxic Substances Control Act

  9. Differential membrane fluidization by active and inactive cannabinoid analogues.

    PubMed

    Mavromoustakos, T; Papahatjis, D; Laggner, P

    2001-06-06

    The effects of the two cannabinomimetic drugs (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl-2-(hexyl)-1,3-dithiolane (AMG-3) and its pharmacologically less active 1-methoxy analogue (AMG-18) on the thermotropic and structural properties of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) liposomes have been studied by X-ray diffraction and differential scanning calorimetry (DSC). DSC data revealed that the incorporation of the drugs affect differently the thermotropic properties of DPPC. The presence of the more active drug distinctly broadened and attenuated both the pretransition and main phase transition of DPPC bilayers, while the inactive analogue had only minor effects. Small and wide angle X-ray diffraction data showed that the two cannabinoids have different effects on the lipid phase structures and on the hydrocarbon chain packing. The pharmacologically active analogue, AMG-3, was found to efficiently fluidize domains of the lipids in the L(beta)' gel phase, and to perturb the regular multibilayer lattice. In the liquid crystalline L(alpha) phase, AMG-3 was also found to cause irregularities in packing, suggesting that the drug induces local curvature. At the same concentration, the inactive AMG-18 had only minor structural effects on the lipids. At about 10-fold or higher concentrations, AMG-18 was found to produce similar but still less pronounced effects in comparison to those observed by AMG-3. The dose-dependent, different thermotropic and structural effects by the two cannabinoid analogues suggest that these may be related to their biological activity.

  10. Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

    PubMed Central

    Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P.; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

    2015-01-01

    Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

  11. Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.

    PubMed

    Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio

    2013-02-13

    The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine.

  12. Natural analogue studies as supplements to biomineralization research

    SciTech Connect

    McNeil, M.B.

    1995-09-01

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

  13. Analogue Investigations into Magma-Cryosphere Interactions on Mars

    NASA Astrophysics Data System (ADS)

    Tyson, S.; Wilson, L.; Lane, S. J.; Airey, M. W.; Gilbert, J. S.

    2011-12-01

    Many landforms and morphological features thought to have resulted from magma-cryosphere interactions have been identified on Mars. However, few experimental studies have been conducted to investigate the physical and thermal changes that should occur in the subsurface during these interactions. This project aims to begin to address this by conducting a series of laboratory analogue experiments. We introduce a heat source into a block of analogue cryosphere material (a carefully-prepared mixture of solid grains and ice) and record the thermal development within the block using thermocouples. We use these measurements to interpret the physical activity within the block, such as when and where phase changes occur, what sequence of shapes the developing melt region takes, and the extent of convection of any fluid phase H20. Blocks are also dissected after each run and documented photographically to record any physical movement of grains. Results will be used to constrain variables within a heat flow model that we are developing. This model will then be applied to the interpretation of landforms on Mars to help determine what set of processes could have realistically occurred during their formation. A second series of experiments will investigate surface morphological changes on the cryosphere analogue blocks. Resultant morphologies will be recorded and compared with existing martian landforms to again provide insight into formation processes.

  14. The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

    PubMed

    Ferronato, María Julia; Alonso, Eliana Noelia; Gandini, Norberto Ariel; Fermento, María Eugenia; Villegas, María Emilia; Quevedo, Mario Alfredo; Arévalo, Julián; López Romero, Alejandro; Rivadulla, Marcos Lois; Gómez, Generosa; Fall, Yagamare; Facchinetti, María Marta; Curino, Alejandro Carlos

    2016-10-01

    Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

  15. Design and synthesis of biotin analogues reversibly binding with streptavidin.

    PubMed

    Yamamoto, Tomohiro; Aoki, Kiyoshi; Sugiyama, Akira; Doi, Hirofumi; Kodama, Tatsuhiko; Shimizu, Yohei; Kanai, Motomu

    2015-04-01

    Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin's cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11% overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11% overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that KD values of these compounds for binding to streptavidin were 6.7×10(-6)  M and 1.7×10(-10)  M, respectively. These values were remarkably greater than that of biotin (KD =10(-15)  M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.

  16. Transdermal delivery of a melanotropic peptide hormone analogue

    SciTech Connect

    Dawson, B.V.; Hadley, M.E.; Kreutzfeld, K.; Dorr, R.T.; Hruby, V.J.; Al-Obeidi, F.; Don, S.

    1988-01-01

    We previously reported that topical application of (Nl3/sup 4/,D-Phe/sup 7/)alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders.

  17. Contact zones and hydrothermal systems as analogues to repository conditions

    SciTech Connect

    Wollenberg, H.A.; Flexser, S.

    1984-10-01

    Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

  18. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G. Saulnier and W. Statham

    2006-04-16

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. The Pena Blanca Natural Analogue Performance Assessment Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash-flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following analogous characteristics as compared to the Yucca Mountain repository site: (1) Analogous source--UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geology--(i.e. fractured, welded, and altered rhyolitic ash-flow tuffs); (3) Analogous climate--Semiarid to arid; (4) Analogous setting--Volcanic tuffs overlie carbonate rocks; and (5) Analogous geochemistry--Oxidizing conditions Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table.

  19. An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.

    PubMed

    Shang, Luqing; Wang, Yaxin; Qing, Jie; Shu, Bo; Cao, Lin; Lou, Zhiyong; Gong, Peng; Sun, Yuna; Yin, Zheng

    2014-12-01

    Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.

  20. Stereochemical Assignment of Strigolactone Analogues Confirms Their Selective Biological Activity.

    PubMed

    Artuso, Emma; Ghibaudi, Elena; Lace, Beatrice; Marabello, Domenica; Vinciguerra, Daniele; Lombardi, Chiara; Koltai, Hinanit; Kapulnik, Yoram; Novero, Mara; Occhiato, Ernesto G; Scarpi, Dina; Parisotto, Stefano; Deagostino, Annamaria; Venturello, Paolo; Mayzlish-Gati, Einav; Bier, Ariel; Prandi, Cristina

    2015-11-25

    Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.

  1. TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES

    PubMed Central

    Rizvi, Ali A.

    2016-01-01

    The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes. PMID:27918600

  2. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed Central

    Blumstein, Daniel T.; Davitian, Richard; Kaye, Peter D.

    2010-01-01

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses. PMID:20504815

  3. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed

    Blumstein, Daniel T; Davitian, Richard; Kaye, Peter D

    2010-12-23

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses.

  4. Noble gas encapsulation: clathrate hydrates and their HF doped analogues.

    PubMed

    Mondal, Sukanta; Chattaraj, Pratim Kumar

    2014-09-07

    The significance of clathrate hydrates lies in their ability to encapsulate a vast range of inert gases. Although the natural abundance of a few noble gases (Kr and Xe) is poor their hydrates are generally abundant. It has already been reported that HF doping enhances the stability of hydrogen hydrates and methane hydrates, which prompted us to perform a model study on helium, neon and argon hydrates with their HF doped analogues. For this purpose 5(12), 5(12)6(8) and their HF doped analogues are taken as the model clathrate hydrates, which are among the building blocks of sI, sII and sH types of clathrate hydrate crystals. We use the dispersion corrected and gradient corrected hybrid density functional theory for the calculation of thermodynamic parameters as well as conceptual density functional theory based reactivity descriptors. The method of the ab initio molecular dynamics (AIMD) simulation is used through atom centered density matrix propagation (ADMP) techniques to envisage the structural behaviour of different noble gas hydrates on a 500 fs timescale. Electron density analysis is carried out to understand the nature of Ng-OH2, Ng-FH and Ng-Ng interactions. The current results noticeably demonstrate that the noble gas (He, Ne, and Ar) encapsulation ability of 5(12), 5(12)6(8) and their HF doped analogues is thermodynamically favourable.

  5. Spin Alignment in Analogues of The Local Sheet

    NASA Astrophysics Data System (ADS)

    Conidis, George J.

    2016-10-01

    Tidal torque theory and simulations of large scale structure predict spin vectors of massive galaxies should be coplanar with sheets in the cosmic web. Recently demonstrated, the giants (K s <= -22.5 mag) in the Local Volume beyond the Local Sheet have spin vectors directed close to the plane of the Local Supercluster, supporting the predictions of Tidal Torque Theory. However, the giants in the Local Sheet encircling the Local Group display a distinctly different arrangement, suggesting that the mass asymmetry of the Local Group or its progenitor torqued them from their primordial spin directions. To investigate the origin of the spin alignment of giants locally, analogues of the Local Sheet were identified in the SDSS DR9. Similar to the Local Sheet, analogues have an interacting pair of disk galaxies isolated from the remaining sheet members. Modified sheets in which there is no interacting pair of disk galaxies were identified as a control sample. Galaxies in face-on control sheets do not display axis ratios predominantly weighted toward low values, contrary to the expectation of tidal torque theory. For face-on and edge-on sheets, the distribution of axis ratios for galaxies in analogues is distinct from that in controls with a confidence of 97.6% & 96.9%, respectively. This corroborates the hypothesis that an interacting pair can affect spin directions of neighbouring galaxies.

  6. Four-quadrant analogue multiplier using operational amplifier

    NASA Astrophysics Data System (ADS)

    Riewruja, Vanchai; Rerkratn, Apinai

    2011-04-01

    A method to realise a four-quadrant analogue multiplier using general-purpose operational amplifiers (opamps) as only the active elements is described in this article. The realisation method is based on the quarter-square technique, which utilises the inherent square-law characteristic of class AB output stage of the opamp. The multiplier can be achieved from the proposed structure with using either bipolar or complementary metal-oxide-semiconductor (CMOS) opamps. The operation principle of the proposed multiplier has been confirmed by PSPICE analogue simulation program. Simulation results reveal that the principle of proposed scheme provides an adequate performance for a four-quadrant analogue multiplier. Experimental implementations of the proposed multiplier using bipolar and CMOS opamps are performed to verify the circuit performances. Measured results of the experimental proposed schemes based on the use of bipolar and CMOS opamps with supply voltage ±2.4 V show the worst-case relative errors of 0.32% and 0.47%, and the total harmonic distortions of 0.47% and 0.98%, respectively.

  7. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  8. Bilateral Choroidal Metastases from Endobronchial Carcinoid Treated with Somatostatin Analogues

    PubMed Central

    De Bruyn, Deborah; Lamont, Jan; Vanderstraeten, Erik; Van Belle, Simon; Platteau, Elise; De Zaeytijd, Julie; Hoornaert, Kristien P.

    2016-01-01

    Objective: To describe a patient with bilateral multifocal choroidal metastases from an endobronchial carcinoid treated with a somatostatin analogue. Method: A 60-year-old woman presenting with photopsia in the left eye underwent an extensive ophthalmic examination, including fluorescein angiography, OCT and ultrasound. Results: Fundoscopy revealed a small retinal tear in the left eye, for which she received laser treatment. In addition, choroidal masses were detected in both eyes. Her medical history of a pneumectomy for a bronchial carcinoid six years earlier together with recent elevated chromogranin A blood levels prompted a diagnosis of choroidal metastases. Subsequently, a Gallium-68 DOTANOC positron emitting tomography/computer tomography scan revealed a spinal cord metastasis and mediastinal as well as mesenterial lymph node invasion. Systemic treatment with Sandostatin®, a somatostatin analogue was started. Up until two years after the initial presentation and treatment, these choroidal lesions remained stable without any signs of growth. Conclusion: Endobronchial carcinoid tumors have an indolent nature and long-term follow-up is recommended for early detection of metastases. Although treatment with somatostatin analogues rarely induces complete tumor regression, tumor stabilization and prevention of symptoms related to hormone secretion is achieved. This well-tolerated systemic treatment provides a worthy alternative treatment for choroidal metastasis compared to classic radiotherapy without any risk of radiation or laser-related visual loss. PMID:27843513

  9. Past and present of analogue modelling, and its future trend

    NASA Astrophysics Data System (ADS)

    Koyi, Hemin

    2015-04-01

    Since Hull (1815) published his article on modelling, analogue modelling has expanded to simulate both a wider range of tectonic regimes and target more challenging set-ups, and has become an integrated part of the fields of tectonics and structural geology. Establishment of new laboratories testifies for the increased attention the technique receives. The ties between modellers and field geoscientists have become stronger with the focus being on understanding the parameters that govern the evolution of a tectonic regime and the processes that dominate it. Since the first sand castle was built with damp sand on a beach, sand has proven to be an appropriate material analogue. Even though granular materials is the most widely used analogue material, new materials are also (re)introduced as rock analogues. Emphasis has been on more precise measurements of the mechanical properties of the materials and on minimizing the preparation effects, which have a great impact on scaling, interpretations and benchmarking. The analytical technique used to quantify model results has also seen a great deal of improvement. In addition to X-ray tomography used to visualise internal structures of models, new techniques (e.g. PIV, high-resolution laser scanning, and interferometry) have enabled monitoring kinematics with a higher precision. Benchmarking exercises have given modelling an additional checking tool by outlining, in addition to the rheology of the modelling materials, the impact of different preparation approaches, the effect of boundary conditions, and the human factor on model results. However, despite the different approaches and deformation rigs, results of models of different tectonic laboratories have shown a great deal of similarities. Even with the introduction of more sophisticated numerical codes and usage of more powerful computers which enable the simulation of more challenging material properties and combinations of those, and 3D model set-up, analogue modelling

  10. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G.J. Saulnier Jr; W. Statham

    2006-03-10

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. the Pena Blanca Natural Analogue Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following characteristics as compared to the Yucca Mountain repository site. (1) Analogous source: UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geologic setting: fractured, welded, and altered rhyolitic ash flow tuffs overlying carbonate rocks; (3) Analogous climate: Semiarid to arid; (4) Analogous geochemistry: Oxidizing conditions; and (5) Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table. The Nopal I deposit is approximately 8 {+-} 0.5 million years old and has been exposed to oxidizing conditions during the last 3.2 to 3.4 million years. The Pena Blanca Natural Analogue Model considers that the uranium oxide and uranium silicates in the ore deposit were originally analogous to uranium-oxide spent nuclear fuel. The Pena Blanca site has been characterized using field and laboratory investigations of its fault and fracture distribution, mineralogy, fracture fillings, seepage into the mine adits, regional hydrology, and mineralization that shows the extent of radionuclide migration. Three boreholes were drilled at the Nopal I mine site in 2003 and these boreholes have provided samples for lithologic characterization, water-level measurements, and water samples for laboratory

  11. Interglacial analogues of the Holocene and its natural near future

    NASA Astrophysics Data System (ADS)

    Yin, Qiuzhen; Berger, André

    2015-07-01

    In an attempt to find potential interglacial analogues of our present interglacial and its natural future, five interglacials (MIS-1, 5, 9, 11 and 19) are studied in terms of their astronomical characteristics, greenhouse gases concentration and climate simulated using both snapshot and transient experiments. Transient simulations covering a full range of obliquity, precession and eccentricity allow to develop an OPE index to estimate the climate sensitivity to astronomical forcing. They also show that obliquity and precession have different weight on the annual mean temperature and precipitation of different latitudinal zones, leading to varying phasing of these climate variables between different latitudes. However, the variations in boreal summer temperature of different latitudes (except the Southern Ocean) are in phase and are dominated by precession. All the interglacials are shown to be warmer than the natural climate of the present day and of the next centuries during boreal summer and for the annual mean temperature with varying duration and intensity. Such warming is mainly caused by changes in insolation, unlike the present global warming which mainly results from anthropogenic CO2 increase. The exceptionally long duration of MIS-11 is confirmed by our simulations, and it is demonstrated to be related to the long-lasting low eccentricity and high CO2 concentration and to the anti-phase relationship between obliquity maximum and precession minimum during MIS-11. As far as the variations of annual and seasonal temperatures are concerned, both snapshot and transient simulations show that MIS-19 is the best analogue of the present interglacial. MIS-11 is also a decent analogue when the impact of insolation alone is considered, but it is warmer than MIS-1 when the impact of CO2 is additionally included. Due to the large amplitude in the variations of insolation, MIS-5 and MIS-9 can hardly be considered as an analogue of the natural present-day climate and of

  12. Crystal structure of a nucleoside model for the inter­strand cross-link formed by the reaction of 2′-de­oxy­guanosine and an abasic site in duplex DNA

    PubMed Central

    Catalano, Michael J.; Ruddraraju, Kasi Viswanatharaju; Barnes, Charles L.; Gates, Kent S.

    2016-01-01

    The title compound, 9-[(2R,4S,5R)-4-hy­droxy-5-(hy­droxy­meth­yl)tetra­hydro­furan-2-yl]-2-{[(2R,4S,5R)-4-meth­oxy-5-(meth­oxy­meth­yl)tetra­hydro­furan-2-yl]amino}-1H-purin-6(9H)-one, C17H25N5O7, crystallizes with two independent mol­ecules (A and B) in the asymmetric unit. In the crystal, the guanosine moieties of mol­ecules A and B are linked by N—H⋯N and O—H⋯N hydrogen-bonding inter­actions, forming ribbons which are stacked to form columns along [100]. These columns are then linked by O—H⋯O hydrogen bonds between the ribose moieties and numerous C—H⋯O inter­actions to complete the three-dimensional structure. PMID:27308004

  13. Inhibition of insulin release by synthetic peptides shows that the H3 region at the C-terminal domain of syntaxin-1 is crucial for Ca(2+)- but not for guanosine 5'-[gamma-thio]triphosphate-induced secretion.

    PubMed Central

    Martin, F; Salinas, E; Vazquez, J; Soria, B; Reig, J A

    1996-01-01

    Recently, we have described the presence and possible role of syntaxin in pancreatic beta-cells by using monoclonal antibodies [F. Martin, F. Moya, L. M. Gutierrez, J.A. Reig, B. Soria (1995) Diabetologia 38, 860-863]. In order to characterize further the importance of specific domains of this protein, the functional role of a particular region of the syntaxin-1 molecule has now been investigated by using two synthetic peptides, SynA and SynB, corresponding to two portions of the H3 region at the C-terminal domain of the protein, residues 229-251 and 197-219 respectively. Functional experiments carried out in permeabilized pancreatic beta-cells demonstrate that these peptides inhibit Ca(2+)-dependent insulin release in a dose-dependent manner. This effect is specific because peptides of the same composition but random sequence do not show the same effect. In contrast with this inhibitory effect on Ca(2+)-induced secretion, both peptides increase basal release. However, under the same conditions, SynA and SynB do not affect guanosine 5'-[gamma-thio]triphosphate-induced insulin release. These results demonstrate that specific portions of the H3 region of syntaxin-1 are involved in critical protein-protein interactions specifically during Ca(2+)-induced insulin secretion. PMID:8947488

  14. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz Argandoña, J.; Errasti, I.

    2011-06-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields, surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built: (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributed to the analogues-calculation stage.

  15. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz de Argandoña, J.; Errasti, I.

    2011-02-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributted to the analogues-calculation stage.

  16. Quantitative comparisons of analogue models of brittle wedge dynamics

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido

    2010-05-01

    Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct implications for comparisons between structures in analogue models and natural field examples. All laboratories used the same frictional analogue materials (quartz and corundum sand) and prescribed model-building techniques (sieving and levelling). Although each laboratory used its own experimental apparatus, the same type of self-adhesive foil was used to cover the base and all the walls of the experimental apparatus in order to guarantee identical boundary conditions (i.e. identical shear stresses at the base and walls). Three experimental set-ups using only brittle frictional materials were examined. In each of the three set-ups the model was shortened by a vertical wall, which moved with respect to the fixed base and the three remaining sidewalls. The minimum width of the model (dimension parallel to mobile wall) was also prescribed. In the first experimental set-up, a quartz sand wedge with a surface slope of ˜20° was pushed by a mobile wall. All models conformed to the critical taper theory, maintained a stable surface slope and did not show internal deformation. In the next two experimental set-ups, a horizontal sand pack consisting of alternating quartz sand and corundum sand layers was shortened from one side by the mobile wall. In one of the set-ups a thin rigid sheet covered part of the model base and was attached to the mobile wall (i.e. a basal velocity discontinuity distant from the mobile wall). In the other set-up a basal rigid sheet was absent and the basal velocity discontinuity was located at the mobile wall. In both types of experiments

  17. Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted analogues.

    PubMed

    Thornton, T J; Jones, T R; Jackman, A L; Flinn, A; O'Connor, B M; Warner, P; Calvert, A H

    1991-03-01

    We report the synthesis of four new 4-thio-5,8-dideazafolic acid analogues and a 4-(methylthio) analogue structurally related to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. Three N10-propargyl-4-thio-5,8-dideazafolic acid analogues had C2 amino, hydrogen, and methyl substituents. A 4-thio and a 4-(methylthio) compound each with hydrogen at C2 and ethyl at N10 were also synthesized. In general, the synthetic route involved thionation of the appropriate 4-oxoquinazoline; the sulfur thus introduced was then protected by methylation. Further protection with a pivaloyl group was required for the quinazoline bearing a 2-amino substituent. The protected quinazolines were treated with N-bromosuccinimide and the resulting 6-(bromomethyl) compounds were then coupled to the appropriate N-monoalkylated diethyl N-(4-aminobenzoyl)-L-glutamate in N,N-dimethylacetamide with calcium carbonate as base. The 4-thio-5,8-dideazafolic acids were obtained by removal of the methylthio group with sodium hydrosulfide, followed by deprotection of the carboxyl groups with cold dilute alkali. For the compound containing a pivaloyl protecting group, hot dilute alkali was used. To obtain the 5,8-dideazafolic acid containing a 4-(methylthio) substituent, the corresponding diester was treated with lithium hydroxide which selectively deprotected the carboxyl groups. The five compounds were tested as inhibitors of L1210 TS. It was found that replacement of the 4-oxygen of the quinazoline moiety by sulfur did not alter the TS inhibition. However, the introduction of a methylthio substituent at position 4 severely impaired TS inhibition. All 4-thio compounds were less cytotoxic to L1210 cells in culture than their 4-oxo counterparts.

  18. Radio-protective effect of some new curcumin analogues.

    PubMed

    El-Gazzar, Marwa G; Zaher, Nashwa H; El-Hossary, Ebaa M; Ismail, Amel F M

    2016-09-01

    In the present study, novel symmetrical curcumin analogues (2-7) have been synthesized by substituting the phenolic OH of curcumin with different linkers providing additional keto-enol tautomerism, very essential for radioprotective activity. The structures of the synthesized compounds (2-7) were elucidated by elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data and were found consistent with the assigned structures. The curative effect of these new compounds, against the oxidative stress due to exposure of rats to the whole body γ-irradiation (7Gy) was investigated. Gamma-irradiated rats exhibited elevations of ALT, AST activities, urea, creatinine, triglycerides, total cholesterol, malondialdehyde (MDA), nitric oxide (NO), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and Nuclear Factor-kappa B (NF-κB) levels. Contrariwise, the total protein, albumin, total calcium level, SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Treatment of gamma-irradiated rats with the new curcumin analogues (2-7) showed significant amelioration in the in-vivo antioxidant status, liver and kidney functions, as well as the anti-inflammatory markers (IL-6, TNF-α and NF-κB). Inhibition of NF-κB could be responsible for the improvement of the antioxidant and anti-inflammatory status in gamma-irradiated animals, by down-regulation of IL-1β and TNF-α level. In conclusion, the new curcumin analogues (2-7) exhibited post-protective effect on gamma-irradiation, by NF-κB inhibition.

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

    SciTech Connect

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

    1988-10-05

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

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

    SciTech Connect

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

    2014-07-21

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

  1. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, M.; Schreurs, G.; Rosenau, M.; Kemnitz, H.

    2016-08-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between c. 100 and 400 μm. Analysis of grain shape factors shows that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling. Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil. Most materials have an internal cohesion in the order of 20-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C < 20 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density after sifting, which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains.

  2. Integration of inherent and induced chirality into subphthalocyanine analogue

    NASA Astrophysics Data System (ADS)

    Zhao, Luyang; Qi, Dongdong; Wang, Kang; Wang, Tianyu; Han, Bing; Tang, Zhiyong; Jiang, Jianzhuang

    2016-06-01

    Conventional conjugated systems are characteristic of only either inherent or induced chirality because of synthetic challenge in combination of chiral segment into the main chromophore. In this work, chiral binaphthyl segment is directly fused into the central chromophore of a subphthalocyanine skeleton, resulting in a novel type of chiral subphthalocyanine analogue (R/S)-1 of integrated inherent and induced chirality. Impressively, an obviously enhanced optical activity is discerned for (R/S)-1 molecules, and corresponding enhancement mechanism is elucidated in detail. The synthesis strategy based on rational molecular design will open the door towards fabrication of chiral materials with giant optical activity, which will have great potential in chiroptical devices.

  3. Stepwise analogue downscaling for hydrology (SANDHY): validation experiments over France

    NASA Astrophysics Data System (ADS)

    Radanovics, Sabine; Vidal, Jean-Philippe; Sauquet, Eric; Ben Daoud, Aurélien; Bontron, Guillaume

    2014-05-01

    Statistical downscaling aims at finding relationships between local precipitation (predictand) and large-scale predictor fields, in various contexts, from medium-term forecasting to climate change impact studies. One of the challenges of statistical downscaling in a climate change context is that the predictor-predictand relationship should still be valid under climate change conditions. A minimum requirement is therefore to test the performance of the downscaling method on independent data under current climate conditions. The downscaling method considered is the Stepwise ANalog Downscaling method for HYdrology (SANDHY). ERA-40 reanalysis data are used as large scale predictors and daily precipitation from the French near surface reanalysis (Safran) as predictand. Two 20-year periods have been selected from the common archive period of the two data sources: 1958-1978 ('early') and 1982-2002 ('late'). SANDHY has been optimised over the late period in terms of geopotential predictor domains individually for 608 target zones covering France. The validation setup consists of 4 experiments, that all use the parameters as optimised for the late period and that are compared in terms of continous ranked probability skill score (CRPSS) with climatology as reference: Reference simulation. A simulation of the late period is performed using the late period as an archive for searching the analogue dates, thus representing the best possible case. The CRPSS shows a spatial distribution similar to the one of the mean precipitation. Out-of-sample validation. The early period is simulated using the late period as an archive for searching the analogue dates. The idea is to simulate a period whose local data is not 'known' by the model as it would be the case in any application. The average skill loss compared to the reference simulation is reasonable with some more skill loss in the northern part of the country and no loss in the southeastern part. Alternative archive. The late

  4. Organofluorine Isoselenocyanate Analogues of Sulforaphane: Synthesis and Anticancer Activity.

    PubMed

    Cierpiał, Tomasz; Łuczak, Jerzy; Kwiatkowska, Małgorzata; Kiełbasiński, Piotr; Mielczarek, Lidia; Wiktorska, Katarzyna; Chilmonczyk, Zdzisław; Milczarek, Małgorzata; Karwowska, Katarzyna

    2016-10-07

    A series of previously unknown sulforaphane analogues with organofluorine substituents bonded to the sulfinyl sulfur atom, an isoselenocyanate moiety in place of the isothiocyanate group, the central sulfur atom in various oxidation states, and different numbers of methylene groups in the central alkyl chain were synthesized and fully characterized. All new compounds were tested for their biological properties in vitro and demonstrated much higher anticancer activity against two breast cancer cell lines than that shown by native sulforaphane; at the same time, the compounds were less toxic for normal cells. The influence of the particular structural changes in the molecules on the cytotoxicity is discussed.

  5. Antineoplastic Efficacy of Novel Polyamine Analogues in Human Breast Cancer

    DTIC Science & Technology

    2007-06-01

    Principles of Molecular Medicine (2nd ed). Runge, M., and Patterson, WC. (eds), Humana Press, 2006. 2. Huang, Y., Pledgie A.M., Casero , R.A., Davidson...Dunn, V.R., Hacker, A., Frydman, B., Kink J.A., Valasinas, A.L., Reddy, V.K., Marton, L.J., Casero , R.A., and Davidson, N.E. A Novel Polyamine...E.R., Smith, R., Frydman, B., Valasinas, A.L., Reddy, V.K., Marton, L.J., Casero , R.A., and Davidson, N.E. Regulation of polyamine analogue

  6. The Canadian space agency planetary analogue materials suite

    NASA Astrophysics Data System (ADS)

    Cloutis, Edward A.; Mann, Paul; Izawa, Matthew R. M.; Applin, Daniel M.; Samson, Claire; Kruzelecky, Roman; Glotch, Timothy D.; Mertzman, Stanley A.; Mertzman, Karen R.; Haltigin, Timothy W.; Fry, Christopher

    2015-12-01

    The Canadian Space Agency (CSA) recently commissioned the development of a suite of over fifty well-characterized planetary analogue materials. These materials are terrestrial rocks and minerals that are similar to those known or suspected to occur on the lunar or martian surfaces. These include: Mars analogue sedimentary, hydrothermal, igneous and low-temperature alteration rock suites; lunar analogue basaltic and anorthositic rock suites; and a generic impactite rock suite from a variety of terrestrial impact structures. Representative thin sections of the materials have been characterized by optical microscopy and electron probe microanalysis (EPMA). Reflectance spectra have been collected in the ultraviolet, visible, near-infrared and mid-infrared, covering 0.2-25 μm. Thermal infrared emission spectra were collected from 5 to 50 μm. Raman spectra with 532 nm excitation, and laser-induced fluorescence spectra with 405 nm excitation were also measured. Bulk chemical analysis was carried out using X-ray fluorescence, with Fe valence determined by wet chemistry. Chemical and mineralogical data were collected using a field-portable Terra XRD-XRF instrument similar to CheMin on the MSL Curiosity rover. Laser-induced breakdown spectroscopy (LIBS) data similar to those measured by ChemCam on MSL were collected for powdered samples, cut slab surfaces, and as depth profiles into weathered surfaces where present. Three-dimensional laser camera images of rock textures were collected for selected samples. The CSA intends to make available sample powders (<45 μm and 45-1000 μm grain sizes), thin sections, and bulk rock samples, and all analytical data collected in the initial characterisation study to the broader planetary science community. Aiming to complement existing planetary analogue rock and mineral libraries, the CSA suite represents a new resource for planetary scientists and engineers. We envision many potential applications for these materials in the

  7. Astrobiology Field Research in Moon/Mars Analogue Environments: Preface

    NASA Technical Reports Server (NTRS)

    Foing, B. H.; Stoker, C.; Ehrenfreund, P.

    2011-01-01

    Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

  8. Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity.

    PubMed

    Rodriguez, Cristian R; Alvarez, Lautaro D; Dansey, M Virginia; Paolo, Luciano S; Veleiro, Adriana S; Pecci, Adali; Burton, Gerardo

    2017-01-01

    Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the

  9. B38: an all-boron fullerene analogue

    NASA Astrophysics Data System (ADS)

    Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

    2014-09-01

    Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. Electronic supplementary information

  10. Isobrassinin and its analogues: novel types of antiproliferative agents.

    PubMed

    Csomós, Péter; Zupkó, István; Réthy, Borbála; Fodor, Lajos; Falkay, George; Bernáth, Gábor

    2006-12-15

    Isobrassinin (2-(S-methyldithiocarbamoylaminomethyl)indole (7a), a regioisomer of the cruciferous phytoalexin brassinin (1), exerted marked antiproliferative effects on the HeLa, A431 and MCF7 cell lines (>78.6% inhibition at 30muM). For structure-activity relationships, further analogues were synthesized. The highest cytotoxic effect was displayed by 2-phenylimino-1,3-thiazino[5,6-b]indole (10) (10 microM, 76.8%-HeLa and 46.3%-MCF7). The effect of the natural phytoalexin brassinin was also determined.

  11. Pena blanca natural analogue project: summary of activities

    SciTech Connect

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

    2010-12-08

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

  12. Pena Blanca Natural Analogue Project: Summary of activities

    SciTech Connect

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

    2011-02-01

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

  13. Ultraviolet variability of the solar analogue star Alpha Centauri A

    NASA Technical Reports Server (NTRS)

    Sofia, Ulysses J.; Bruhweiler, Frederick C.; Sofia, Sabatino

    1989-01-01

    Fifty-seven observations of the solar analogue Alpha Centauri A made by the IUE over a 3-year interval have been examined for variability. It is found that the UV continuum flux of this star in the 1715- to 1915-A range varies by as much as 19 percent. However, nearly all of this range in variability can occur within one stellar rotation period. Consequently, if Alpha Cen A undergoes a stellar activity cycle similar to that of the sun, the results indicate that the amplitude of this modulation is small, contrary to recently proposed empirical (theoretical) models of solar activity.

  14. Resist outgassing contamination on EUV multilayer mirror analogues

    NASA Astrophysics Data System (ADS)

    Alvarado, Diego; Kandel, Yudhishthir; Sohn, Jaewoong; Chakraborty, Tonmoy; Ashworth, Dominic; Denbeaux, Gregory

    2014-04-01

    EUV lithography is a technology enabling next generation electronic devices, but issues with photoresist sensitivity, resolution and line edge roughness as well as tool downtime and throughput remain. As part of the industry's efforts to address these problems we have worked with resist suppliers to quantify the relative contamination rate of a variety of resists on EUV multilayer mirror analogues following ASML approved protocols. Here we present results of our ongoing program to better understand the effect of process parameters such as dose and resist thickness on the contamination rate of ruthenium coated witness plates, additionally we present results from a study on the effectiveness of hydrogen cleaning.

  15. Investigation of HVDC inverter with series compensation on analogue simulator

    SciTech Connect

    Nyati, S.; Gueth, G. ); Mathur, R.M. ); Koschik, V. )

    1990-04-01

    HVdc converters connected into weak ac systems require effective application of voltage control devices to ensure satisfactory voltage control and recovery following disturbances. Both an MOV arrangement and a series capacitor were found to be potentially very cost effective solutions in investigations using digital simulation. However, although the series capacitor performed well in controlling temporary overvoltage following HVdc load rejection, satisfactory recovery from faults was difficult to obtain. This paper presents a follow-up study which uses a state-of-the-art analogue simulator to further investigate the performance of the MOV and series capacitor arrangements, especially the fault recovery performance of the latter.

  16. Oxazole-bridged combretastatin A analogues with improved anticancer properties.

    PubMed

    Biersack, Bernhard; Effenberger, Katharina; Schobert, Rainer; Ocker, Matthias

    2010-03-01

    Three new oxazole-bridged combretastatin A analogues with additional functional groups at the B-ring [-SMe, -OH, p-quinone] were tested for antiproliferative activity and specificity on human HL-60 leukemia, 518A2 melanoma, and colon carcinomas HCT-116 (wt)/(p53(-/-)) and HT-29 cells. While all oxazoles, except quinone 8, were efficacious against HCT-116 cells at submicromolar IC(50) values (48 h incubation), only thioanisole 5 achieved this potency in combretastatin-refractory HT-29 cells by significant upregulation of p21(cip1/waf1) associated with an S/G(2) cell-cycle arrest.

  17. Biological activity of silylated amino acid containing substance P analogues.

    PubMed

    Cavelier, F; Marchand, D; Martinez, J; Sagan, S

    2004-03-01

    The need to replace natural amino acids in peptides with nonproteinogenic counterparts to obtain new medicinal agents has stimulated a great deal of innovation on synthetic methods. Here, we report the incorporation of non-natural silylated amino acids in substance P (SP), the binding affinity for the two hNK-1 binding sites and, the potency to stimulate phospholipase C (PLC) and adenylate cyclase of the resulting peptide. We also assess the improvement of their stability towards enzyme degradation. Altogether, we found that replacing glycine with silaproline (Sip) in position 9 of SP leads to a potent analogue exhibiting an increased resistance to angiotensin-converting enzyme hydrolysis.

  18. Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues

    PubMed Central

    Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong

    2014-01-01

    A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

  19. Stimulated emission in black holes and in analogue gravity

    NASA Astrophysics Data System (ADS)

    Belgiorno, F.; Cacciatori, S. L.

    2016-11-01

    Stimulated emission by black holes is discussed in light of the analogue gravity program. We first consider initial quantum states containing a definite number of particles, and then we take into account the case where the initial state is a coherent state. The latter case is particularly significant in the case where Hawking radiation is studied in dielectric black holes, and the emission is stimulated by a laser probe. We are particularly interested in the case of the electromagnetic field, for which examples of stimulated radiation are considered.

  20. α-Azido bisphosphonates: synthesis and nucleotide analogues

    PubMed Central

    Chamberlain, Brian T.; Upton, Thomas G.; Kashemirov, Boris A.

    2011-01-01

    The first examples of α-azido bisphosphonates [(RO)2P(O)]2CX(N3) (1, R = i-Pr, X = Me; 2, R = i-Pr, X = H; 3, R = H, X = Me; 4, R = H, X = H) and corresponding β,γ-CX(N3) dGTP (5–6) and α,β-CX(N3) dATP (7–8) analogues are described. The individual diastereomers of 7 (7a, 7b) were obtained by HPLC separation of the dADP synthetic precursor (14a/b). PMID:21462930

  1. Novel nicotine analogues with potential anti-mycobacterial activity.

    PubMed

    Gandhi, Paresh T; Athmaram, Thimmasandra Narayanappa; Arunkumar, Gundaiah Ramesh

    2016-04-15

    Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations.

  2. Frequency converter implementing an optical analogue of the cosmological redshift.

    PubMed

    Ginis, Vincent; Tassin, Philippe; Craps, Ben; Veretennicoff, Irina

    2010-03-01

    According to general relativity, the frequency of electromagnetic radiation is altered by the expansion of the universe. This effect-commonly referred to as the cosmological redshift--is of utmost importance for observations in cosmology. Here we show that this redshift can be reproduced on a much smaller scale using an optical analogue inside a dielectric metamaterial with time-dependent material parameters. To this aim, we apply the framework of transformation optics to the Robertson-Walker metric. We demonstrate theoretically how perfect redshifting or blueshifting of an electromagnetic wave can be achieved without the creation of sidebands with a device of finite length.

  3. Analysis of Vitamins D, Their Metabolites and Analogues

    NASA Astrophysics Data System (ADS)

    Makin, Hugh L. J.; Jones, Glenville; Kaufmann, Martin; Calverley, Martin J.

    The analysis of vitamins D and their metabolites and analogues has been reviewed by us on two occasions (Makin et al., 1995; Jones and Makin, 2000) over the last 10-15 years. In this chapter, we have drawn heavily on the 2000 review, up-dating it to take account of the developments in methodology that have occurred in the intervening years, but including elements of our 1995 review so that the reader can get a picture of the historical context as well as the modern developments.

  4. Captopril analogues as metallo-β-lactamase inhibitors.

    PubMed

    Yusof, Yusralina; Tan, Daniel T C; Arjomandi, Omid Khalili; Schenk, Gerhard; McGeary, Ross P

    2016-03-15

    A number of captopril analogues were synthesised and tested as inhibitors of the metallo-β-lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.

  5. Large scale biosynthesis of ganglioside analogues by RERF-LC-AI cells cultured in HYPERFlask.

    PubMed

    Shimura, Yumiko; Suzuki, Junya; Muraoka, Miho; Kasuya, Maria Carmelita Zulueta; Matsuoka, Koji; Hatanaka, Kenichi

    2012-01-01

    The efficient production of ganglioside analogues was accomplished using RERF-LC-AI cells cultured in HYPERFlask (High Yield PERformance Flask). Eight kinds of ganglioside analogues (GM3, GM2, sialylparagloboside, GD3, di-sialylated lacto-N-tetraose, and another three kinds of analogues with intricate structures) were synthesized by the saccharide primer method using lung squamous-cell carcinoma line RERF-LC-AI and 12-azidododecyl β-lactoside primer. The yield for each analogue obtained using HYPERFlask was higher than yields obtained from 100-mm dishes.

  6. Neurotoxicity of acrylamide and its analogues and effects of these analogues and other agents on acrylamide neuropathy.

    PubMed Central

    Edwards, P M

    1975-01-01

    N-Hydroxymethylacrylamide, N-methylacrylamide, and N,N-diethylacrylamide produce peripheral neuropathy in rats. Seven other compounds related to acrylamide do not produce neuropathy. Rats given one of the three neurotoxic compounds are more susceptible to acrylamide. A regime for testing acrylamide analogues for neuro-toxicity is suggested. DDT, phenobarbitone, or high dietary concentrations of vitamin A or E have no effect on the development of acrylamide neuropathy in rats. Acrylamide produces neuropathy in hens but not in frogs or goldfish. PMID:164879

  7. Historical space psychology: Early terrestrial explorations as Mars analogues

    NASA Astrophysics Data System (ADS)

    Suedfeld, Peter

    2010-03-01

    The simulation and analogue environments used by psychologists to circumvent the difficulties of conducting research in space lack many of the unique characteristics of future explorations, especially the mission to Mars. This paper suggests that appropriate additional analogues would be the multi-year maritime and terrestrial explorations that mapped the surface of the Earth in previous centuries. These, like Mars, often involved a hazardous trek through unknown territory, flanked by extended, dangerous voyages to and from the exploration sites. Characteristic issues included interpersonal relationships under prolonged stress, stretches of boredom interspersed with intense work demands, the impossibility of rescue, resupply, or other help from home, chronic danger, physical discomfort and lack of privacy, and the crucial role of the leader. Illustrative examples of one important factor, leadership style, are discussed. The examination of such expeditions can help to identify the psychological stressors that are likely to be experienced by Mars explorers, and can also indicate countermeasures to reduce the damaging impact of those stressors.

  8. Metabolites of saxitoxin analogues in bivalves contaminated by Gymnodinium catenatum.

    PubMed

    Vale, Paulo

    2010-01-01

    Bivalve metabolites of saxitoxin analogues, not present in microalgae, were recently described as an important toxin fraction in mussels contaminated by Alexandrium tamarense. These possess very low fluorescence, and require mass spectrometry detection. HILIC-MS was implemented to look for these metabolites in bivalves contaminated during Gymnodinium catenatum blooms at the Portuguese coast. The presence of M1 was tentatively identified in several bivalves, ranging from estuarine (Mytilus galloprovinciallis, Cerastoderma edule and Ruditapes decussatus) to oceanic habitat (Donax trunculus and Ensis spp.). It was hypothesized that M1 could contribute to an important fraction of the profile of STX analogues. M1 was more abundant in estuarine bivalves that retain longer PSP toxins, in the following order: mussels>cockles>clams. These data highlight that the study by fluorimetry alone of the carbamoyl, N-sulfocarbamoyl, and decarbamoyl families is manifestly insufficient to fully understand toxin dynamics in bivalves feeding on G. catenatum without a proper study of hydroxybenzoate and hydroxylated M-toxins.

  9. Carbon storage at defect sites in mantle mineral analogues

    NASA Astrophysics Data System (ADS)

    Wu, Jun; Buseck, Peter R.

    2013-10-01

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

  10. A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

    PubMed Central

    2015-01-01

    Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1–/– cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease. PMID:24707965

  11. A selective phenelzine analogue inhibitor of histone demethylase LSD1.

    PubMed

    Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A; Basso, Manuela; Givens, Jeffrey; Li, Xin; Hu, Jianfei; Taylor, Martin S; Cieniewicz, Anne M; Hsiao, Po-Yuan; Huang, Rong; Roberson, Heather; Adejola, Nkosi; Avery, Lindsay B; Casero, Robert A; Taverna, Sean D; Qian, Jiang; Tackett, Alan J; Ratan, Rajiv R; McDonald, Oliver G; Feinberg, Andrew P; Cole, Philip A

    2014-06-20

    Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.

  12. Synthesis of 5-azacastanospermine, a conformationally restricted azafagomine analogue.

    PubMed

    Søndergaard, K; Liang, X; Bols, M

    2001-06-01

    The 5-aza-6-deoxy analogue of castanospermine (+/-)-5a and its 1-epimer (+/-)-5b was synthesized. The synthesis started from the known compound 5-benzyloxy-7-hydroxyhepta-1,3-diene, which was protected and subjected to Diels-Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to give two epimeric adducts. One of these was transformed through epoxidation, acetolysis, a series of side-chain transformations that converted it into a terminally protected aldehyde, deprotection, and hydrogenolysis/reductive amination into 5a. By a similar set of reactions the other adduct epimer was converted into 5b. The castanospermine analogue 5a was a weaker inhibitor of almond beta-glucosidase and rice alpha-glucosidase than castanospermine (2) or 1-azafagomine (4), but was considerably more potent than its epimer 5b. This suggests that these enzymes have a strong preference for binding substrates or azasugars with the 6-OH in an axial conformation.

  13. Thermal conductivity determination of cometary and asteroid material analogues

    NASA Astrophysics Data System (ADS)

    Banaszkiewicz, M.; Seweryn, K.; Wawrzaszek, R.

    Measurements of physical properties of surface and subsurface layers of planetary bodies often provide important information about the structure of the medium and processes that occur there Thermal properties of cometary nuclues subsurface material are crucial in determining the heat and gas transport Similarly asteroid s regolith is a buffering zone in heat transfer from to surface to from interior of a body There are space experiments planned to perform temperature and thermal conductivity measurements on a comet ROSETTA and one can easily foresee such measurements carried out by future robotic missions on Mars planetary satellites and asteroids In the paper we present the results of measurements carried out with a new type of thermal sensors The elementary cylindrical sensor is made of platinum wire resistance thermometer and isotan wire heating element that can operate independently By choosing these materials the problems of temperature measurement calibration and constant heating power are resolved We confront the results of measurements made for a number of sensors combined into a long cylinder in delrin basalt ice-dust mixture comet analogue and regolith-like material with models and show that agreement is very good Therefore we can recommend both the sensors and the method of data interpretation for the thermal conductivity determination as very useful tools in future space missions and in laboratory experiments on cometary and asteroid material analogues

  14. Process standardization for rennet casein based Mozzarella cheese analogue.

    PubMed

    Shah, Rahul; Jana, Atanu H; Aparnathi, K D; Prajapati, P S

    2010-10-01

    A process for manufacture of Mozzarella cheese analogue (MCA) using rennet casein and plastic cream as protein and fat sources respectively was standardized. The formulation comprised of 25% plastic cream (72% fat), 27% rennet casein along with 3% tri-sodium citrate as emulsifying salt, 2% maltodextrin as binder, 0.55% lactic acid as pH regulator, 1% common salt for seasoning, 1% Mozzarella cheese bud as flavouring and 40.4% water. The process involved (a) dissolving the dry mixture of casein, maltodextrin, flavouring and common salt in hot emulsifying salt solution, (b) incorporation of half the quantity of acid solution in casein-maltodextrin dough, followed by addition and emulsification of plastic cream, and (c) addition of remaining half of the acid solution and heating the mass to 80 °C until a plastic cheese mass was obtained. The analogue was shaped in ball form, cooled and packaged in polyethylene bag. The MCA conformed to the PFA requirements for pizza cheese and had all the requisite baking characteristics expected of pizza cheese topping.

  15. The antiviral activity of tetrazole phosphonic acids and their analogues.

    PubMed Central

    Hutchinson, D W; Naylor, M

    1985-01-01

    5-(Phosphonomethyl)-1H-tetrazole and a number of related tetrazoles have been prepared and their effects on the replication of Herpes Simplex Viruses-1 and -2 have been investigated as well as their abilities to inhibit the DNA polymerases induced by these viruses and the RNA transcriptase activity of influenza virus A. Contrary to an earlier report, 5-(phosphonomethyl)-1H-tetrazole was not an efficient inhibitor of the replication of HSV-1 and HSV-2 in tissue culture. Analogues of 5-(phosphonomethyl)-1H-tetrazole were also devoid of significant antiviral activity. Only 5-(phosphonomethyl)-1H-tetrazole and 5-(thiophosphonomethyl)-1H-tetrazole inhibited the influenza virus transcriptase, and both were more effective as inhibitors than phosphonoacetic acid under the same conditions. The DNA polymerases induced by HSV-1 and HSV-2 were inhibited slightly by 5-(phosphonomethyl)-1H-tetrazole and to a lesser extent by its N-ethyl analogue and 3-(phosphonomethyl)-1H-1,2,4-triazole. None of these compounds were as effective as phosphonoacetic acid. 5-(Thiophosphonomethyl)-1H-tetrazole was a better inhibitor of the DNA polymerase induced by HSV-1 than 5-(phosphonomethyl)-1H-tetrazole. PMID:2417198

  16. Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin.

    PubMed

    Yadav, Babasaheb; Taurin, Sebastien; Rosengren, Rhonda J; Schumacher, Marc; Diederich, Marc; Somers-Edgar, Tiffany J; Larsen, Lesley

    2010-09-15

    A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-kappaB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC50 values below 1 microM and inhibition of NF-kappaB activation below 7.5 microM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18 h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.

  17. Stability and exfoliation of germanane: a germanium graphane analogue.

    PubMed

    Bianco, Elisabeth; Butler, Sheneve; Jiang, Shishi; Restrepo, Oscar D; Windl, Wolfgang; Goldberger, Joshua E

    2013-05-28

    Graphene's success has shown not only that it is possible to create stable, single-atom-thick sheets from a crystalline solid but that these materials have fundamentally different properties than the parent material. We have synthesized for the first time, millimeter-scale crystals of a hydrogen-terminated germanium multilayered graphane analogue (germanane, GeH) from the topochemical deintercalation of CaGe2. This layered van der Waals solid is analogous to multilayered graphane (CH). The surface layer of GeH only slowly oxidizes in air over the span of 5 months, while the underlying layers are resilient to oxidation based on X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy measurements. The GeH is thermally stable up to 75 °C; however, above this temperature amorphization and dehydrogenation begin to occur. These sheets can be mechanically exfoliated as single and few layers onto SiO2/Si surfaces. This material represents a new class of covalently terminated graphane analogues and has great potential for a wide range of optoelectronic and sensing applications, especially since theory predicts a direct band gap of 1.53 eV and an electron mobility ca. five times higher than that of bulk Ge.

  18. [Use of somatostatin analogue for intestinal and pancreatic fistulas].

    PubMed

    Paran, H; Neufeld, D; Epstein, T; Bendahan, J; Freund, U

    1991-02-15

    The hormone somatostatin, a tetra-deca-peptide, was discovered in 1972. It inhibits the central nervous system and the endocrine and exocrine secretions of the gastrointestinal tract. The first clinical use of the hormone was to inhibit hormone-secreting tumors of the CNS. It has also been used to treat hormone-secreting tumors of the pancreas and GI tract. Treatment of small bowel and pancreatic fistulas has also been attempted. A new synthetic analogue of the hormone, SMS 210-995, (Sandostatin) has a long half-life and is highly effective after subcutaneous injection. It was used in the treatment of 3 patients with fistulas of the small bowel and pancreas. In all impressive reduction of fistula secretion was achieved within 24 hours. In 2 there was complete, spontaneous closure of the fistula: in 1 after 10 days and in the other after 15 days of treatment. In the 3rd, there was significant reduction of fistula output. There were no side-effects except for mild pain at the injection site in 1 patient. Previous reports and our own results indicate that this somatostatin analogue may be very useful in the nonsurgical treatment of GI tract fistulas.

  19. Optical Dust Characterization in Manned Mars Analogue Research Stations

    NASA Technical Reports Server (NTRS)

    Bos, B. J.; Krebs, Carolyn (Technical Monitor)

    2003-01-01

    Martian dust has been identified as a potentially serious hazard to any manned Mars landing mission. NASA and other organizations realize this risk and continue to support Martian dust research through the Matador project led by researchers at the University of Arizona. The Mars Society can contribute to this work by beginning a regimen of monitoring and measuring dust properties at its Mars analogue research stations. These research facilities offer the unique opportunity to study the transport and distribution of dust particles within a crewed habitat supporting active geologic exploration. Information regarding the amount, location and size of dust particles that may accumulate in a Mars habitat will be required to design a real Mars habitat and habitat equipment. Beginning such an effort does not require a large outlay of equipment and can be accomplished using crewmembers experienced with station operations. Various optical techniques, such as dark-field illumination, coupled with image processing algorithms enable the collection of dust grain relative size and frequency information. Such approaches can be applied in several different zones within the research stations to evaluate the various dust reduction and isolation procedures implemented during a particular crew rotation. As the stations simulation fidelity increases, the applicability of such data to a functional Mars lander will increase. This presentation describes the optical equipment and procedures for measuring dust properties in Mars analogue research stations that can be implemented during the next field season.

  20. Electromagnetic induction in New Zealand: analogue model and field results

    NASA Astrophysics Data System (ADS)

    Chen, J.; Dosso, H. W.; Ingham, M.

    The behaviour of electric and magnetic variations over North Island (New Zealand) is studied with the aid of a laboratory analogue model. The source field frequencies used in the analogue modelling simulate naturally occurring geomagnetic variations of 5-120 min periods. In-phase and quadrature magnetic and electric fields for a selection of traverses for the modelled region of North Island are presented. Since North Island is of a relatively narrow cross-section, the field responses, even for inland locations, are expected to show strongly the effects of the surrounding ocean. The irregular coastlines, as well as the strait between North and South Islands, lead to coastal and inland field anomalies due to induced currents being deflected and channelled to produce localized current densities. The comparison of model results with field station measurements obtained earlier individually by Ingham and by Midha for sites in the northeastern, central, and southern (near Cook Strait) regions of North Island demonstrates the large role the ocean has in the observed field responses. Differences in the model and field results at some sites are expected and should reflect the effects of the local geology and the conductive substructure related to the complex tectonics of the region not simulated in the model.

  1. B38: an all-boron fullerene analogue.

    PubMed

    Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

    2014-10-21

    Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (∼2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.

  2. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

    PubMed

    Ghaly, Peter E; Abou El-Magd, Rabab M; Churchill, Cassandra D M; Tuszynski, Jack A; West, F G

    2016-06-28

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

  3. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation

    PubMed Central

    Ghaly, Peter E.; Abou El-Magd, Rabab M.; Churchill, Cassandra D. M.; Tuszynski, Jack A.; West, F. G.

    2016-01-01

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug. PMID:27777381

  4. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

    PubMed

    Ghaly, Peter E; El-Magd, Rabab M Abou; Churchill, Cassandra D M; Tuszynski, Jack A; West, F G

    2016-05-26

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

  5. Drug-likeness of Phytic Acid and Its Analogues.

    PubMed

    Joy, Amitha; Balaji, S

    2015-01-01

    Inositol hexakisphosphate is known to be the phosphorous reserve in plants particularly in the seeds. Though it has been known for its antinutrient properties for many years, recent research shed light to reveal it as a novel anticancer agent. Hence the present study investigates the drug-likeness of phytic acid and its analogues through bioinformatics methods. Two potential cancer drug targets such as mitogen activated kinase and inositol 1,4,5-triphosphate receptor are included in the study. Out of 50 selected analogues of phytic acid, 42 structures interact well with the chosen drug targets. The best interacting structures are 1-diphosinositol pentakisphosphate and 2,3,4,5,6-pentaphosphonooxycyclohexyl dihydrogen phosphate. For both of these structures, the negative binding energy obtained was -49.5 KJ/mol; this affirms the stability of the complex. ADME properties are also predicted to assess the drug-like properties of the compounds. The structure activity relationship model is generated for 12 compounds with experimental IC50 values.

  6. Clinical uses of gonadotropin-releasing hormone analogues.

    PubMed Central

    Casper, R F

    1991-01-01

    Gonadotropin-releasing hormone (Gn-RH) analogues are synthetic derivatives of the native hypothalamic peptide with alterations in their chemical structure that result in changes in biologic activity. Several Gn-RH agonists are available for clinical use, and all act through the same mechanism: first to stimulate and then to inhibit gonadotropin and gonadal steroid secretion by downregulating the pituitary Gn-RN receptors. This review should provide clinicians with a working knowledge of the physiologic and pharmacokinetic features of Gn-RH agonists. Although over 2000 articles concerning Gn-RH analogues have been published I chose to review only those that were the first to report a novel clinical application. Gn-RH agonists have proved to be extremely efficacious in treating gonadal steroid-dependent problems such as endometriosis, uterine leiomyoma, precocious puberty and prostate and breast cancers, and they have resulted in very few side effects. Long-term use may, however, lead to skeletal calcium loss in women as a consequence of hypoestrogenism. Further research is needed to prevent this and maintain clinical efficacy. PMID:1986827

  7. Martian Analogues Emissivity Spectra From the Berlin Emissivity Database (BED)

    NASA Astrophysics Data System (ADS)

    Maturilli, A.; Helbert, J.; Moroz, L.

    2006-12-01

    Remote sensing infrared spectroscopy is the principal field of investigation for planetary surfaces composition. Past, present and future missions to bodies in the solar system include in their payload instruments measuring the emerging radiation in the infrared range. For the interpretation of the measured data an emissivity spectral library of planetary analog materials is needed. The Berlin Emissivity Database (BED) currently contains emissivity spectra of plagioclase and potassium feldspars, low Ca and high Ca pyroxenes, olivine, elemental sulphur, and Martian analogue minerals, measured in the wavelength range from 7 to 22 microns as a function of particle size. For each sample we measured the spectra of four particle size separates ranging from 0 to 250 microns. The device we used is built at DLR (Berlin) and is coupled to a Fourier transform infrared spectrometer (Bruker IFS 88), purged with dry air and equipped with a cooled detector (MCT). All spectra were acquired with a spectral resolution of 4 cm-1. We present here the results of our analysis on well knew and characterized Martian analogue minerals: JSC Mars-1, Salten Skov, and Palagonite from Mauna Kea, Hawaii. We are currently working to upgrade our emissivity facility. A new spectrometer (Bruker VERTEX 80v) and new detectors will allow us to measure the emissivity of samples in the wavelength range from 1 to 50 microns, even in a vacuum environment.

  8. The molecular interactions of buspirone analogues with the serotonin transporter.

    PubMed

    Jarończyk, Małgorzata; Chilmonczyk, Zdzisław; Mazurek, Aleksander P; Nowak, Gabriel; Ravna, Aina W; Kristiansen, Kurt; Sylte, Ingebrigt

    2008-10-15

    A major problem with the selective serotonin reuptake inhibitors (SSRIs) is the delayed onset of action. A reason for that may be that the initial SSRI-induced increase in serotonin levels activates somatodendritic 5-HT(1A) autoreceptors, causing a decrease in serotonin release in major forebrain areas. It has been suggested that compounds combining inhibition of the serotonin transport protein with antagonistic effects on the 5-HT(1A) receptor will shorten the onset time. The anxiolytic drug buspirone is known as 5-HT(1A) partial agonist. In the present work, we are studying the inhibition of the serotonin transporter protein by a series of buspirone analogues by molecular modelling and by experimental affinity measurements. Models of the transporter protein were constructed using the crystal structure of the Escherichia coli major facilitator family transporter-LacY and the X-ray structure of the neurotransmitter symporter family (NSS) transporter-LeuT(Aa) as templates. The buspirone analogues were docked into both SERT models and the interactions with amino acids within the protein were analyzed. Two putative binding sites were identified on the LeuT(Aa) based model, one suggested to be a high-affinity site, and the other suggested to be a low-affinity binding site. Molecular dynamic simulations of the LacY based model in complex with ligands did not induce a helical architecture of the LacY based model into an arrangement more similar to that of the LeuT(Aa) based model.

  9. The costal landslide from analogue experiments: perspectives and limitation

    NASA Astrophysics Data System (ADS)

    Del Ventisette, C.; Nolesini, T.; Moretti, S.; Fanti, R.

    2010-12-01

    Understanding the triggering mechanism of coastal landslides (triggered and/or developed at air-water interface) and their evolution is fundamental to evaluate their hazard and, predicting the energy, the associated tsunami risk. The aim of this work is to verify the suitability of analogue modelling to understand the triggering mechanism and the evolution of landslide along the costal line. As a starting case study the Sciara del Fuoco (SdF), northwest flank of the volcanic island of Stromboli (Italy), was chosen. The analogue modelling technique has been proven to represent an useful tool to understand many geological processes, as it allows studying the progressive deformation, providing also useful indications about the role of distinct factors controlling the final deformation pattern. The models simulated at a first approximation the geological geometries observed at Stromboli, a composite volcano forming the northernmost island of the Aeolian Archipelago (Tyrrhenian Sea). The activity of Stromboli volcano is characterized by a persistent mild explosive activity at the summit craters sporadically interrupted by episodes of lava effusion and violent paroxysmal explosions as in 2002-2003 and in 2007. During the 2002 effusion a large landslide occurred on the SdF. The landslide caused a tsunami, which produced severe damages along the island shores. A series of analogue models was performed to investigate the influence of two different types of triggering mechanism and the behaviour of landslides both in air and air-water interface: 1) surface bulging due to the intrusion of a dike; 2) accumulation of material due to an uppermost landslide or due to opening of a new vent. The models, constructed in a Plexiglas tank, were scaled to the natural prototype following the geometrical, rheological, kinematical and dynamical similarities (e.g. Hubbert, 1937; Ramberg, 1981). The modelling material (Fontainbleau sand and rice) was sieved on a slope, inclination of which

  10. Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon

    NASA Astrophysics Data System (ADS)

    Lebeuf, Martin

    Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As

  11. Monitoring of Geoengineering Effects and their Natural and Anthropogenic Analogues

    NASA Astrophysics Data System (ADS)

    Duren, R. M.; Robock, A.; Stephens, G. L.; MacMynowski, D. G.

    2011-12-01

    A number of climate intervention concepts, referred to as "geoengineering," are being considered as an alternative approach to managing climate change. However, before we go down the path of deliberate climate intervention including precursor field-experiments, it is essential that we take the necessary steps to validate our understanding that underpins any of the proposed intervention concepts in order to understand all likely consequences and put in place the necessary strategies for monitoring the expected and unintended consequences of such intervention. The Keck Institute for Space Studies (KISS) is undertaking a project to identify specific priorities for improved scientific understanding and focused efforts to address selected priorities. The KISS project does not advocate the deployment of geoengineering or monitoring systems for potential field experiments but is rather a precautionary study with the following goals: 1) enumeration of where major gaps in our understanding exist in solar radiation management (SRM) approaches, 2) identification of the research that would be required to improve understanding of such impacts including modeling and observation of natural and anthropogenic analogues to geoengineering, and 3) a preliminary assessment of where gaps exist in observations of relevance to SRMs and what is needed to fill such gaps. This study focuses primarily on SRM rather than other proposed geoengineering techniques such as carbon dioxide removal from the atmosphere because there exist a number of analogues to the SRMs that currently operate on Earth that provide a unique opportunity to assess our understanding of the response of the climate system to associated changes in solar radiation. Additionally, the processes related to these analogues are also fundamental to understanding climate change itself being of central relevance to how climate is forced by aerosol and respond through clouds, among other influences (e.g., such research has potential

  12. Isoelectronic analogues of PN: Remarkably stable multiply charged cations

    SciTech Connect

    Wong, Ming Wah; Radom, L. )

    1990-01-25

    The structures and stabilities of PN and its 27 isoelectronic analogues, CS, SiO, BCl, AlF, BeAr, MgNe, Sn{sup +}, PO{sup +}, CCl{sup +}, SiF{sup +}, BAr{sup +}, AlNe{sup +}, SO{sup 2+}, NCl{sup 2+}, PF{sup 2+}, CAr{sup 2+}, SiNe{sup 2+}, OCl{sup 3+}, SF{sup 3+}, NAr{sup 3+}, PNe{sup 3+}, FCl{sup 4+}, OAr{sup 4+}, SNe{sup 4+}, FAr{sup 5+}, ClNe{sup 5+}, and ArNe{sup 6+}, have been examined by ab initio molecular orbital theory. The CASSCF/6-311G(MC)(d) level was used to determine the ground-state potential energy curves and spectroscopic constants for the 28 diatomic systems. Equilibrium structures were also obtained with the 6-311G(MC)(d) basis set at the MP3 and ST4CCD levels, and dissociation energies were determined at the MP4/6-311 + G(MC)(2df) and MP4/6-311 + G(MC)(3d2f) levels. For the neutral and monocation analogues of PN, the calculated equilibrium geometries (at MP3/6-311G(MC)(d)) and dissociation energies (at MP4/6-311 + G(MC)(3d2f)) are in very good agreement with available experimental values. All the dication analogues of PN, namely, SO{sup 2+}, NCl{sup 2+}, PF{sup 2+}, CAr{sup 2+}, and SiNe{sup 2+}, are predicted to be experimentally observable species. Of these, the SO{sup 2+}, NCl{sup 2+}, and CAr{sup 2+} dications are calculated to be kinetically stable species, with large barriers associated with the exothermic charge-separation reactions, while the PF{sup 2+} and SiNe{sup 2+} dications are predicted not only to be kinetically stable but also to be thermodynamically stable species.

  13. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, Matthias; Schreurs, Guido; Rosenau, Matthias; Kemnitz, Helga

    2016-04-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between (c. 100 and 400 micrometer). Analysis of grain shape factors show that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling . Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil., Most materials have a cohesion in the order of 10-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C <10 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density reached during sieving which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains. Also, models

  14. Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis

    NASA Astrophysics Data System (ADS)

    Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

    2012-08-01

    Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

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

    ERIC Educational Resources Information Center

    Sidney, Pooja G.; Alibali, Martha W.

    2015-01-01

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

  16. How Analogue Research Can Advance Descriptive Evaluation Theory: Understanding (and Improving) Stakeholder Dialogue

    ERIC Educational Resources Information Center

    Campbell, Bernadette; Mark, Melvin M.

    2015-01-01

    Evaluation theories can be tested in various ways. One approach, the experimental analogue study, is described and illustrated in this article. The approach is presented as a method worthy to use in the pursuit of what Alkin and others have called descriptive evaluation theory. Drawing on analogue studies conducted by the first author, we…

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

    PubMed Central

    Roth, Bryan L.; Gibbons, Simon; Arunotayanun, Warunya; Huang, Xi-Ping; Setola, Vincent; Treble, Ric; Iversen, Les

    2013-01-01

    In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. PMID:23527166

  18. Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone.

    PubMed

    Durán, Fernando J; Edelsztein, Valeria C; Ghini, Alberto A; Rey, Mariana; Coirini, Héctor; Dauban, Philippe; Dodd, Robert H; Burton, Gerardo

    2009-09-15

    The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.

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

    PubMed

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

    2016-08-01

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

  20. Isoxazole analogues bind the System xc− Transporter: Structure-activity Relationship and Pharmacophore Model

    PubMed Central

    Patel, Sarjubhai A.; Rajale, Trideep; O’Brien, Erin; Burkhart, David J.; Nelson, Jared K.; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I.; Gerdes, John M.; Bridges, Richard J.; Natale, Nicholas R.

    2009-01-01

    Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc−. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc−, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y′=3,5-(CF3)2, which both inhibited glutamate up-take by the System xc− transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

  1. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

    PubMed

    Redwan, Elrashdy M; Linjawi, Moustafa H; Uversky, Vladimir N

    2016-03-17

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein?

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

    PubMed

    Wang, Yen-Chih; Distefano, Mark D

    2016-02-01

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

  3. New optimized piperamide analogues with potent in vivo hypotensive properties.

    PubMed

    de Mattos Duarte, Carolina; Verli, Hugo; de Araújo-Júnior, João Xavier; de Medeiros, Isac Almeida; Barreiro, Eliezer J; Fraga, Carlos Alberto Manssour

    2004-12-01

    We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. 1H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4'-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates.

  4. Measurement of stimulated Hawking emission in an analogue system.

    PubMed

    Weinfurtner, Silke; Tedford, Edmund W; Penrice, Matthew C J; Unruh, William G; Lawrence, Gregory A

    2011-01-14

    Hawking argued that black holes emit thermal radiation via a quantum spontaneous emission. To address this issue experimentally, we utilize the analogy between the propagation of fields around black holes and surface waves on moving water. By placing a streamlined obstacle into an open channel flow we create a region of high velocity over the obstacle that can include surface wave horizons. Long waves propagating upstream towards this region are blocked and converted into short (deep-water) waves. This is the analogue of the stimulated emission by a white hole (the time inverse of a black hole), and our measurements of the amplitudes of the converted waves demonstrate the thermal nature of the conversion process for this system. Given the close relationship between stimulated and spontaneous emission, our findings attest to the generality of the Hawking process.

  5. Quasinormal modes and classical wave propagation in analogue black holes

    SciTech Connect

    Berti, Emanuele; Cardoso, Vitor; Lemos, Jose P.S.

    2004-12-15

    Many properties of black holes can be studied using acoustic analogues in the laboratory through the propagation of sound waves. We investigate in detail sound wave propagation in a rotating acoustic (2+1)-dimensional black hole, which corresponds to the 'draining bathtub' fluid flow. We compute the quasinormal mode frequencies of this system and discuss late-time power-law tails. Because of the presence of an ergoregion, waves in a rotating acoustic black hole can be superradiantly amplified. We also compute superradiant reflection coefficients and instability time scales for the acoustic black hole bomb, the equivalent of the Press-Teukolsky black hole bomb. Finally we discuss quasinormal modes and late-time tails in a nonrotating canonical acoustic black hole, corresponding to an incompressible, spherically symmetric (3+1)-dimensional fluid flow.

  6. The Mojave vadose zone: a subsurface biosphere analogue for Mars.

    PubMed

    Abbey, William; Salas, Everett; Bhartia, Rohit; Beegle, Luther W

    2013-07-01

    If life ever evolved on the surface of Mars, it is unlikely that it would still survive there today, but as Mars evolved from a wet planet to an arid one, the subsurface environment may have presented a refuge from increasingly hostile surface conditions. Since the last glacial maximum, the Mojave Desert has experienced a similar shift from a wet to a dry environment, giving us the opportunity to study here on Earth how subsurface ecosystems in an arid environment adapt to increasingly barren surface conditions. In this paper, we advocate studying the vadose zone ecosystem of the Mojave Desert as an analogue for possible subsurface biospheres on Mars. We also describe several examples of Mars-like terrain found in the Mojave region and discuss ecological insights that might be gained by a thorough examination of the vadose zone in these specific terrains. Examples described include distributary fans (deltas, alluvial fans, etc.), paleosols overlain by basaltic lava flows, and evaporite deposits.

  7. Analogue of Cosmological Particle Creation in an Ion Trap

    SciTech Connect

    Schuetzhold, Ralf; Uhlmann, Michael; Petersen, Lutz; Schmitz, Hector; Friedenauer, Axel; Schaetz, Tobias

    2007-11-16

    We study phonons in a dynamical chain of ions confined by a trap with a time-dependent (axial) potential strength and demonstrate that they behave in the same way as quantum fields in an expanding or contracting Universe. Based on this analogy, we present a scheme for the detection of the analogue of cosmological particle creation which should be feasible with present day technology. In order to test the quantum nature of the particle creation mechanism and to distinguish it from classical effects such as heating, we propose to measure the two-phonon amplitude via the 2nd red sideband transition and to compare it with the one-phonon amplitude (1st red sideband)

  8. Total Synthesis and Evaluation of Phostriecin and Key Structural Analogues

    PubMed Central

    Burke, Christopher P.; Swingle, Mark R.; Honkanen, Richard E.; Boger, Dale L.

    2010-01-01

    Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12–C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective). PMID:20669916

  9. A computational study of open-chain epothilone analogue

    NASA Astrophysics Data System (ADS)

    Kamel, Karol; Rusinska-Roszak, Danuta

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

  10. Nitrooxymethyl-substituted analogues of rofecoxib: synthesis and pharmacological characterization.

    PubMed

    Boschi, Donatella; Cena, Clara; Di Stilo, Antonella; Rolando, Barbara; Manzini, Paola; Fruttero, Roberta; Gasco, Alberto

    2010-05-01

    Nitrooxymethyl-substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet-rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti-aggregatory properties, are closely dependent on the position at which the NO-donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose-dependent manner, through a cGMP-dependent mechanism. Compound 10 emerged as a quite potent COX-2-selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX-1 inhibitor, and displayed good vasodilator and anti-aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.

  11. Nitrooxymethyl-substituted analogues of celecoxib: synthesis and pharmacological characterization.

    PubMed

    Boschi, Donatella; Lazzarato, Loretta; Rolando, Barbara; Filieri, Andrea; Cena, Clara; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto

    2009-03-01

    Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.

  12. Integration of inherent and induced chirality into subphthalocyanine analogue

    PubMed Central

    Zhao, Luyang; Qi, Dongdong; Wang, Kang; Wang, Tianyu; Han, Bing; Tang, Zhiyong; Jiang, Jianzhuang

    2016-01-01

    Conventional conjugated systems are characteristic of only either inherent or induced chirality because of synthetic challenge in combination of chiral segment into the main chromophore. In this work, chiral binaphthyl segment is directly fused into the central chromophore of a subphthalocyanine skeleton, resulting in a novel type of chiral subphthalocyanine analogue (R/S)-1 of integrated inherent and induced chirality. Impressively, an obviously enhanced optical activity is discerned for (R/S)-1 molecules, and corresponding enhancement mechanism is elucidated in detail. The synthesis strategy based on rational molecular design will open the door towards fabrication of chiral materials with giant optical activity, which will have great potential in chiroptical devices. PMID:27294871

  13. Modelling the warm interglacials: analogues of MIS1

    NASA Astrophysics Data System (ADS)

    Herold, N.; Yin, Q. Z.; Karami, M. P.; Berger, A.

    2012-04-01

    Determining interglacial diversity, primarily as a function of duration, intensity and unique climate responses to Earth's orbital variations has become a focal point for researchers trying to better understand our current interglacial. Numerous interglacials have been espoused as Marine Isotopic Stage (MIS) 1 analogues or windows into the future of Holocene climate based on their astronomical characteristics, seasonal insolation patterns or their similarity with predicted anthropogenic warming. However, to date there has been little quantitative study of the climate of these interglacials within a physically robust framework. Here we examine the climate response to peak interglacial forcing during MIS1, 5, 9, 11 and 19 using the Community Climate System Model 3. We determine which interglacial provides the closest analogue to peak MIS1 conditions as well as the mechanisms which dominate the surface climate responses of these interglacials. Considering the differences in astronomical parameters and greenhouse gases we discount MIS5 and 9 as analogues to peak MIS1 conditions due to their significant warmth and stronger precipitation and vegetation responses. Conversely, based on seasonal and hemispheric averages of surface temperature, precipitation and sea-ice cover, MIS11 and 19 are most similar to MIS1, with MIS11 actually exhibiting a higher affinity particularly during boreal summer. This is attributed to a greater similarity in the seasonal and latitudinal distribution of insolation over middle latitude Eurasia and North America, which are the regions most sensitive to insolation change given the absence of ice-sheet dynamics in our model. Global ocean overturning circulation during MIS11 is also closer to MIS1 than circulation during MIS19 is, due predominantly to differences in Weddell Sea bottom water formation. Thus, under the assumption of present-day ice-sheets MIS11 appears to be the better climatic analogue to peak MIS1 conditions. In addition to the

  14. Raman spectroscopy of ion-irradiated interplanetary carbon dust analogues

    NASA Astrophysics Data System (ADS)

    Baratta, G. A.; Mennella, V.; Brucato, J. R.; Colangeli, L.; Leto, G.; Palumbo, M. E.; Strazzulla, G.

    Interplanetary dust particles (IDPs) and meteorites provide an unique opportunity to study extraterrestrial materials in laboratory. Different Raman studies have shown that most of IDPs exhibit the characteristic amorphous carbon Raman feature. Different degrees of order have been recognised in the amorphous carbon phase of IDPs testifying either to different origin or to different processing under different physical conditions (temperature, pressure etc.). This paper presents a comparison between the amorphous carbon Raman features of IDPs, and those of carbon dust analogues obtained in the laboratory by ion irradiation of carbon containing frozen gases and by arc discharge. We propose a possible mechanism able to induce an "evolution" of IDPs. In particular amorphous carbon with different degrees of order could be indicative of different irradiation doses by solar wind particles and fast solar protons, suffered by IDPs in the interplanetary medium before collection in the Earth's atmosphere.

  15. Mechanism of cis-prenyltransferase reaction probed by substrate analogues.

    PubMed

    Lu, Yen-Pin; Liu, Hon-Ge; Teng, Kuo-Hsun; Liang, Po-Huang

    2010-10-01

    Undecaprenyl pyrophosphate synthase (UPPS) is a cis-type prenyltransferases which catalyzes condensation reactions of farnesyl diphosphate (FPP) with eight isopentenyl pyrophosphate (IPP) units to generate C(55) product. In this study, we used two analogues of FPP, 2-fluoro-FPP and [1,1-(2)H(2)]FPP, to probe the reaction mechanism of Escherichia coli UPPS. The reaction rate of 2-fluoro-FPP with IPP under single-turnover condition is similar to that of FPP, consistent with the mechanism without forming a farnesyl carbocation intermediate. Moreover, the deuterium secondary KIE of 0.985±0.022 measured for UPPS reaction using [1,1-(2)H(2)]FPP supports the associative transition state. Unlike the sequential mechanism used by trans-prenyltransferases, our data demonstrate E. coli UPPS utilizes the concerted mechanism.

  16. Superconducting analogue of the parafermion fractional quantum Hall states

    NASA Astrophysics Data System (ADS)

    Vaezi, Abolhassan

    2014-03-01

    Read and Rezayi Zk parafermion wavefunctions describe ν = 2 + k /(kM + 2) fractional quantum Hall (FQH) states. These states support non-Abelian excitations from which protected quantum gates can be designed. However, there is no experimental evidence for these non-Abelian anyons to date. In this talk, we discuss the ν = 2 / k FQH-superconductor heterostructure and through analytical and numerical calculations we argue that it can yield the superconducting analogue of the Zk parafermion FQH state. The resulting topological state has a gapless chiral edge state with Zk parafermion conformal field theory description. For instance, we find that a ν = 2 / 3 FQH in proximity to a superconductor produces a Z3 parafermion superconducting state. This state can host Fibonacci anyons capable of performing universal quantum computation through braiding operations. We finally discuss our experimental proposal for realizing parafermion superconductors. Reference: arXiv:1307.8069

  17. Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues

    PubMed Central

    Woods, Laura M.; Arico, Joseph W.; Frein, Jeffrey D.; Sackett, Dan L.; Taylor, Richard E.

    2017-01-01

    The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides. PMID:28304361

  18. Procedures for monitoring recombinant erythropoietin and analogues in doping control.

    PubMed

    Segura, Jordi; Pascual, José A; Gutiérrez-Gallego, Ricardo

    2007-08-01

    The present report summarizes the main analytical strategies developed to identify the presence of recombinant erythropoietin (EPO) administered as a doping agent. Indirect evidence is based on the analysis of blood parameters (haemoglobin, haematocrit, reticulocytes, macrocytes, etc.) and serum markers (concentration of EPO and serum transferrin receptors, etc.). The problem of intertechnique comparison for reliable results evaluation is emphasized, especially for serum markers. Charge differences between isoforms of recombinant EPO and native urinary EPO are the grounds for the isoelectric focusing-double blotting-chemiluminescence detection method presently approved for doping control. Works addressing its advantages and limitations are presented and commented on. The chemical bases of the differential detection are highlighted and some future approaches for detection are also presented. The appearance and detectability of EPO analogues and mimetics susceptible for abuse are also addressed.

  19. Synthesis, characterization and biological studies of diosgenyl analogues.

    PubMed

    Huang, Baozhan; Du, Dan; Zhang, Rui; Wu, Xiaohua; Xing, Zhihua; He, Yang; Huang, Wen

    2012-12-15

    A series of optical amino acid diosgenyl esters and diosgenyl salicylate conjugates were designed and synthesized to develop new anticancer and anti-inflammatory agents. The analogue 9c that contains an 6-aminohexanoic acid residue at C-3 of diosgenin exhibits higher potency against all three tumor cell lines with IC(50) values ranging from 4.7 μM in C26 cells to 14.6 μM in Hep G2 cells. In addition, seven of newly synthesized compounds significantly inhibit xylene-induced ear edema and exhibit comparable or better anti-inflammatory activities than those of diosgenin and aspirin. Furthermore, preliminary structure-activity relationship studies demonstrate that diosgenyl salicylate conjugates have stronger anti-inflammatory activities than amino acid diosgenyl esters.

  20. Phosphorus-based SAHA analogues as histone deacetylase inhibitors.

    PubMed

    Kapustin, Galina V; Fejér, György; Gronlund, Jennifer L; McCafferty, Dewey G; Seto, Edward; Etzkorn, Felicia A

    2003-08-21

    [structure: see text] Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC(50) = 0.57-6.1 mM), HDAC8 (IC(50) = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC(50) = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC(50) = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.

  1. Global analogue of the Aharonov-Bohm effect

    SciTech Connect

    Navin, R.L.

    1993-12-31

    This thesis deals with a global analogue of the Aharonov-Bohm effect previously pointed out by other authors. The effect was not well understood because the pure Aharonov-Bohm cross section was thought to be merely an approximate low energy limit. This thesis provides a detailed analysis and reveals that in the particular model considered, there is an exact Aharonov-Bohm cross section over the energy range that a mass splitting occurs. At energies slightly above the mass splitting, the effect has completely disappeared and there is effectively no scattering at large distances. This is a curious observation as it was previously thought that a global theory would not act exactly like a local one over an extended range of energies. It begs the heretical speculation that experimentally observed forces modelled with Lagrangians possessing local symmetries may have an underlying global theory.

  2. Simulated Milky Way analogues: implications for dark matter indirect searches

    SciTech Connect

    Calore, Francesca; Bozorgnia, Nassim; Lovell, Mark; Bertone, Gianfranco; Schaller, Matthieu; Frenk, Carlos S.; Theuns, Tom; Trayford, James W.; Crain, Robert A.; Schaye, Joop E-mail: N.Bozorgnia@uva.nl E-mail: g.bertone@uva.nl E-mail: C.S.Frenk@durham.ac.uk E-mail: schaye@strw.leidenuniv.nl E-mail: j.w.trayford@durham.ac.uk

    2015-12-01

    We study high-resolution hydrodynamic simulations of Milky Way type galaxies obtained within the 'Evolution and Assembly of GaLaxies and their Environments' (EAGLE) project, and identify those that best satisfy observational constraints on the Milky Way total stellar mass, rotation curve, and galaxy shape. Contrary to mock galaxies selected on the basis of their total virial mass, the Milky Way analogues so identified consistently exhibit very similar dark matter profiles inside the solar circle, therefore enabling more accurate predictions for indirect dark matter searches. We find in particular that high resolution simulated haloes satisfying observational constraints exhibit, within the inner few kiloparsecs, dark matter profiles shallower than those required to explain the so-called Fermi GeV excess via dark matter annihilation.

  3. Synthesis and biological evaluation of novel tamoxifen analogues.

    PubMed

    Christodoulou, Michael S; Fokialakis, Nikolas; Passarella, Daniele; García-Argáez, Aída Nelly; Gia, Ornella Maria; Pongratz, Ingemar; Dalla Via, Lisa; Haroutounian, Serkos A

    2013-07-15

    A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17β-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed.

  4. Photochemical hole burning of ionic porphins and the deuterated analogues

    NASA Astrophysics Data System (ADS)

    Sakoda, Kazuaki; Maeda, Masayuki

    1994-01-01

    The quantum yields of photochemical hole burning (PHB) of three ionic porphins and their deuterated analogues doped in poly(vinylalcohol) and poly(sodium 4-styrenesulfonate) were estimated. The deuterated compounds, whose two hydrogen atoms at the nitrogen sites in the porphin ring were exchanged with deuterium atoms, were synthesized by reacting the non-deuterated compounds with heavy water. The quantum yield of the deuterated porphin was 18 to 45 times smaller than that of the non-deuterated compound. Besides, the hole area did not decrease at least up to about 60 K. These two facts definitely show that the main mechanism of PHB in this system is not a photophysical process, but the tautomerization of the porphin ring.

  5. Novel Cyclic Biphalin Analogue with Improved Antinociceptive Properties

    PubMed Central

    2014-01-01

    Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties. PMID:25221662

  6. [Antioxidant properties of 3-oxypyridine analogues: mexidol, emoxipin, proxipin].

    PubMed

    Klebanov, G I; Liubitskiĭ, O B; Vasil'eva, O V; Klimov, Iu V; Penzulaeva, O B; Tepliashin, A S; Tolstykh, M P; Promorenko, V K; Vladimirov, Iu A

    2001-01-01

    Using three chemiluminescent model systems of oxidation (suspension of phospholipid liposomes, a geous solution of haemoglobin-hydrogen peroxide-luminol and a geous solution 2,2'-azo-bis-(2-methylpropionamidine)dihydrochloride-luminol) the antioxidant activity and mechanism of antioxidant action of three 3-oxypyridine analogues: (mexidol, emoxipin and proxipin) were studied. These compounds were shown: a) to interact with catalitically active two valency iron ions (Fe2+), that causes elimination of ions from the model system; b) to scavenge reactive oxygen species and/or luminol radicals produced in the model systems. Their activity reduced in the following order: mexidol > emoxipin > proxipin. The antioxidant activity of 3-oxypyridines may underline known clinical effects of these compounds.

  7. Synthesis of Dihydropyridine Analogues for Sperm Immobilizing Activity

    NASA Astrophysics Data System (ADS)

    Sadeghipour Roodsari, H. R.; Amini, M.; Naghibi Harat, Z.; Daneshgar, P.; Vosooghi, M.; Shafiee, A.

    In the present study, the activity of seven newly synthesized dihydropyridine analogues on the motility of sperm were determined and compared to nifedipine activity that was used as standard. Sperm motility reduced value for test compounds 6a-g shows a gradual increase proportional to the size elongation of alkyl ester groups. Consequently the size of alkyl is important in the activity of test compounds and finally increase in the lipophil size of hydrocarbon`s ester (R1) is inversely related to the activity of the synthetic compounds. As a result, the methyl ester of the test compounds with 50% of nifedipine activity (in two hours group) is the most active test compound.

  8. Scattering matrices and expansion coefficients of martian analogue palagonite particles

    NASA Astrophysics Data System (ADS)

    Laan, E. C.; Volten, H.; Stam, D. M.; Muñoz, O.; Hovenier, J. W.; Roush, T. L.

    2009-01-01

    We present measurements of ratios of elements of the scattering matrix of martian analogue palagonite particles for scattering angles ranging from 3° to 174° and a wavelength of 632.8 nm. To facilitate the use of these measurements in radiative transfer calculations we have devised a method that enables us to obtain, from these measurements, a normalized synthetic scattering matrix covering the complete scattering angle range from 0° to 180°. Our method is based on employing the coefficients of the expansions of scattering matrix elements into generalized spherical functions. The synthetic scattering matrix elements and/or the expansion coefficients obtained in this way, can be used to include multiple scattering by these irregularly shaped particles in (polarized) radiative transfer calculations, such as calculations of sunlight that is scattered in the dusty martian atmosphere.

  9. A novel nucleic acid analogue shows strong angiogenic activity

    SciTech Connect

    Tsukamoto, Ikuko; Sakakibara, Norikazu; Maruyama, Tokumi; Igarashi, Junsuke; Kosaka, Hiroaki; Kubota, Yasuo; Tokuda, Masaaki; Ashino, Hiromi; Hattori, Kenichi; Tanaka, Shinji; Kawata, Mitsuhiro; Konishi, Ryoji

    2010-09-03

    Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.

  10. Using analogues to quantify geological uncertainty in stochastic reserve modelling

    SciTech Connect

    Wells, B.; Brown, I.

    1995-08-01

    The petroleum industry seeks to minimize exploration risk by employing the best possible expertise, methods and tools. Is it possible to quantify the success of this process of risk reduction? Due to inherent uncertainty in predicting geological reality and due to changing environments for hydrocarbon exploration, it is not enough simply to record the proportion of successful wells drilled; in various parts of the world it has been noted that pseudo-random drilling would apparently have been as successful as the actual drilling programme. How, then, should we judge the success of risk reduction? For many years the E&P industry has routinely used Monte Carlo modelling to generate a probability distribution for prospect reserves. One aspect of Monte Carlo modelling which has received insufficient attention, but which is essential for quantifying risk reduction, is the consistency and repeatability with which predictions can be made. Reducing the subjective element inherent in the specification of geological uncertainty allows better quantification of uncertainty in the prediction of reserves, in both exploration and appraisal. Building on work reported at the AAPG annual conventions in 1994 and 1995, the present paper incorporates analogue information with uncertainty modelling. Analogues provide a major step forward in the quantification of risk, but their significance is potentially greater still. The two principal contributors to uncertainty in field and prospect analysis are the hydrocarbon life-cycle and the geometry of the trap. These are usually treated separately. Combining them into a single model is a major contribution to the reduction risk. This work is based in part on a joint project with Oryx Energy UK Ltd., and thanks are due in particular to Richard Benmore and Mike Cooper.

  11. Analogue modeling of instabilities in crater lake hydrothermal systems

    NASA Astrophysics Data System (ADS)

    Vandemeulebrouck, Jean; Stemmelen, Didier; Hurst, Tony; Grangeon, Jacques

    2005-02-01

    We carried out analogue experiments on two-phase boiling systems, using a porous vertical cylinder, saturated with water. The base of the cylinder was heated, and the top was cooled, as in a natural hydrothermal system. Previous work had shown that once the two-phase zone reached a certain level, thermal instabilities would develop. We made measurements of the acoustic energy related to boiling, and we found that high levels of acoustic noise were associated with the part of the cycle in which there was upward water movement. We repeated our experiments with a cooling water tank at the top of the system, representing a crater lake. This showed that periodic thermal instabilities still developed in this situation. We then compared our analogue measurements to two natural systems known to exhibit periodic behavior. There is good agreement between the thermal and acoustic cycling seen in our model and the observations made at Inferno Crater Lake in the Waimangu Geothermal area, New Zealand, whose level cycles by nearly 10 m, with a typical period of 38 days. Particularly notable is how in both systems high levels of acoustic noise are associated with rising water level. The much larger Ruapehu Crater Lake, also in New Zealand, cycled with a period of several months to a year for over a decade prior to the 1995 eruption. Strong acoustic and seismic energy usually occurred just before the lake temperature started to rise. This suggests a slightly different model, in which the increasing two-phase flow zone triggers more general convection once it reaches the base of the lake.

  12. Early Earth rock analogues for Martian subsurface processes

    NASA Astrophysics Data System (ADS)

    Bishop, J. L.; Grosch, E. G.; Maturilli, A.; Helbert, J.

    2015-12-01

    Sub-surface mafic-ultramafic crustal and hydrothermal environments on early Earth and Mars may have been very similar [1]. Hydrogen production from low-temperature alteration of ultramafic and basaltic rocks has been proposed to support early microbial life in Earth's earliest subsurface environments [1]. Similarly, evidence for microbial sulphate reduction has been reported from early Archean metabasaltic pillow lavas [2]. As such, Archean terrestrial rock environments preserved in greenstone belts may play an important role in understanding early Martian subsurface environments, which in turn may have led to preservation of early traces of life. In this context, the rock sequences of the Paleoarchean Barberton greenstone belt of South Africa provide unique Martian analogues as these rocks are exceptionally well preserved and record early Earth (and perhaps Martian-type) subsurface processes. In-situ exploration by rovers, remote sensing studies, and meteorite evidence has indicated the presence of altered gabbros, olivine-/pyroxene-bearing basalts and possible felsic porphyries on Mars. In this study we present a range of relevant 3.5 billion year old Archean greenstone belt analogue samples that include altered tholeiitic basalts, basaltic komatiites, serpentinized ultramafic komatiites and a felsic tonalite. The petrography and mineralogy of the samples are presented in terms of relic igneous phases and clay mineral alteration. We are acquiring visible/near-infrared reflectance and mid-IR emission spectra on these early Archean samples with the aim of using the hyperspectral data for ground truthing remote sensing data and mineral identification/environments on Mars.[1]. Grosch et al. (2014). Microscale mapping of alteration conditions and potential biosignatures in basaltic-ultramafic rocks on early Earth and beyond, Astrobiology 14 (3), 216-228. [2]. McLoughlin et al. (2012) Sulfur isotope evidence for a Paleoarchean subseafloor biosphere, Barberton, South

  13. Mapping Densities in Analogue Laboratory Turbulent Plumes Using Dye Concentration

    NASA Astrophysics Data System (ADS)

    Fisher, M. A.; Kobs-Nawotniak, S. E.

    2014-12-01

    Changing tephra concentration in volcanic eruption columns is difficult to measure in the field due to fluid opacity. The bulk fluid erupted may be higher density than the surrounding atmosphere at the vent and then transition to positive buoyancy through the ingestion and heating of ambient air; thus, the concentration of the plume fluid as it rises is critical to determining whether the material rises in a sustained plume or collapses into a pyroclastic density current. We evaluate the changing concentration of an analogue plume via tracer dye intensity and relate it to plume radius expansion and vent distance. To calibrate our concentration metric, we calculated the density and dye concentration of pre-determined tracer-water mixtures. The density of the solution was directly measured using a micropipette and high precision balance. The calculated density falls within the standard error of the measured density for each step. Five photographs were taken of each concentration using a mounted Ex-FH100 digital camera with identical lighting. Using a MATLAB script, the RGB (Red-Green-Blue) color value was extracted from five pixels located at the same coordinates in each image, confirming that there was no inherent error caused by the camera and that the RGB value was the same across an entire image. We created a color map to convert from the RGB color value of a pixel in an image to its corresponding concentration. This method algorithm can then be applied to an analogue volcanic tank model, using the color variations in the plume eddies to determine the tracer concentration, and thereby density distribution, in the plume.

  14. Cyclic cholecystokinin analogues with high selectivity for central receptors.

    PubMed Central

    Charpentier, B; Pelaprat, D; Durieux, C; Dor, A; Reibaud, M; Blanchard, J C; Roques, B P

    1988-01-01

    Taking as a model the N-terminal folding of the cholecystokinin tyrosine-sulfated octapeptide [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] deduced from conformational studies, two cyclic cholecystokinin (CCK) analogues were synthesized by conventional peptide synthesis: Boc-D-Asp-Tyr(SO3H)-Ahx-D-Lys-Trp-Ahx-Asp-Phe-NH2 [compound I (Ahx, 2-aminohexanoic acid)] and Boc-gamma-D-Glu-Tyr(SO3H)-Ahx-D-Lys-Trp-Ahx-Asp-Phe-NH2 (compound II). The binding characteristics of these peptides were investigated on brain cortex membranes and pancreatic acini of guinea pig. Compounds I and II were competitive inhibitors of [3H]Boc[Ahx28,31]CCK-(27-33) binding to central CCK receptors and showed a high degree of selectivity for these binding sites (compound I: Ki for pancreas/Ki for brain, 179; compound II: Ki for pancreas/Ki for brain, 1979). This high selectivity was associated with a high affinity for central CCK receptors (compound I: Ki, 5.1 nM; compound II: Ki, 0.49 nM). Similar affinities and selectivities were found when 125I Bolton-Hunter-labeled CCK-8 was used as a ligand. Moreover, these compounds were only weakly active in the stimulation of amylase release from guinea pig pancreatic acini (EC50 greater than 10,000 nM) and were unable to induce contractions in the guinea pig ileum (to 10(-6) M). The two cyclic CCK analogues, therefore, appear to be synthetic ligands exhibiting both high affinity and high selectivity for central CCK binding sites. These compounds could help clarify the respective role of central and peripheral receptors for various CCK-8-induced pharmacological effects. PMID:3162318

  15. The Arctic Mars Analogue Svalbard Expedition 2010. (Invited)

    NASA Astrophysics Data System (ADS)

    Steele, A.; Benning, L. G.; Fogel, M. L.; Amundsen, H.; Schmitz, N.; Amase 2010 Team

    2010-12-01

    The Arctic Mars Analogue Svalbard Expeditions (AMASE) 2010 was the latest of a series of expeditions that are NASA ASTEP and ESA funded and have as their primary goals 1) testing portable instruments for their robustness as field instruments for life detection, 2) assessing Mars analogue environments for abiosignatures and biosignatures, 3) refining protocols for contamination reduction, 4) defining a minimal instrument suite for Astrobiology science on Mars and 5) sample acquisition, collection and caching of suitable samples by rover platforms containing sample acquisition hardware: first Cliffbot, then Athena. As well as testing ESA instrumentation for the ExoMars mission and NASA instruments for Mars Science Laboratory, the goals and technologies used during this 2010 campaign are very similar to that proposed by the current MEPAG MAX-C mission concept and therefore set the stage for future sample return missions. As such the field-tested technologies, procedures and protocols can be used to address specific science objectives proposed for the 2018 Mars mission opportunity. As NASA and ESA enter a new era of collaboration, AMASE has provided and will continue to provide, a test bed for both current in-situ robotic missions and Mars Sample Return mission architectures. AMASE has proved to be a unique platform to build understanding and collaboration amongst scientists and engineers from Europe and the USA. AMASE 2010 team (other than those mentioned above): Ivar Midtkandal, Kjell Ove Storvik, Garret Huntress, Verena Starke, Pan Conrad, Francis McCubbin, Tor Viscor, Antonio Sensano, Laureline Josset, Jean-Luc Josset, Mihaela Glamoclija, Steve Squyres, Inge Loes Ten Kate, Kyong Hou, Jen Stern, Amy McAdam, Dave Blake, Dick Morris, Claire Cousins, Arnold Bauer, Carole Phillippon, Eckhard Steinmetz, Dave Potts, Dominique Tobler, Guillermo Lopez.

  16. Chicoric acid analogues as HIV-1 integrase inhibitors.

    PubMed

    Lin, Z; Neamati, N; Zhao, H; Kiryu, Y; Turpin, J A; Aberham, C; Strebel, K; Kohn, K; Witvrouw, M; Pannecouque, C; Debyser, Z; De Clercq, E; Rice, W G; Pommier, Y; Burke, T R

    1999-04-22

    The present study was undertaken to examine structural features of L-chicoric acid (3) which are important for potency against purified HIV-1 integrase and for reported cytoprotective effects in cell-based systems. Through a progressive series of analogues, it was shown that enantiomeric D-chicoric acid (4) retains inhibitory potency against purified integrase equal to its L-counterpart and further that removal of either one or both carboxylic functionalities results in essentially no loss of inhibitory potency. Additionally, while two caffeoyl moieties are required, attachment of caffeoyl groups to the central linking structure can be achieved via amide or mixed amide/ester linkages. More remarkable is the finding that blockage of the catechol functionality through conversion to tetraacetate esters results in almost no loss of potency, contingent on the presence of at least one carboxyl group on the central linker. Taken as a whole, the work has resulted in the identification of new integrase inhibitors which may be regarded as bis-caffeoyl derivatives of glycidic acid and amino acids such as serine and beta-aminoalanine. The present study also examined the reported ability of chicoric acid to exert cytoprotective effects in HIV-infected cells. It was demonstrated in target and cell-based assays that the chicoric acids do not significantly inhibit other targets associated with HIV-1 replication, including reverse transcription, protease function, NCp7 zinc finger function, or replication of virus from latently infected cells. In CEM cells, for both the parent chicoric acid and selected analogues, antiviral activity was observable under specific assay conditions and with high dependence on the multiplicity of viral infection. However, against HIV-1- and HIV-2-infected MT-4 cells, the chicoric acids and their tetraacetylated esters exhibited antiviral activity (50% effective concentration (EC50) ranging from 1.7 to 20 microM and 50% inhibitory concentration (IC50

  17. Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.

    PubMed

    Beedie, Shaunna L; Peer, Cody J; Pisle, Steven; Gardner, Erin R; Mahony, Chris; Barnett, Shelby; Ambrozak, Agnieszka; Gütschow, Michael; Chau, Cindy H; Vargesson, Neil; Figg, William D

    2015-10-01

    Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 μmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.

  18. Transitional lava flows as potential analogues for lunar impact melts

    NASA Astrophysics Data System (ADS)

    Neish, Catherine; Hughes, Scott; Hamilton, Christopher; Kobs Nawotniak, Shannon; Garry, William Brent; Skok, John Roma; Elphic, Richard; Carter, Lynn; Bandfield, Joshua; Osinski, Gordon; Lim, Darlene; Heldmann, Jennifer

    2015-11-01

    Lunar impact melt deposits are among the roughest surface materials on the Moon at the decimeter scale, even though they appear smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will inform us as to the circumstances under which they were formed. Although there is no perfect archetype for lunar impact melts on Earth, certain terrestrial environments lend themselves as functional analogues. Specifically, a variety of transitional lava flow types develop if the surface of a pāhoehoe-like flow is disrupted, producing ‘slabby’ or ‘rubbly’ flows that are extremely rough at the decimeter scale. We investigated the surface roughness of transitional lava flows at Craters of the Moon (COTM) National Monument, comparing radar imagery and high-resolution topographic profiles to similar data sets acquired by the Lunar Reconnaissance Orbiter for impact melt deposits on the Moon. Results suggest that the lava flows at COTM have similar radar properties to lunar impact melt deposits, but the terrestrial flows are considerably rougher at the meter scale. It may be that lunar impact melts represent a unique lava type not observed on Earth, whose surface texture is influenced by their high emplacement temperatures and/or cooling in a vacuum. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  19. Correlation between vibrational frequencies and hydrogen bonding states of the guanine ring studied by UV resonance Raman spectroscopy of 2'-deoxy-3',5'-bis(triisopropylsilyl)guanosine dissolved in various solvents

    NASA Astrophysics Data System (ADS)

    Toyama, Akira; Hamuara, Mutsuo; Takeuchi, Hideo

    1996-06-01

    Ultraviolet resonance Raman spectra of 2'-deoxy-3',5'-bis(triisopropylsilyl)guanosine (TPS-dGuo) were recorded in non-hydrogen bonding, proton acceptor, and proton donor/acceptor solvents. Raman spectral changes observed on going from inert to proton acceptor solvents were ascribed to the hydrogen bonding at the proton donor sites of the guanine ring (N1H and C2NH 2), and the spectral changes associated with the solvent change from proton acceptor to donor/acceptor were ascribed to the hydrogen bonding at the proton acceptor sites (N3, C6O, and N7). A Raman band appearing at 1624 cm -1 in inert solvents is assigned mainly to the NH 2 scissors mode and its frequency changes to ≈ 1640 cm -1 in acceptor solvents, reflecting the hydrogen bonding at C2NH 2. Another band at 1581 cm -1, arising largely from the N1H bend, shows an upshift of ≈ 10 cm -1 upon hydrogen bonding at either N1H or acceptor sites. Hydrogen bonding at the acceptor sites also produces frequency shifts of other Raman bands (at 1710, 1565, 1528, 1481, and 1154 cm -1 in 1,2-dichloroethane solution). Among the Raman bands listed above, the 1710 cm -1 band due to the C6O stretch decreases in frequency, whereas the others increase. The downshift of the C6O stretching frequency is correlated with the strength of hydrogen bonding at C6O. The frequency of the 1481 cm -1 band increases with a decrease of the C6O stretching frequency, indicating that the 1481 cm -1 band is also a marker of hydrogen bonding at C6O. This finding is in sharp contrast to the previously proposed correlation with the hydrogen bonding at N7. The 1565 cm -1 band is assigned to a vibration mainly involving the N1C2N3 linkage, and its frequency increases with increasing strength of the hydrogen bond at N3. Three bands around 1315, 1180, and 1030 cm -1, which are known to be sensitive to the ribose ring puckering and glycosidic bond orientation, also show small frequency changes upon hydrogen

  20. Sex Difference in κ-Opioid Receptor (KOPR)-Mediated Behaviors, Brain Region KOPR Level and KOPR-Mediated Guanosine 5′-O-(3-[35S]Thiotriphosphate) Binding in the Guinea Pig

    PubMed Central

    Wang, Yu-Jun; Rasakham, Khampaseuth; Huang, Peng; Chudnovskaya, Darina; Cowan, Alan

    2011-01-01

    We examined whether sex differences in κ-opioid receptor (KOPR) pharmacology exist in guinea pigs, which are more similar to humans in the expression level and distribution of KOPR in the brain than rats and mice. The KOPR agonist trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)benzeneacetamide methanesulfonate (U50,488H) produced a dose-dependent increase in abnormal postures and immobility with more effects in males than females. Males also showed more U50,488H-induced antinociception in the paw pressure test than females. Pretreatment with the KOPR antagonist norbinaltorphimine blocked U50,488H-induced abnormal body postures and antinociception. In contrast, inhibition of cocaine-induced hyperambulation by U50,488H was more effective in females than males. Thus, sex differences in the effects of U50,488H are endpoint-dependent. We then examined whether sex differences in KOPR levels and KOPR-mediated G protein activation in brain regions may contribute to the observed differences using quantitative in vitro autoradiography of [3H](5a,7a,8b)-(−)-N-methyl-N-(7-(1-pyrrolidinyl)1-oxaspiro(4,5)dec-8-yl)benzeacetamide ([3H]U69,593) binding to the KOPR and U50,488H-stimulated guanosine 5′-O-(3-[35S]thiotriphosphate ([35S]GTPγS) binding. Compared with females, males exhibited more [3H]U69,593 binding in the deep layers of somatosensory and insular cortices, claustrum, endopiriform nucleus, periaqueductal gray, and substantial nigra. Concomitantly, U50,488H-stimulated [35S]GTPγS binding was greater in males than females in the superficial and deep layers of somatosensory and insular cortices, caudate putamen, claustrum, medial geniculate nucleus, and cerebellum. In contrast, compared with males, females showed more U50,488H-stimulated [35S]GTPγS binding in the dentate gyrus and a trend of higher [35S]GTPγS binding in the hypothalamus. These data demonstrate that males and females differ in KOPR expression and KOPR-mediated G protein activation

  1. Chemistry of HIV-1 virucidal Pt complexes having neglected bidentate sp2 N-donor carrier ligands with linked triazine and pyridine rings. synthesis, NMR spectral features, structure, and reaction with guanosine.

    PubMed

    Maheshwari, Vidhi; Bhattacharyya, Debadeep; Fronczek, Frank R; Marzilli, Patricia A; Marzilli, Luigi G

    2006-09-04

    Complexes of the types LPtCl2 and [L2Pt]X2 [L = substituted 3-(pyridin-2'-yl)-1,2,4-triazine] were synthesized and characterized by NMR spectroscopy and, for the first time, by X-ray crystallography in an effort to determine the coordination properties of this novel class of inorganic medicinal agents possessing HIV-1 virucidal activity. The agents containing either one or two sp2 N-donor bidentate ligands are referred to as ptt (platinum triazine) agents. The X-ray structures of three LPtCl2 compounds revealed the expected pseudo-square-planar geometry. The X-ray structure of [(pyPh2t)2Pt](BF4)2 [pyPh2t = 3-(pyridin-2'-yl)-5,6-diphenyl-1,2,4-triazine] has the expected trans relationship of the unsymmetrical L and is essentially planar, an unusual property for a Pt(II) complex with two bidentate sp2 N donors. HIV-1 is an RNA virus; the guanosine ribonucleoside (Guo) binds (MepyMe2t)PtCl2 at both (inequivalent) available coordination sites to form [(MepyMe2t)Pt(Guo)2]2+ [MepyMe2t = 3-(4'-methylpyridin-2'-yl)-5,6-dimethyl-1,2,4-triazine]. This adduct has four nearly equally intense Guo H8 signals attributed to two pairs of head-to-tail (HT) and head-to-head (HH) conformers, which interchange rapidly within each pair. However, equilibration between pairs requires rotation of the Guo cis to the MepyMe2t pyridyl ring, and the H6' proton on this ring projects toward the Guo and hinders Guo rotation about the Pt-N7 bond. Thus, the HT/HH pairs do not interchange; such behavior is rare. Guo did not add to [(MepyMe2t)2Pt]2+, a result suggesting the possibility that the virucidal activity of LPtCl2 and [L2Pt]2+ ptt agents arises respectively from covalent and noncovalent (possibly intercalative interactions favored by [L2Pt]2+ planarity) binding to biomolecular targets.

  2. NMDA Receptors and the L-Arginine–Nitric Oxide–Cyclic Guanosine Monophosphate Pathway Are Implicated in the Antidepressant-Like Action of the Ethanolic Extract from Tabebuia avellanedae in Mice

    PubMed Central

    Freitas, Andiara E.; Moretti, Morgana; Budni, Josiane; Balen, Grasiela O.; Fernandes, Sinara C.; Veronezi, Patricia O.; Heller, Melina; Micke, Gustavo A.; Pizzolatti, Moacir G.

    2013-01-01

    Abstract Bark infusion of Tabebuia avellanedae Lorentz ex Griseb is consumed in tropical America folk medicine for the treatment of several diseases, including depressive disorders. It was recently demonstrated that the extract from this plant has antidepressant properties. The present study was aimed at investigating the contribution of N-methyl-D-aspartate (NMDA) receptors and the L-arginine–nitric oxide (NO)–cyclic guanosine 3′5′-monophosphate (cGMP) pathway to the antidepressant-like action of the ethanolic extract from T. avellanedae (EET) in the tail suspension test (TST). The anti-immobility effect of the extract (30 mg/kg, orally [p.o.]) was prevented by pretreatment of mice with NMDA (0.1 pmol/site, intracerebroventicular [i.c.v.]), L-arginine (750 mg/kg, intraperitoneally [i.p.]), and sildenafil (5 mg/kg, i.p.). Additionally, the combination of MK-801 (0.01 mg/kg, p.o.), 7-nitroindazole (25 mg/kg, i.p.), and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30 pmol/site, i.c.v.) with a subeffective dose of EET (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing significant alterations in the locomotor activity. Moreover, the administration of an effective dose of EET (30 mg/kg, p.o.) produced a reduction in NOx levels in the cerebral cortex. Conversely, a subeffective dose of EET (1 mg/kg, p.o.) caused no changes in the cortical NOx levels. Results suggest that the antidepressant-like effect of EET in the TST is dependent on a blockade of NMDA receptor activation and inhibition of NO-cGMP synthesis, significantly extending literature data about the antidepressant-like action of this plant and reinforcing the notion that this plant may be useful in the management of depressive disorders. PMID:24236576

  3. Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.

    PubMed

    Kaya, Abdullah; Kar, Taner; Aksoy, Yakup; Özalper, Veysel; Başbuğ, Barbaros

    2013-12-01

    Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal

  4. Quality of shrimp analogue product as affected by addition of modified potato starch.

    PubMed

    Remya, S; Basu, S; Venkateshwarlu, G; Mohan, C O

    2015-07-01

    The present study was aimed to investigate the effects of addition of modified potato starch on the biochemical and textural properties of shrimp analogue/imitation shrimp, a popular value-added product prepared from surimi. Three batches of shrimp analogues were prepared with 0 % (NPS), 50 % (CPS) and 100 % (MPS) of modified starch incorporation and various quality attributes were monitored at regular intervals during frozen storage (-20 °C). Loss of myofibrillar protein was least for the shrimp analogue sample added with 100 % modified potato starch. The expressible moisture content of MPS (2.48 %) was less affected by long term storage compared to CPS (3.38 %) and NPS (3.99 %). During extended low temperature storage, the textural quality of sea food analogue was highly influenced by the type of starch added to it. The percentage of modified potato starch added to shrimp analogue significantly (p ≤ 0.05) affected its hardness and fracturability. MPS samples did not show significant changes in hardness during storage as compared to other two samples. Springiness of shrimp analogue increased 2.57, 1.5 and 1.77 times with the storage period for samples with NPS, CPS and MPS, respectively. Addition of modified potato starch improved the sensory quality and textural properties of shrimp analogue and reduced the quality degradation during frozen storage as compared to NPS which contained only native potato starch.

  5. Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

    PubMed

    de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

    2012-01-01

    For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

  6. Analogue Models Of Volcanic Spreading At Mt. Vesuvius

    NASA Astrophysics Data System (ADS)

    De Matteo, Ada; Castaldo, Raffaele; D'Auria, Luca; James, Michael; Lane, Steve; Massa, Bruno; Pepe, Susi; Tizzani, Pietro

    2015-04-01

    Somma-Vesuvius is a quiescent strato-volcano of the Neapolitan district, southern Italy, for which various geophysical and geological evidences (e.g. geodetic measurements, geological and structural data, seismic profiles interpretations and surface deformation analysis with Differential Interferometric Synthetic Aperture Radar (DInSAR)) indicate ongoing spreading deformation. In this research we investigate the spreading deformation and associated surface deformation pattern by performing analogue experiments and comparing the results with actual ground deformation as measured using DInSAR data recorded between 1992 and 2010. Somma-Vesuvius consists of a volcanic cone (Gran Cono) lying within an asymmetric caldera (Somma). The Somma caldera is the result of at least 7 Plinian eruptions, the last of which was the 79 CE. Pompeii eruption. The current cone of Mt. Vesuvius grew within the caldera in the following centuries as the effect of continued explosive and effusive activity of the volcano. The volcano lies on a substratum consisting of a Mesozoic carbonatic basement, overlapped by Holocene clastic sediments and volcanic rocks. Our analogue models were built to simulate the shape of the Somma-Vesuvius top a scale of about 1:100000, emplaced on a sand layer (brittle behaviour) laid on a silicone layer (ductile behaviour). Models are based on the Fluid-dynamics Dimensionless Analysis (FDA), according to the Buckingham-Π theorem. In this context, we considered few dimensionless parameters that allowed the setting of a reliable scaled model. To represent the complex Somma-Vesuvius geometry, an asymmetric model was built by setting a truncated cone (mimicking the topography of Somma edifice) topped by another small cone (mimicking the Gran Cono) shifted off the axis of the main cone. Different experiments were carried out in which the thickness of the basal sand layer and of the silicone one were varied. To quantify the vertical and horizontal displacements the

  7. Chasing An Analogue For The Holocene : The Astronomical Forcing

    NASA Astrophysics Data System (ADS)

    Loutre, M.; Crucifix, M.; Berger, A.

    2008-12-01

    Astronomical theories of paleoclimate, e.g. the Milankovitch theory, explain the long-term variations of climate by the changes in the Earth orbit and position against the Sun, and consequently by the change in the distribution of the solar energy reaching the Earth. On the other hand, anthropogenic activities from early agricultural practices to more recent fossil fuel burning also impact climate change. Models, from conceptual ones to the most sophisticated general circulation models can be used to try to disentangle the contribution from human activity and the natural contribution in the record of climate change. Alternatively, a comparison of the climate records during past interglacials similar to the one we are living in can give some insight into the natural behaviour of the climate system during an interglacial. As far as the long-term climate change is mostly orbitally driven, we will search orbital and insolation time series for past analogues of the non-human perturbed Holocene. When doing so, some key questions must be answered. The first one is related to the time interval to be used as target. A previous study (Loutre and Berger, 2000) focused on the interglacial itself, assuming that the preceding deglaciation had a negligible impact on the interglacial. Rather we decided here to choose a target time interval that includes the deglaciation. Another question is related to the choice of the variable that will be used for correlation. It can be the orbital parameters themselves. It is also possible to use top-of-the-atmosphere insolation. If daily insolation is chosen, the latitude and time in the year for which it is computed are crucial; if a more time- integrated insolation is used (e.g. seasonal insolation), the time interval for the integration is an essential feature. Loutre and Berger (2000) used mid-June insolation at 65N and identified MIS11 as the most recent potential analogue for the future climate. A higher correlation of the insolation was

  8. Efficacy of Antimicrobials on Bacteria Cultured in a Spaceflight Analogue

    NASA Technical Reports Server (NTRS)

    Nickerson, CA; Wotring, Virginia; Barrila, Jennifer; Crabbe, Aurelie; Castro, Sarah; Davis, Richard; Rideout, April; McCarthy, Breanne; Ott, C. Mark

    2014-01-01

    As humans travel in space, they will interact with microbial flora from themselves, other crewmembers, their food, and the environment. While evaluations of microbial ecology aboard the Mir and ISS suggest a predominance of common environmental flora, the presence of (and potential for) infectious agents has been well documented. Likewise, pathogens have been detected during preflight monitoring of spaceflight food, resulting in the disqualification of that production lot from flight. These environmental and food organisms range from the obligate pathogen, Salmonella enterica serovar Typhimurium (S. Typhimurium), which has been responsible for disqualification and removal of food destined for ISS and has previously been reported from Shuttle crew refuse, to the opportunistic pathogen Staphylococcus aureus, isolated numerous times from ISS habitable compartments and the crew. Infectious disease events have affected spaceflight missions, including an upper respiratory infection that delayed the launch of STS-36 and an incapacitating Pseudomonas aeruginosa urinary tract infection of a crewmember during Apollo 13. These observations indicate that the crew has the potential to be exposed to obligate and opportunistic pathogens. This risk of exposure is expected to increase with longer mission durations and increased use of regenerative life support systems. As antibiotics are the primary countermeasure after infection, determining if their efficacy during spaceflight missions is comparable to terrestrial application is of critical importance. The NASA Rotating Wall Vessel (RWV) culture system has been successfully used as a spaceflight culture analogue to identify potential alterations in several key microbial characteristics, such as virulence and gene regulation, in response to spaceflight culture. We hypothesized that bacteria cultured in the low fluid shear RWV environment would demonstrate changes in efficacy of antibiotics compared to higher fluid shear controls

  9. Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

    PubMed Central

    Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D’Alvise, Paul; Gram, Lone

    2014-01-01

    Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

  10. The stereospecific synthesis of P-chiral biophosphates and their analogues by the Stec reaction.

    PubMed

    Wozniak, Lucyna A; Okruszek, Andrzej

    2003-05-01

    This manuscript summarizes the results of studies on the application of the reaction of dialkyl (aryl) phosphoramidate anions with carbonyl electrophiles for stereospecific synthesis of P-chiral biophosphates (Stec reaction). Following the results obtained with organic phosphoramidates which delineated the scope of the reaction and its stereochemical course, the application of the title reaction is presented for the preparation of diastereomerically pure P-chiral cyclic nucleotide analogues (phosphorothioates, phosphoroselenoates, phosphoroselenothioates, isotopomeric 18O-phosphates), and P-chiral nucleoside monophosphate analogues, as well as dinucleoside phosphate analogues (phosphorothioates, methanephosphonates).

  11. New synthetic strategies towards psammaplin A, access to natural product analogues for biological evaluation.

    PubMed

    Baud, Matthias G J; Leiser, Thomas; Meyer-Almes, Franz-Josef; Fuchter, Matthew J

    2011-02-07

    New synthetic routes towards the natural product psammaplin A were developed with the particular view to preparing diverse analogues for biological assessment. These routes utilize cheap and commercially available starting materials, and allowed access to psammaplin A analogues not accessible via currently reported methods. Preliminary biological studies revealed these compounds to be the most potent non peptidic inhibitors of the enzyme histone deacetylase 1 (HDAC1, class I) discovered so far. Interestingly, psammaplin A and our synthetic analogues show class I selectivity in vitro, an important feature for the design and synthesis of future isoform selective inhibitors.

  12. GnRH Analogues in the Prevention of Ovarian Hyperstimulation Syndrome

    PubMed Central

    Alama, Pilar; Bellver, Jose; Vidal, Carmen; Giles, Juan

    2013-01-01

    The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article. PMID:23825982

  13. 3D-QSAR-Assisted Design, Synthesis, and Evaluation of Novobiocin Analogues

    PubMed Central

    2012-01-01

    Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure–activity relationships. On the basis of the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure–activity (3D QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced antiproliferative activity at midnanomolar concentrations, which results through Hsp90 inhibition. PMID:23606927

  14. Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil.

    PubMed

    Lee, Ji Hyun; Park, Han Na; Ganganna, Bogonda; Jeong, Ji Hye; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

    2016-06-01

    A new tadalafil analogue was found, along with nortadalafil, using HPLC-DAD during the inspection of a health product sold without official approval. The analogue was separated using a semi-preparative HPLC system and its structure was determined by a combination of mass spectrometry and NMR spectroscopy. The compound was identified as a tadalafil analogue in which the N-methyl group of tadalafil was replaced with a tadalafil precursor moiety. Nuclear Overhauser effect spectroscopy experiments suggested a cis-relationship between the substituents on a piperidine ring in the tadalafil moiety.

  15. Hierarchically Superstructured Prussian Blue Analogues: Spontaneous Assembly Synthesis and Applications as Pseudocapacitive Materials

    SciTech Connect

    Yue, Yanfeng; Zhang, Zhiyong; Binder, Andrew J.; Chen, Jihua; Jin, Xianbo; Overbury, Steven; Dai, Sheng

    2014-11-10

    Hierarchically superstructured Prussian blue analogues (hexa- conventional hybrid graphene/MnO2 nanostructured textiles. cyanoferrate, M = NiII, CoII and CuII) are synthesized through Because sodium or potassium ions are involved in energy stor- a spontaneous assembly technique. In sharp contrast to mac- age processes, more environmentally neutral electrolytes can roporous-only Prussian blue analogues, the hierarchically su- be utilized, making the superstructured porous Prussian blue perstructured porous Prussian blue materials are demonstrated analogues a great contender for applications as high-per- to possess a high capacitance, which is similar to those of the formance pseudocapacitors.

  16. The role of the "Casimir force analogue" at the microscopic processes of crystallization and melting

    NASA Astrophysics Data System (ADS)

    Chuvildeev, V. N.; Semenycheva, A. V.

    2016-10-01

    Melting (crystallization), a phase transition from a crystalline solid to a liquid state, is a common phenomenon in nature. We suggest a new factor, "the Casimir force analogue", to describe mechanisms of melting and crystallization. The Casimir force analogue is a force occurring between the surfaces of solid and liquid phases of metals caused by different energy density of phonons of these phases. It explains abrupt changes in geometry and thermodynamic parameters at a melting point. "The Casimir force analogue" helps to estimate latent melting heat and to gain an insight into a solid-liquid transition problem.

  17. Hierarchically Superstructured Prussian Blue Analogues: Spontaneous Assembly Synthesis and Applications as Pseudocapacitive Materials

    DOE PAGES

    Yue, Yanfeng; Zhang, Zhiyong; Binder, Andrew J.; ...

    2014-11-10

    Hierarchically superstructured Prussian blue analogues (hexa- conventional hybrid graphene/MnO2 nanostructured textiles. cyanoferrate, M = NiII, CoII and CuII) are synthesized through Because sodium or potassium ions are involved in energy stor- a spontaneous assembly technique. In sharp contrast to mac- age processes, more environmentally neutral electrolytes can roporous-only Prussian blue analogues, the hierarchically su- be utilized, making the superstructured porous Prussian blue perstructured porous Prussian blue materials are demonstrated analogues a great contender for applications as high-per- to possess a high capacitance, which is similar to those of the formance pseudocapacitors.

  18. Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core.

    PubMed

    Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi; Lewin, Nancy E; Peach, Megan L; Blumberg, Peter M; Keck, Gary E

    2014-09-24

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues.

  19. Pyrrolines as prodrugs of gamma-aminobutyric acid analogues.

    PubMed

    Callery, P S; Geelhaar, L A; Nayar, M S; Stogniew, M; Rao, K G

    1982-04-01

    delta 1-Pyrroline, 5-methyl-delta 1-pyrroline, and 5,5-dimethyl-delta 1-pyrroline have been identified as substances metabolized to gamma-aminobutyric acid (GABA), 4-aminopentanoic acid (methylGABA), and 4-amino-4-methylpentanoic acid (dimethylGABA), respectively. An enzyme system residing in the soluble fraction of rabbit liver catalyzes the conversion of delta 1-pyrroline to GABA and its lactam, 2-pyrrolidinone. Acetaldehyde, allopurinol, and cyanide inhibited the reaction. Incubation of deuterium-labeled delta 1-pyrroline with mouse brain homogenates produced deuterated GABA. Mouse liver 10,000 g supernatant and mouse brain homogenates converted 5-methyl-delta 1-pyrroline to methylGABA, and 5,5-dimethyl-delta 1-pyrroline to dimethylGABA. Four hours after intraperitoneal injection of 5-methyl-delta 1-pyrroline (200 mg/kg), methylGABA was detected in mouse brain (0.27 mumol/g). DimethylGABA (1.21 mumol/g) was determined in mouse brain 30 min after intraperitoneal administration of 5,5-dimethyl-delta 1-pyrroline (200 mg/kg). Neither methylGABA nor dimethylGABA penetrated into the central nervous system when administered in the periphery. The present studies suggest that pyrrolines may represent a chemical class of brain-penetrating precursors of pharmacologically active analogues of GABA.

  20. Bioactive phenylpropanoid analogues from Piper betle L. var. haldia leaves.

    PubMed

    Atiya, Akhtar; Sinha, Barij Nayan; Lal, Uma Ranjan

    2017-02-15

    Phytochemical analyses of the chloroform extract of Piper betle L. var. birkoli, Piperaceae, leaves led to the isolation of two new phenylpropanoid analogues: bis-chavicol dodecanoyl ester (2) and bis-hydroxychavicol dodecanoyl ester (3), along with one known compound: allyl-3-methoxy-4-hydroxybenzene (1) on the basis of spectroscopic data 1D ((1)H and (13)C) and 2D ((1)H-(1)H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS. Compound 2 and 3 exhibited excellent antioxidant DPPH radical scavenging activity with IC50 values of 12.67 μg/mL and 1.08 μg/mL compared to ascorbic acid as a standard antioxidant drug with IC50 value of 6.60 μg/mL. Evaluation of cytotoxic activity against two human oral cancer cell lines (AW13516 and AW8507) showed significant effect with GI50 values of 19.61 and 23.01 μg/mL for compound 2 and 10.25 and 13.12 μg/mL for compound 3, compared to Doxorubicin(®) as a standard cytotoxic drug with GI50 value of < 10 μg/mL.

  1. An analogue of Wagner's theorem for decompositions of matrix algebras

    NASA Astrophysics Data System (ADS)

    Ivanov, D. N.

    2004-12-01

    Wagner's celebrated theorem states that a finite affine plane whose collineation group is transitive on lines is a translation plane. The notion of an orthogonal decomposition (OD) of a classically semisimple associative algebra introduced by the author allows one to draw an analogy between finite affine planes of order n and ODs of the matrix algebra M_n(\\mathbb C) into a sum of subalgebras conjugate to the diagonal subalgebra. These ODs are called WP-decompositions and are equivalent to the well-known ODs of simple Lie algebras of type A_{n-1} into a sum of Cartan subalgebras. In this paper we give a detailed and improved proof of the analogue of Wagner's theorem for WP-decompositions of the matrix algebra of odd non-square order an outline of which was earlier published in a short note in "Russian Math. Surveys" in 1994. In addition, in the framework of the theory of ODs of associative algebras, based on the method of idempotent bases, we obtain an elementary proof of the well-known Kostrikin-Tiep theorem on irreducible ODs of Lie algebras of type A_{n-1} in the case where n is a prime-power.

  2. Bioactivity of permselective PVA hydrogels with mixed ECM analogues.

    PubMed

    Nafea, Eman H; Poole-Warren, Laura A; Martens, Penny J

    2015-12-01

    The presentation of multiple biological cues, which simulate the natural in vivo cell environment within artificial implants, has recently been identified as crucial for achieving complex cellular functions. The incorporation of two or more biological cues within a largely synthetic network can provide a simplified model of multifunctional ECM presentation to encapsulated cells. Therefore, the aim of this study was to examine the effects of simultaneously and covalently incorporating two dissimilar biological molecules, heparin and gelatin, within a PVA hydrogel. PVA was functionalized with 7 and 20 methacrylate functional groups per chain (FG/c) to tailor the permselectivity of UV photopolymerized hydrogels. Both heparin and gelatin were covalently incorporated into PVA at an equal ratio resulting in a final PVA:heparin:gelatin composition of 19:0.5:0.5. The combination of both heparin and gelatin within a PVA network has proven to be stable over time without compromising the PVA base characteristics including its permselectivity to different proteins. Most importantly, this combination of ECM analogues supplemented PVA with the dual functionalities of promoting cellular adhesion and sequestering growth factors essential for cellular proliferation. Multi-functional PVA hydrogels with synthetically controlled network characteristics and permselectivity show potential in various biomedical applications including artificial cell implants.

  3. Hydrogen adsorption in thin films of Prussian blue analogue

    SciTech Connect

    Yang, Dali; Ding, Vivian; Luo, Junhua; Currier, Robert P; Obrey, Steve; Zhao, Yusheng

    2008-01-01

    Quartz crystal microbalance with dissipation (QCM-D) measurement was used to investigate the kinetics of the molecular hydrogen adsorption into thin films of prussian blue analogues - Cu{sub 3}[Co(CN){sub 6}]{sub 2} at ambient conditions. Although the equilibrium adsorption seems to be independent of the thickness, the adsorption rate substantially decreases with the thickness of the films. In addition, the reversibility of H{sub 2} adsorption into the Cu{sub 3}[Co(CN){sub 6}]{sub 2} films was investigated. The results indicate that the Cu{sub 3}[Co(CN){sub 6}]{sub 2} maily interacts with H{sub 2} molecules physically. The highest H{sub 2} uptake by the Cu{sub 3}[Co(CN){sub 6}]{sub 2} films is obtained when the gas phase is stagnant inside the testing cell. However, the unusual high H{sub 2} uptake obtained from the QCM-D measurement makes us question how reliable this analytic methodology is.

  4. Encoding complexity within supramolecular analogues of frustrated magnets

    NASA Astrophysics Data System (ADS)

    Cairns, Andrew B.; Cliffe, Matthew J.; Paddison, Joseph A. M.; Daisenberger, Dominik; Tucker, Matthew G.; Coudert, François-Xavier; Goodwin, Andrew L.

    2016-05-01

    The solid phases of gold(I) and/or silver(I) cyanides are supramolecular assemblies of inorganic polymer chains in which the key structural degrees of freedom—namely, the relative vertical shifts of neighbouring chains—are mathematically equivalent to the phase angles of rotating planar (‘XY’) spins. Here, we show how the supramolecular interactions between chains can be tuned to mimic different magnetic interactions. In this way, the structures of gold(I) and/or silver(I) cyanides reflect the phase behaviour of triangular XY magnets. Complex magnetic states predicted for this family of magnets—including collective spin-vortices of relevance to data storage applications—are realized in the structural chemistry of these cyanide polymers. Our results demonstrate how chemically simple inorganic materials can behave as structural analogues of otherwise inaccessible ‘toy’ spin models and also how the theoretical understanding of those models allows control over collective (‘emergent’) phenomena in supramolecular systems.

  5. The degree of biogenicity of micrites and terrestrial Mars analogues .

    NASA Astrophysics Data System (ADS)

    D'Elia, M.; Blanco, A.; Orofino, V.; Fonti, S.; Mastandrea, A.; Guido, A.; Tosti, F.; Russo, F.

    A number of indications, as the past presence of water, a denser atmosphere and a mild climate on early Mars, suggest that environmental conditions favorable to the emergence of life must have been present on that planet in the first hundred million years, or even more recently. If life actually existed on Mars, biomarkers could be still preserved with some degree of degradation. In previous laboratory works we have investigated the infrared spectral modifications induced by thermal processing on different carbonate samples, in the form of recent shells and fossils of different ages, whose biogenic origin is indisputable. The goal was to develop a method able to discriminate carbonate biogenic samples from their abiogenic counterparts. The method has been successfully applied to microbialites, i.e. bio-induced carbonates deposits, and particularly to stromatolites, the laminated fabric of microbialites, some of which can be ascribed among the oldest traces of biological activity known on Earth. This result is of valuable importance since such carbonates are linked to primitive living organisms which can be considered as good analogues for putative Martian life forms. In this work we show that, studying different parts of the same carbonate rock sample, we are able to distinguish, on the base of the degree of biogenicity, the various micrite types (i.e. detrital vs autochthonous).

  6. Effects of cognitive and pharmacologic strategies on analogued labor pain.

    PubMed

    Geden, E A; Beck, N C; Anderson, J S; Kennish, M E; Mueller-Heinze, M

    1986-01-01

    Using an analogued labor pain procedure, the efficacy of combinations of five cognitive and one pharmacologic approach to pain management was examined. Nulliparous undergraduates (N = 120) were randomly assigned to 1 of 12 groups. Cognitive groups included: systematic desensitization (SYS DENS); sensory description (SEN DESC); sensory transformation (ST); modeling (M); and relaxation (R); combined groups: SYS DENS, SEN DESC, and ST; SEN DESC, ST, and R; SEN DESC, R, ST, and Demerol. Pharmacologic groups included expected Demerol, did not expect Demerol, placebo, and no treatment control. Subjects assigned to a cognitive group received two 1-hour training sessions 1 week apart. Remaining subjects were given the assigned pharmacologic treatment one-half hour prior to the exposure to the painful stimulus. Assessment of the cognitive and pharmacologic approaches were made in a 1-hour session involving twenty 80-second exposures to a laboratory pain stimulus patterned to resemble labor contractions. Dependent variables included self-reported pain, blood pressure, frontalis electromyograph, heart rate, and respiratory rate. Significant treatment by trials and treatment effects were found for self-reported pain. No other effects achieved statistical significance.

  7. The Disk and Planets of Solar Analogue τCeti

    NASA Astrophysics Data System (ADS)

    Lawler, S. M.; Francesco, J. Di; Kennedy, G.; Sibthorpe, B.; Booth, M.; Vandenbussche, B.; Matthews, B.; Tuomi, M.

    2015-01-01

    τ Ceti is a nearby, mature star very similar to our Sun, with a massive Kuiper belt analogue tep{Greavesetal2004} and possible multiplanet system tep{Tuomietal2013} that has been compared to our Solar System. We present infrared and submillimeter observations of the debris disk from the Herschel Space Observatory and the James Clerk Maxwell Telescope (JCMT). We find the best model of the disk is a wide annulus ranging from 5-55 AU, inclined from face-on by 30°. tet{Tuomietal2013} report five possible super-Earths tightly nestled inside 1.4 AU, and we model this planetary system and place dynamical constraints on the inner edge of the disk. We find that due to the low masses and fairly circular orbits of the planets, the disk could reach as close to the star as 1.5 AU, with some stable orbits even possible between the two outermost planets. The photometric modelling cannot rule out a disk inner edge as close to the star as 1 AU, though 5-10 AU produces a better fit to the data. Dynamical modelling shows that the 5 planet system is stable with the addition of a Saturn-mass planet on an orbit outside 5 AU, where the Tuomi et al. analysis would not have detected a planet of this mass.

  8. High-affinity carbamate analogues of morphinan at opioid receptors.

    PubMed

    Peng, Xuemei; Knapp, Brian I; Bidlack, Jean M; Neumeyer, John L

    2007-03-15

    A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro for their binding affinity at mu, delta, and kappa opioid receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for kappa receptor (K(i)=0.046 and 0.051 nM) and for mu receptor (K(i)=0.11 and 0.12 nM). Compound 1c showed the highest mu selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [(35)S]GTPgammaS binding mediated by the kappa opioid receptor illustrated that all of these ligands were kappa agonists. At the mu receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were mu agonists/antagonists.

  9. A Visual Analogue Scale in the Assessment of Dental Anxiety

    PubMed Central

    Luyk, Neil H.; Beck, Frank M.; Weaver, Joel M.

    1988-01-01

    The purpose of this study is to determine the validity of the visual analogue scale (VAS) in the assessment of changing levels of dental anxiety, through correlation with the dental anxiety scale (DAS) and the state portion (A-state) of the statetrait anxiety inventory (STAI). Forty-five adult patients attending an oral surgery clinic for a routine dental extraction participated. Before any treatment, each patient completed the DAS, the STAI, and a 100mm VAS. The order of administration was randomly determined. Following completion of the dental extraction under local anesthesia and just before discharge, the patients were once more asked to complete the DAS, the A-State, and a VAS which were again randomly ordered. All three measures demonstrate a significant reduction in mean anxiety scores from presurgery to postsurgery. There are significant correlations among the three measures both pre- and postsurgery. The VAS appears to correlate well with both the DAS and the A-State under changing levels of anxiety. PMID:3166350

  10. Digitally Programmable Analogue Circuits for Sensor Conditioning Systems

    PubMed Central

    Zatorre, Guillermo; Medrano, Nicolás; Sanz, María Teresa; Aldea, Concepción; Calvo, Belén; Celma, Santiago

    2009-01-01

    This work presents two current-mode integrated circuits designed for sensor signal preprocessing in embedded systems. The proposed circuits have been designed to provide good signal transfer and fulfill their function, while minimizing the load effects due to building complex conditioning architectures. The processing architecture based on the proposed building blocks can be reconfigured through digital programmability. Thus, sensor useful range can be expanded, changes in the sensor operation can be compensated for and furthermore, undesirable effects such as device mismatching and undesired physical magnitudes sensor sensibilities are reduced. The circuits were integrated using a 0.35 μm standard CMOS process. Experimental measurements, load effects and a study of two different tuning strategies are presented. From these results, system performance is tested in an application which entails extending the linear range of a magneto-resistive sensor. Circuit area, average power consumption and programmability features allow these circuits to be included in embedded sensing systems as a part of the analogue conditioning components. PMID:22412331

  11. Digitally programmable analogue circuits for sensor conditioning systems.

    PubMed

    Zatorre, Guillermo; Medrano, Nicolás; Sanz, María Teresa; Aldea, Concepción; Calvo, Belén; Celma, Santiago

    2009-01-01

    This work presents two current-mode integrated circuits designed for sensor signal preprocessing in embedded systems. The proposed circuits have been designed to provide good signal transfer and fulfill their function, while minimizing the load effects due to building complex conditioning architectures. The processing architecture based on the proposed building blocks can be reconfigured through digital programmability. Thus, sensor useful range can be expanded, changes in the sensor operation can be compensated for and furthermore, undesirable effects such as device mismatching and undesired physical magnitudes sensor sensibilities are reduced. The circuits were integrated using a 0.35 μm standard CMOS process. Experimental measurements, load effects and a study of two different tuning strategies are presented. From these results, system performance is tested in an application which entails extending the linear range of a magneto-resistive sensor. Circuit area, average power consumption and programmability features allow these circuits to be included in embedded sensing systems as a part of the analogue conditioning components.

  12. Role of Cosmic Dust Analogues in prebiotic chemistry

    NASA Astrophysics Data System (ADS)

    Brucato, J. R.; Strazzulla, G.; Baratta, G. A.; Saladino, R.; di Mauro, E.

    Dust grains could have played an important role in driving the formation of complex molecular compounds relevant for the prebiotic chemistry occurred in the early Earth. Dust and molecular compounds present in space experienced very different environments, with temperatures ranging from few to thousands of Kelvins, and with very harsh conditions due to particle and UV irradiations. Astronomical observations of the interstellar medium, coupled with direct in-situ investigations of solar system bodies performed by space missions and laboratory analyses of extraterrestrial material have shown the presence of large amount of organic molecules. The detection of more than one hundred molecules demonstrates that chemical reactions can proceed successfully in space. However, due to low efficiency, formation of complex molecules in gas phase is not feasible, then an active chemistry has been suggested to take place at cryogenic temperatures (~10 K) on cosmic dust grains acting as catalysts. We will present laboratory results on catalytic effects of Cosmic Dust Analogues (CDAs) with olivine composition, in the synthesis of organic molecules under different physical conditions by using formamide (NH2COH). We will show the important role of CDAs in prebiotic chemistry experiments simulating processes occurring in astronomical environments relevant for the origin of life in the Solar System.

  13. Detecting Pyrolysis Products from Bacteria in a Mars Soil Analogue

    NASA Technical Reports Server (NTRS)

    Glavin, D. P.; Cleaves, H. J.; Schubert, M.; Aubrey, A.; Buch, A.; Mahaffy, P. R.; Bada, J. L.

    2004-01-01

    One of the primary objectives of the 1976 Viking missions was to determine whether organic compounds, possibly of biological origin, were present in the Martian surface soils. The Viking gas chromatography mass spectrometry (GCMS) instruments found no evidence for any organic compounds of Martian origin above a few parts per billion in the upper 10 cm of surface soil, suggesting the absence of a widely distributed Martian biota. However, it is now known that key organic compounds important to biology, such as amino acids, carboxylic acids and nucleobases, would likely have been missed by the Viking GCMS instruments. In this study, a Mars soil analogue that was inoculated with approx. 10 billion Escherichia coli cells was heated at 500 C under Martian ambient pressure to release volatile organic compounds from the sample. The pyrolysis products were then analyzed for amino acids and nucleobases using high performance liquid chromatography (HPLC) and GCMS. Our experimental results indicate that at the part per billion level, the degradation products generated from several million bacterial cells per gram of Martian soil would not have been detected by the Viking GCMS instruments. Upcoming strategies for Mars exploration will require in-situ analyses by instruments that can assess whether any organic compounds, especially those that might be associated with life, are present in Martian surface samples.

  14. Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues.

    PubMed

    Chen, Liuhong; Cressina, Elena; Dixon, Neil; Erixon, Karl; Agyei-Owusu, Kwasi; Micklefield, Jason; Smith, Alison G; Abell, Chris; Leeper, Finian J

    2012-08-14

    The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, thiamine pyrophosphate (TPP or thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch-ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.

  15. Upheaval Dome, An Analogue Site for Gale Center

    NASA Technical Reports Server (NTRS)

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

    2011-01-01

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

  16. Preliminary results of Mn partitioning experiments on Murchison analogues

    NASA Technical Reports Server (NTRS)

    Boesenberg, Joseph S.; Delaney, Jeremy S.

    1993-01-01

    Eucrites, howardites, and diogenites have Fe/Mn ratios between 30 and 45, while carbonaceous chondrites have much higher values between 90 and 150. Stolper (1977) first showed that basaltic achondrites could evolve from a precursor chondritic material through simple partial melting. These experiments indicated that chondritic material heated to temperatures near 1180 C with a fugacity of one log unit below the iron-wustite buffer curve, produced a eucritic mineralogy that contained olivine, pigeonite, plagioclase, spinel, glass, and metal. The partial melting experiments of Jurewicz et al. (1992) on an hydrous Murchison and Allende also showed that HED compositions were produceable at temperatures between 1130 C and 1325 C with fugacities below and above the iron-wustite buffer curve. However, the MnO abundances of Jurewicz were too low to produce suitable Fe/Mn ratios for HED's. We present below our results of partial melting experiments on Murchison analogues that involved temperatures between 1180 C and 1580 C and fugacities below the iron-wustite buffer curve. Our experiments resulted in MnO abundances nearly twice that of Jurewicz and indicate that the production of basaltic achondrite-like Fe/Mn ratios from precursor chondritic material are possible.

  17. Effects of melatonin and its analogues on neural stem cells.

    PubMed

    Chu, Jiaqi; Tu, Yalin; Chen, Jingkao; Tan, Dunxian; Liu, Xingguo; Pi, Rongbiao

    2016-01-15

    Neural stem cells (NSCs) are multipotent cells which are capable of self-replication and differentiation into neurons, astrocytes or oligodendrocytes in the central nervous system (CNS). NSCs are found in two main regions in the adult brain: the subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ). The recent discovery of NSCs in the adult mammalian brain has fostered a plethora of translational and preclinical studies to investigate novel approaches for the therapy of neurodegenerative diseases. Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. Recently, accumulated experimental evidence showed that melatonin plays an important role in NSCs, including its proliferation, differentiation and survival, which are modulated by many factors including MAPK/ERK signaling pathway, histone acetylation, neurotrophic factors, transcription factors, and apoptotic genes. The purpose of this review is to summarize the beneficial effects of melatonin on NSCs and further to discuss the potential usage of melatonin and its derivatives or analogues in the treatment of CNS neurodegenerative diseases.

  18. Generalized uncertainty principle and analogue of quantum gravity in optics

    NASA Astrophysics Data System (ADS)

    Braidotti, Maria Chiara; Musslimani, Ziad H.; Conti, Claudio

    2017-01-01

    The design of optical systems capable of processing and manipulating ultra-short pulses and ultra-focused beams is highly challenging with far reaching fundamental technological applications. One key obstacle routinely encountered while implementing sub-wavelength optical schemes is how to overcome the limitations set by standard Fourier optics. A strategy to overcome these difficulties is to utilize the concept of a generalized uncertainty principle (G-UP) which has been originally developed to study quantum gravity. In this paper we propose to use the concept of G-UP within the framework of optics to show that the generalized Schrödinger equation describing short pulses and ultra-focused beams predicts the existence of a minimal spatial or temporal scale which in turn implies the existence of maximally localized states. Using a Gaussian wavepacket with complex phase, we derive the corresponding generalized uncertainty relation and its maximally localized states. Furthermore, we numerically show that the presence of nonlinearity helps the system to reach its maximal localization. Our results may trigger further theoretical and experimental tests for practical applications and analogues of fundamental physical theories.

  19. Herkinorin Analogues with Differential Beta-Arrestin-2 Interactions

    PubMed Central

    Tidgewell, Kevin; Groer, Chad E.; Harding, Wayne W.; Lozama, Anthony; Schmidt, Matthew; Marquam, Alfred; Hiemstra, Jessica; Partilla, John S.; Dersch, Christina M.; Rothman, Richard B.; Bohn, Laura M.; Prisinzano, Thomas E.

    2008-01-01

    Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of βarrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of βarrestin-2 to the μOR and receptor internalization. Considering the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor ligands with the ability to produce analgesia while limiting adverse side effects. PMID:18380425

  20. Molecular mechanisms underlying a cellular analogue of operant reward learning

    PubMed Central

    Lorenzetti, Fred D.; Baxter, Douglas A.; Byrne, John H.

    2008-01-01

    SUMMARY Operant conditioning is a ubiquitous but mechanistically poorly understood form of associative learning in which an animal learns the consequences of its behavior. Using a single-cell analogue of operant conditioning in neuron B51 of Aplysia, we examined second-messenger pathways engaged by activity and reward and how they may provide a biochemical association underlying operant learning. Conditioning was blocked by Rp-cAMP, a peptide inhibitor of PKA, a PKC inhibitor and by expressing a dominant negative isoform of Ca2+-dependent PKC (apl-I). Thus, both PKA and PKC were necessary for operant conditioning. Injection of cAMP into B51 mimicked the effects of operant conditioning. Activation of PKC also mimicked conditioning, but was dependent on both cAMP and PKA, suggesting that PKC acted at some point upstream of PKA activation. Our results demonstrate how these molecules can interact to mediate operant conditioning in an individual neuron important for the expression of the conditioned behavior. PMID:18786364

  1. Laboratory simulation on EUV photolysis of inorganic interstellar ice analogues

    NASA Astrophysics Data System (ADS)

    Chen, Y. J.; Nuevo, M.; Yih, T. S.; Ip, W. H.; Wu, C. Y.; Fung, H. S.; Lee, Y. Y.; Cheng, C.; Tsai, H. R.

    In this report we focused on the formation of large organic molecules from most simple cosmic inorganic ice analogues consisting of H 2 O CO 2 and NH 3 irradiated by extreme ultraviolet EUV photons We employed an ultra-high vacuum chamber equipped with a closed- cycle helium cryostat to simulate the environment of the space beyond the atmosphere The necessary intense simulation of solar radiation is provided by a synchrotron beam in the wide 4 -- 20eV range at National Synchrotron Radiation Research Center in Hsinchu Taiwan After exposure to 10 20 photon dose the icy sample was warmed up to room temperature under dynamic vacuum then we deposited another icy sample as well as last one and EUV irradiated and warmed up to room temperature again and again for six times the KBr substrate was then removed in an environment filled with argon gas After removed into laboratory the sample was washed with distilled water and hydrolyzed in a standard procedure the residue was then analyzed by HPLC The result shows that we could clearly identify 8 amino acids such as glycine Banaline Bserine ldots etc which were left over in the residue Associated with those basic amino acids are several other large molecules that could be tentatively identified as basic organic materials evolved from photolysis process

  2. Muscarinic receptor subtype selectivity of novel heterocyclic QNB analogues

    SciTech Connect

    Baumgold, J.; Cohen, V.I.; Paek, R.; Reba, R.C. )

    1991-01-01

    In an effort at synthesizing centrally-active subtype-selective antimuscarinic agents, the authors derivatized QNB (quinuclidinyl benzilate), a potent muscarinic antagonist, by replacing one of the phenyl groups with less lipophilic heterocyclic moieties. The displacement of ({sup 3}H)-N-methyl scopolamine binding by these novel compounds to membranes from cells expressing ml - m4 receptor subtypes was determined. Most of the novel 4-bromo-QNB analogues were potent and slightly selective for ml receptors. The 2-thienyl derivative was the most potent, exhibiting a 2-fold greater potency than BrQNB at ml receptors, and a 4-fold greater potency than BrQNB at ml receptors, and a 4-fold greater potency at m2 receptors. This compound was also considerably less lipophilic than BrQNB as determined from its retention time on C18 reverse phase HPLC. This compound may therefore be useful both for pharmacological studies and as a candidate for a radioiodinated SPECT imaging agent for ml muscarinic receptors in human brain.

  3. Modern freshwater microbialite analogues for ancient dendritic reef structures

    NASA Technical Reports Server (NTRS)

    Laval, B.; Cady, S. L.; Pollack, J. C.; McKay, C. P.; Bird, J. S.; Grotzinger, J. P.; Ford, D. C.; Bohm, H. R.

    2000-01-01

    Microbialites are organosedimentary structures that can be constructed by a variety of metabolically distinct taxa. Consequently, microbialite structures abound in the fossil record, although the exact nature of the biogeochemical processes that produced them is often unknown. One such class of ancient calcareous structures, Epiphyton and Girvanella, appear in great abundance during the Early Cambrian. Together with Archeocyathids, stromatolites and thrombolites, they formed major Cambrian reef belts. To a large extent, Middle to Late Cambrian reefs are similar to Precambrian reefs, with the exception that the latter, including terminal Proterozoic reefs, do not contain Epiphyton or Girvanella. Here we report the discovery in Pavilion Lake, British Columbia, Canada, of a distinctive assemblage of freshwater calcite microbialites, some of which display microstructures similar to the fabrics displayed by Epiphyton and Girvanella. The morphologies of the modern microbialites vary with depth, and dendritic microstructures of the deep water (> 30 m) mounds indicate that they may be modern analogues for the ancient calcareous structures. These microbialites thus provide an opportunity to study the biogeochemical interactions that produce fabrics similar to those of some enigmatic Early Cambrian reef structures.

  4. Design and synthesis of novel stiripentol analogues as potential anticonvulsants.

    PubMed

    Aboul-Enein, Mohamed N; El-Azzouny, Aida A; Attia, Mohamed I; Maklad, Yousreya A; Amin, Kamilia M; Abdel-Rehim, Mohamed; El-Behairy, Mohammed F

    2012-01-01

    A series of stiripentol (STP) analogues namely, 2-[(1E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ylidene]-N-(aryl/H)hydrazinecarboxamides 7a-h, (±)-(5RS)-N-(aryl/H)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carboxamides (±)-8a-h, and (±)-[(5RS)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazol-1-yl](aryl)methanones (±)-13a-f was synthesized by adopting appropriate synthetic routes and was pharmacologically evaluated in the preliminary anticonvulsant screens. The selected bioactive new chemical entities were subjected to ED(50) determination and neurotoxicity evaluation. The most active congeners are 7h in MES screen and (±)-13b in scPTZ screen which displayed ED(50) values of 87 and 110 mg/kg, respectively, as compared to that of STP (ED(50) = 277.7 and 115 mg/kg in MES and scPTZ, respectively).

  5. Antimicrobial Activity of Xanthohumol and Its Selected Structural Analogues.

    PubMed

    Stompor, Monika; Żarowska, Barbara

    2016-05-11

    The objective of this study was to evaluate the antimicrobial activity of structural analogues of xanthohumol 1, a flavonoid compound found in hops (Humulus lupulus). The agar-diffusion method using filter paper disks was applied. Biological tests performed for selected strains of Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria, fungi (Alternaria sp.), and yeasts (Rhodotorula rubra, Candida albicans) revealed that compounds with at least one hydroxyl group-all of them have it at the C-4 position-demonstrated good activity. Our research showed that the strain S. aureus was more sensitive to chalcones than to the isomers in which the heterocyclic ring C is closed (flavanones). The strain R. rubra was moderately sensitive to only one compound: 4-hydroxy-4'-methoxychalcone 8. Loss of the hydroxyl group in the B-ring of 4'-methoxychalcones or its replacement by a halogen atom (-Cl, -Br), nitro group (-NO₂), ethoxy group (-OCH₂CH₃), or aliphatic substituent (-CH₃, -CH₂CH₃) resulted in the loss of antimicrobial activity towards both R. rubra yeast and S. aureus bacteria. Xanthohumol 1, naringenin 5, and chalconaringenin 7 inhibited growth of S. aureus, whereas 4-hydroxy-4'-methoxychalcone 8 was active towards two strains: S. aureus and R. rubra.

  6. Onboard Detection of Active Canadian Sulfur Springs: A Europa Analogue

    NASA Technical Reports Server (NTRS)

    Castano, Rebecca; Wagstaff, Kiri; Gleeson, Damhnait; Pappalardo, Robert; Chien, Steve; Tran, Daniel; Scharenbroich, Lucas; Moghaddam, Baback; Tang, Benyang; Bue, Brian; Doggett, Thomas; Mandl, Dan; Frye, Stuart

    2008-01-01

    We discuss a current, ongoing demonstration of insitu onboard detection in which the Earth Observing-1 spacecraft detects surface sulfur deposits that originate from underlying springs by distinguishing the sulfur from the ice-rich glacial background, a good analogue for the Europan surface. In this paper, we describe the process of developing the onboard classifier for detecting the presence of sulfur in a hyperspectral scene, including the use of a training/testing set that is not exhaustively labeled, i.e.not all true positives are marked, and the selection of 12, out of 242, Hyperion instrument wavelength bands to use in the onboard detector. This study aims to demonstrate the potential for future missions to capture short-lived science events, make decisions onboard, identify high priority data for downlink and perform onboard change detection. In the future, such capability could help maximize the science return of downlink bandwidth-limited missions, addressing a significant constraint in all deep-space missions.

  7. Mechanism of cis-prenyltransferase reaction probed by substrate analogues

    SciTech Connect

    Lu, Yen-Pin; Liu, Hon-Ge; Teng, Kuo-Hsun; Liang, Po-Huang

    2010-10-01

    Research highlights: {yields} The extremely slow trans-OPPS reaction using 2-Fluoro-FPP supports the sequential mechanism with the carbocation intermediate. {yields} The similar UPPS reaction rate under single turnover supports the concerted mechanism, without the carbocation intermediate. {yields} The secondary kinetic isotope effect also supports associate transition state for UPPS reaction, without the carbocation intermediate. -- Abstract: Undecaprenyl pyrophosphate synthase (UPPS) is a cis-type prenyltransferases which catalyzes condensation reactions of farnesyl diphosphate (FPP) with eight isopentenyl pyrophosphate (IPP) units to generate C{sub 55} product. In this study, we used two analogues of FPP, 2-fluoro-FPP and [1,1-{sup 2}H{sub 2}]FPP, to probe the reaction mechanism of Escherichia coli UPPS. The reaction rate of 2-fluoro-FPP with IPP under single-turnover condition is similar to that of FPP, consistent with the mechanism without forming a farnesyl carbocation intermediate. Moreover, the deuterium secondary KIE of 0.985 {+-} 0.022 measured for UPPS reaction using [1,1-{sup 2}H{sub 2}]FPP supports the associative transition state. Unlike the sequential mechanism used by trans-prenyltransferases, our data demonstrate E. coli UPPS utilizes the concerted mechanism.

  8. Fetal bovine serum influences the stability and bioactivity of resveratrol analogues: A polyphenol-protein interaction approach.

    PubMed

    Tang, Fen; Xie, Yixi; Cao, Hui; Yang, Hua; Chen, Xiaoqing; Xiao, Jianbo

    2017-03-15

    Fetal bovine serum (FBS) is a universal growth supplement of cell and tissue culture media. Herein, the influences of FBS on the stability and antioxidant activity of 21 resveratrol analogues were investigated using a polyphenol-protein interaction approach. The structure-stability relationships of resveratrol analogues in FBS showed a clear decrease in the stability of hydroxylated resveratrol analogues in the order: resorcinol-type>pyrogallol-type>catechol-type. The glycosylation and methoxylation of resveratrol analogues enhanced their stability. A linear relationship between the stability of resveratrol analogues in FBS and the affinity of resveratrol analogues-FBS interaction was found. The oxidation process is not the only factor governing the stability of resveratrol analogues in FBS. These results facilitated the insightful investigation of the role of polyphenol-protein interactions in serum, thereby providing some fundamental clues for future clinical research and pharmacological studies on natural small molecules.

  9. C5-substituents of uridines and 2-thiouridines present at the wobble position of tRNA determine the formation of their keto-enol or zwitterionic forms - a factor important for accuracy of reading of guanosine at the 3'-end of the mRNA codons.

    PubMed

    Sochacka, Elzbieta; Lodyga-Chruscinska, Elzbieta; Pawlak, Justyna; Cypryk, Marek; Bartos, Paulina; Ebenryter-Olbinska, Katarzyna; Leszczynska, Grazyna; Nawrot, Barbara

    2017-01-13

    Modified nucleosides present in the wobble position of the tRNA anticodons regulate protein translation through tuning the reading of mRNA codons. Among 40 of such nucleosides, there are modified uridines containing either a sulfur atom at the C2 position and/or a substituent at the C5 position of the nucleobase ring. It is already evidenced that tRNAs with 2-thiouridines at the wobble position preferentially read NNA codons, while the reading mode of the NNG codons by R5U/R5S2U-containing anticodons is still elusive. For a series of 18 modified uridines and 2-thiouridines, we determined the pKa values and demonstrated that both modifying elements alter the electron density of the uracil ring and modulate the acidity of their N3H proton. In aqueous solutions at physiological pH the 2-thiouridines containing aminoalkyl C5-substituents are ionized in ca. 50%. The results, confirmed also by theoretical calculations, indicate that the preferential binding of the modified units bearing non-ionizable 5-substituents to guanosine in the NNG codons may obey the alternative C-G-like (Watson-Crick) mode, while binding of those bearing aminoalkyl C5-substituents (protonated under physiological conditions) and especially those with a sulfur atom at the C2 position, adopt a zwitterionic form and interact with guanosine via a 'new wobble' pattern.

  10. Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide.

    PubMed

    Matsui, Hisanori; Masaki, Tsuneo; Akinaga, Yumiko; Kiba, Atsushi; Takatsu, Yoshihiro; Nakata, Daisuke; Tanaka, Akira; Ban, Junko; Matsumoto, Shin-ichi; Kumano, Satoshi; Suzuki, Atsuko; Ikeda, Yukihiro; Yamaguchi, Masashi; Watanabe, Tatsuya; Ohtaki, Tetsuya; Kusaka, Masami

    2014-07-15

    Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008-8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3-7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683.

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

    SciTech Connect

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

    2008-09-07

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

  12. Unsaturated Analogues of the Neurotransmitter GABA: trans-4-Aminocrotonic, cis-4-Aminocrotonic and 4-Aminotetrolic Acids.

    PubMed

    Johnston, Graham A R

    2016-03-01

    Analogues of the neurotransmitter GABA containing unsaturated bonds are restricted in the conformations they can attain. This review traces three such analogues from their synthesis to their use as neurochemicals. trans-4-Aminocrotonic acid was the first conformationally restricted analogue to be extensively studied. It acts like GABA across a range of macromolecules from receptors to transporters. It acts similarly to GABA on ionotropic receptors. cis-4-Aminocrotonic acid selectively activates bicuculline-insensitive GABAC receptors. 4-Aminotetrolic acid, containing a triple bond, activates bicuculline-sensitive GABAA receptors. These findings indicate that GABA activates GABAA receptors in extended conformations and GABAC receptors in folded conformations. These and related analogues are important for the molecular modelling of ionotropic GABA receptors and to the development of new agents acting selectively on these receptors.

  13. In vitro antifungal and antibiofilm activities of halogenated quinoline analogues against Candida albicans and Cryptococcus neoformans.

    PubMed

    Zuo, Ran; Garrison, Aaron T; Basak, Akash; Zhang, Peilan; Huigens, Robert W; Ding, Yousong

    2016-08-01

    With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments.

  14. Mars Methane Analogue Mission (M3): Near Subsurface Electromagnetic Techniques and Analysis

    NASA Astrophysics Data System (ADS)

    Boivin, A.; Samson, C.; Holladay, J. S.; Cloutis, E. A.; Ernst, R. E.

    2012-03-01

    As part of the Canadian Space Agency's Mars Methane Analogue Mission, a micro-rover mission, an Electromagnetic Induction Sounder (EMIS) was used with the goal of demonstrating its value as a potential science instrument onboard future rovers.

  15. Identification of a new tadalafil analogue in commercial dietary supplements: isopropylnortadalafil.

    PubMed

    Park, Han Na; Lee, Ji Hyun; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

    2017-02-01

    A new tadalafil analogue was found in a commercial dietary supplement for enhancing sexual performance. The compound was detected by a high-performance liquid chromatography-diode array detector (HPLC-DAD). The analogue was isolated using semi-preparative HPLC, and its accurate mass was established by two LC-high-resolution-mass spectrometers (LC-HRMS). The structure was determined by nuclear magnetic resonance (NMR) spectroscopy. The accurate mass of the compound corresponded to a molecular formula of C24H23N3O4. The compound was identified as a structural analogue of tadalafil in which the N-methyl group of tadalafil was replaced with an N-isopropyl group. We have named the new analogue isopropylnortadalafil and it is first reported herein.

  16. On an analogue signal processing circuit in the Nematode C. elegans.

    PubMed

    Skandari, Roghieh; Iino, Yuichi; Manton, Jonathan H

    2016-08-01

    In this work we will work on analogue signal processing in the neural circuit of C. elegans which is able to detect the analogue signals from the environment and produce locomotive behaviours which are in accordance with experiments. The signals in C. elegans are processed in a purely analogue procedure, since no action potential has been recorded in its neural activity. We aim to show how signal processing can be executed in analogue domain in a living creature. In order to do that we will model two different behaviours of C. elegans which are generated in the same network of neurons, klinotaxis behaviour and isothermal tracking. We will implement a Genetic Algorithm to find appropriate sets of parameters of the model. Our contribution is to show how relatively straight forward differential equations can lead to relatively complex and different behaviours.

  17. Analogues of arginine vasopressin modified in position 2 and 3 with conformationally constrained dipeptide fragments.

    PubMed

    Łempicka, Elzbieta; Derdowska, Izabela; Kowalczyk, Wioleta; Dawidowska, Olga; Prahl, Adam; Janecki, Marcin; Jasiński, Tomasz; Trzeciak, Henryk I; Lammek, Bernard

    2005-02-01

    This study describes the synthesis and some pharmacological properties of ten new analogues of arginine vasopressin (AVP) containing a conformationally constrained dipeptide fragment in the N-terminal part of their molecules. Amino acid residues in positions 2 and 3 of AVP and some of its agonistic analogues were replaced with -Phe-Phe and D-Phe-D-Phe, dipeptides having a -CH2-CH2- link bridging two nitrogens. All the new peptides were tested for vasopressor and antidiuretic activities. Four peptides with pA2 values ranging from 5.96 to 7.21 turned out to be weak or moderately potent V1a antagonists. The results supplied new information about the structure-activity relationship of AVP analogues. As some of these were unexpected, they point to the need for caution when extrapolating previously known effects of modifications to analogues having conformationally constrained fragments in their molecules.

  18. Charge-transfer complexes of Cu(II)/HD analogue in sol gel sensors

    NASA Astrophysics Data System (ADS)

    Brinkley, J. F.; Kirkey, M. L.; Marques, A. D. S.; Lin, C. T.

    2003-01-01

    An optically transparent xerogel encapsulating Cu(II) acetate is fabricated to detect mustard gas (HD) analogues via a charge-transfer mechanism. A fast response (color change from sky blue to canary yellow) is observed for the chlorinated sulfide, and is accompanied by an absorption band at 370-420 nm. MO calculations revealed that the chlorinated HD analogue displays a charge-transfer transition extended from sulfur to chlorine atom. A 1:1 complex of Cu(II)/HD analogue is preferred. For a colorimetric sol-gel detector prepared at pH 3, the detection limit of HD analogue is calibrated at 0.03 μl per 1.5 ml sensor volume.

  19. [Proteolysis of semax analogues with different N-terminal amino acids by aminopeptidases].

    PubMed

    Shevchenko, K V; V'iunova, T V; Nagaev, I Iu; Andreeva, L A; Alfeeva, L Iu; Miasoedov, N F

    2011-01-01

    Proteolysis of semax (Met-Glu-His-Phe-Pro-Gly-Pro, Sem) and its analogues ([Ala1]Sem, [Gly1]Sem, [Thr1]Sem, [Trp1]Sem) that are differ from semax in substitution of N-terminal Met residue were studied. It is shown that such replacement changes the rate of peptides degradation by N-aminopeptidases (EC 3.4.11.2, Sigma, Type VI, 9.2 units. Akt. / mg). [Ala1]Sem, [Gly1]Sem and [Thr1]Sem semax analogues proved to be more stable to proteolysis than semax (Sem), and their initial product of proteolysis is His-Phe-Pro-Gly-Pro (Sem-5). For triptophan analogue both Glu-His-Phe-Pro-Gly-Pro (Sem-6) and Sem-5 product are formed in similar quantities. It is found that all investigated analogues can be used as inhibitors in Sem proteolysis.

  20. Βasalts from Santorini Volcano: A New Candidate Martian Analogue

    NASA Astrophysics Data System (ADS)

    Pantazidis, A.; Baziotis, I.; Manoutsoglou, E.; Solomonidou, A.; Schwander, F.; Palles, D.; Kamitsos, E.; Koukouzas, N.; Keklikoglou, N.; Arvanitidis, C.; Martinez-Frias, J.; Asimow, P. D.

    2016-08-01

    We compared volcanic rocks from Santorini Volcano and ISAR basalts from Iceland, South Africa and Norway, which are considered as strong candidates for martian analogues. We conclude that Santorini expands the list of terrestrial Mars-like sites.