Evidence for an imidazoline by-product from glycans using tandem mass spectrometry.

Science.gov (United States)

Duff, Robert J; Smith, Elaine; Li, Wenzhou; Fodor, Szilan

2017-06-09

Herein is reported the separation and identification of a previously unknown imidazoline by-product originating from the fluorescent labeling procedure when applied to enzymatically released N-linked glycans of a human IgG1. The imidazoline by-product was generated via the reductive amination procedure with either sodium cyanoborohydride or 2-picoline borane. Using ultra performance liquid chromatography (UPLC) in conjunction with hydrophilic interaction-based chromatography (HILIC), the 2-aminobenzoic acid (2-AA)-labeled glycans were well-resolved from imidazoline by-products to facilitate direct identification utilizing electrospray ionization mass spectrometry (ESI-MS) with fragmentation. It was found that this minor species (∼2%) was 18.0105u less than the neighboring peak GlcNAc 2 Man 3 GlcNAc 2 Fuc peak, abbreviated as A2G0F at 1582.5899u. While this mass loss corresponds to the mass of a water molecule, the molecular location of loss of water was not straightforward in consideration of the biantennary A2G0F structure. Model studies were carried out using A2G0F standard and N-acetyllactosamine to identify the impurity as an imidazoline ring structure located at the reducing end of the glycan as confirmed by high resolution mass fragment ions. Imidazoline content decreased when the reductant concentration was increased. To conclude, evidence for the imidazoline structure was accomplished through high resolution, high accuracy mass spectrometry (HRAM), and experiments showing chemical susceptibility and isotopically labeled tracers. This study is the first to identify these minor species which likely impact all N-acetylglucosamine-type N-linked glycans from biologics. Copyright © 2017 Elsevier B.V. All rights reserved.

The putative imidazoline receptor agonist, harmane, promotes intracellular calcium mobilisation in pancreatic beta-cells.

Science.gov (United States)

Squires, Paul E; Hills, Claire E; Rogers, Gareth J; Garland, Patrick; Farley, Sophia R; Morgan, Noel G

2004-10-06

beta-Carbolines (including harmane and pinoline) stimulate insulin secretion by a mechanism that may involve interaction with imidazoline I(3)-receptors but which also appears to be mediated by actions that are additional to imidazoline receptor agonism. Using the MIN6 beta-cell line, we now show that both the imidazoline I(3)-receptor agonist, efaroxan, and the beta-carboline, harmane, directly elevate cytosolic Ca(2+) and increase insulin secretion but that these responses display different characteristics. In the case of efaroxan, the increase in cytosolic Ca(2+) was readily reversible, whereas, with harmane, the effect persisted beyond removal of the agonist and resulted in the development of a repetitive train of Ca(2+)-oscillations whose frequency, but not amplitude, was concentration-dependent. Initiation of the Ca(2+)-oscillations by harmane was independent of extracellular calcium but was sensitive to both dantrolene and high levels (20 mM) of caffeine, suggesting the involvement of ryanodine receptor-gated Ca(2+)-release. The expression of ryanodine receptor-1 and ryanodine receptor-2 mRNA in MIN6 cells was confirmed using reverse transcription-polymerase chain reaction (RT-PCR) and, since low concentrations of caffeine (1 mM) or thimerosal (10 microM) stimulated increases in [Ca(2+)](i), we conclude that ryanodine receptors are functional in these cells. Furthermore, the increase in insulin secretion induced by harmane was attenuated by dantrolene, consistent with the involvement of ryanodine receptors in mediating this response. By contrast, the smaller insulin secretory response to efaroxan was unaffected by dantrolene. Harmane-evoked changes in cytosolic Ca(2+) were maintained by nifedipine-sensitive Ca(2+)-influx, suggesting the involvement of L-type voltage-gated Ca(2+)-channels. Taken together, these data imply that harmane may interact with ryanodine receptors to generate sustained Ca(2+)-oscillations in pancreatic beta-cells and that this effect

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

Science.gov (United States)

Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was

Tentative identification of 2-imidazoline as a transformation product of ethylenebisdithiocarbamate fungicides

NARCIS (Netherlands)

Vonk, J.W.; Kaars Sijpesteijn, A.

2-Imidazoline has been identified tentatively as a minor conversion product of ethylenethiourea in seedlings of cucumber and wheat. As ethylenethiourea is known to be present in plants after root treatment with ethylenebisdithiocarbamate fungicides, 2-imidazoline is assumed to be a terminal residue

Imidazoline2 (I2) receptor- and alpha2-adrenoceptor-mediated modulation of hypothalamic-pituitary-adrenal axis activity in control and acute restraint stressed rats.

Science.gov (United States)

Finn, David P; Hudson, Alan L; Kinoshita, Hiroshi; Coventry, Toni L; Jessop, David S; Nutt, David J; Harbuz, Michael S

2004-03-01

Central noradrenaline regulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis and the neuroendocrine response to stress. alpha2-adrenoceptors and imidazoline2 (I2) receptors modulate the activity of the central noradrenergic system. The present set of experiments investigated the role of alpha2-adrenoceptors and I2 receptors in the regulation of HPA axis activity under basal conditions and during exposure to the acute psychological stress of restraint. Three separate experiments were carried out in which rats were given an i.p. injection of either saline vehicle, the combined alpha2-adrenoceptor antagonist and I2 receptor ligand idazoxan (10 mg/kg), the selective I2 receptor ligand BU224 (2.5 or 10 mg/kg) or the selective alpha2-adrenoceptor antagonist RX821002 (2.5 mg/kg) with or without restraint stress. Drugs were administered immediately prior to restraint of 60 min duration. Blood was sampled pre-injection, 30, 60 and 240 min post-injection and plasma corticosterone was measured by radioimmunoassay. In experiment 1, idazoxan increased plasma corticosterone levels in naive animals and potentiated the corticosterone response to acute restraint stress. In experiment 2, BU224 administration increased plasma corticosterone levels in a dose-related manner in naive rats. The results of experiment 3 indicated that RX821002 also elevated plasma corticosterone levels in naive rats, however, only BU224 potentiated the corticosterone response to restraint stress. These studies suggest that both alpha2-adrenoceptors and I2 receptors play a role in modulating basal HPA axis activity and that I2 receptors may play a more important role than alpha2-adrenoceptors in modulating the HPA axis response to the acute psychological stress of restraint.

Radioprotective effect of low doses of 2-(1-naphthylmethyl)-2-imidazoline alone or associated with phosphorothioates

International Nuclear Information System (INIS)

Laval, J.D.; Roman, V.; Fatome, M.; Laduranty, J.; Miginiac, L.; Lion, C.; Sentenac-Roumanou, H.

1993-01-01

In the mouse, the intraperitoneal injection of 2-(1-naphthylmethyl)-2-imidazoline has a radioprotective effect even at low doses. Its association with S-[2-(3-aminopropyl)aminoethyl] phosphorothioate (WR 2721) or S-[3-(3-methylaminopropyl)-aminopropyl]phosphorothioate (WR 151327) at low doses led to an enhancement of their respective radioprotective activities without any apparent side effects. These results strengthen the interest of this non-sulphur compound as a radioprotector

Inhibition properties of self-assembled corrosion inhibitor talloil diethylenetriamine imidazoline for mild steel corrosion in chloride solution saturated with carbon dioxide

International Nuclear Information System (INIS)

Jevremović, Ivana; Singer, Marc; Nešić, Srđan; Mišković-Stanković, Vesna

2013-01-01

Highlights: •Corrosion inhibitor talloil diethylenetriamine imidazoline effectively protects mild steel from CO 2 corrosion. •Quartz crystal microbalance measurements were used to the investigate kinetics of corrosion inhibitor adsorption. •Adsorption of talloil diethylenetriamine imidazoline can be described by Langmuir adsorption isotherm. -- Abstract: The inhibition effect of talloil diethylenetriamine imidazoline (TOFA/DETA imidazoline) on corrosion of mild steel in chloride solutions saturated with CO 2 was investigated by weight loss measurements (WL) and atomic force microscopy (AFM). Adsorption mechanism and kinetics of self-assembled (TOFA/DETA imidazoline) monolayers formation on gold were studied using the quartz crystal microbalance measurements (QCM). WL and AFM results demonstrated that TOFA/DETA imidazoline can effectively protect mild steel surface from corrosion. QCM measurements shown that the adsorption of TOFA/DETA imidazoline onto gold follows Langmuir adsorption isotherm and further investigation of the adsorption process will be carried out on a corroding metal surface

Electrochemical behavior of Q235 steel in saltwater saturated with carbon dioxide based on new imidazoline derivative inhibitor

International Nuclear Information System (INIS)

Liu, F.G.; Du, M.; Zhang, J.; Qiu, M.

2009-01-01

The electrochemical behavior of carbon steel in saltwater saturated with CO 2 with/without an new synthesized imidazoline inhibitor was studied using polarization and electrochemical impedance spectrum (EIS), and the inhibitive ability of the inhibitor was evaluated by weight-loss method in 298-328 K temperature range. Results showed that the inhibition efficiency is up to above 80%, and imidazoline is a kind of mixed-type inhibitor. It was seen that the adsorption of imidazoline on Q235 steel can be fitted to Frumkin isotherm equation. Quantum chemistry calculation results show that the imidazoline ring and heteroatoms are the active sites of the inhibitors

A Biomarker to Differentiate between Primary and Cocaine-Induced Major Depression in Cocaine Use Disorder: The Role of Platelet IRAS/Nischarin (I1-Imidazoline Receptor

Directory of Open Access Journals (Sweden)

Benjamin Keller

2017-12-01

Full Text Available The association of cocaine use disorder (CUD and comorbid major depressive disorder (MDD; CUD/MDD is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD or cocaine-induced (CUD-induced MDD. Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A receptor and imidazoline receptor antisera selected (IRAS/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16 or CUD-induced MDD (n = 9; antidepressant free, AD−; antidepressant treated, AD+ and controls (n = 10 at basal level and/or after acute tryptophan depletion (ATD. Basal platelet 5-HT2A receptor (monomer was reduced in comorbid CUD/MDD subjects (all patients: 43% compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD−: 47%, and in AD+: 40%. No basal differences were found for IRAS/nischarin contents in AD+ and AD− comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.

Synthesis, spectral and structural properties of bis-imidazoline selones

Indian Academy of Sciences (India)

The solid state structures of bis-imidazoline selones were ... two biologically active selones are expected to function. ∗ .... The organic extract was washed with brine solution .... mentioned CH2 carbon and the quaternary carbon of benzene ...

Agmatine attenuates acquisition but not the expression of ethanol conditioned place preference in mice: a role for imidazoline receptors.

Science.gov (United States)

Sameer, Shaikh M; Chakraborty, Suwarna S; Ugale, Rajesh R

2013-04-01

The present study investigated the effect of agmatine on acquisition and expression of ethanol conditioned place preference (CPP) and its modulation by imidazoline agents. Swiss albino mice were treated intraperitoneally with saline or agmatine (20-40 mg/kg) before injection of ethanol (1.25 mg/kg) during conditioning days or on a test day (20-120 mg/kg), to observe the effect on acquisition or expression of CPP, respectively. Agmatine inhibited the acquisition but not the expression of ethanol CPP. Furthermore, both the I₁ receptor antagonist, efaroxan (9 mg/kg) and the I₂ receptor antagonist, BU224 (5 mg/kg) attenuated the agmatine-induced inhibition of the ethanol CPP acquisition. In contrast, the I₂ receptor agonist, 2-BFI (5 mg/kg) and I₁ receptor agonist, moxonidine (0.4 mg/kg) alone, or a combination of their subeffective doses, significantly attenuated the effect of agmatine (20 mg/kg) on acquisition of ethanol CPP. Agmatine or imidazoline agents alone produced neither place preference nor aversion, and at the doses used in the present study did not affect locomotor activity. Thus, agmatine attenuates the acquisition of ethanol CPP at least in part by imidazoline (I₁ or I₂) receptors. In future studies, agmatine or agents acting at the imidazoline receptors could be explored for their therapeutic potential in ethanol dependence.

Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

Directory of Open Access Journals (Sweden)

Sugawara A.M.

2001-01-01

Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

Allantoin ameliorates chemically-induced pancreatic β-cell damage through activation of the imidazoline I3 receptors

Directory of Open Access Journals (Sweden)

Marie Amitani

2015-08-01

Full Text Available Objective. Allantoin is the primary active compound in yams (Dioscorea spp.. Recently, allantoin has been demonstrated to activate imidazoline 3 (I3 receptors located in pancreatic tissues. Thus, the present study aimed to investigate the role of allantoin in the effect to improve damage induced in pancreatic β-cells by streptozotocin (STZ via the I3 receptors.Research Design and Methods. The effect of allantoin on STZ-induced apoptosis in pancreatic β-cells was examined using the ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and Western blottings. The potential mechanism was investigated using KU14R: an I3 receptor antagonist, and U73122: a phospholipase C (PLC inhibitor. The effects of allantoin on serum glucose and insulin secretion were measured in STZ-treated rats.Results. Allantoin attenuated apoptosis and cytotoxicity and increased the viability of STZ-induced β-cells in a dose-dependent manner; this effect was suppressed by KU14R and U73112. Allantoin decreased the level of caspase-3 and increased the level of phosphorylated B-cell lymphoma 2 (Bcl-2 expression detected by Western blotting. The improvement in β-cells viability was confirmed using flow cytometry analysis. Daily injection of allantoin for 8 days in STZ-treated rats significantly lowered plasma glucose and increased plasma insulin levels. This action was inhibited by treatment with KU14R.Conclusion. Allantoin ameliorates the damage of β-cells induced by STZ. The blockade by pharmacological inhibitors indicated that allantoin can activate the I3 receptors through a PLC-related pathway to decrease this damage. Therefore, allantoin and related analogs may be effective in the therapy for β-cell damage.

Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor.

Science.gov (United States)

Olmos, G; DeGregorio-Rocasolano, N; Paz Regalado, M; Gasull, T; Assumpció Boronat, M; Trullas, R; Villarroel, A; Lerma, J; García-Sevilla, J A

1999-07-01

This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L-glutamate (1-100 microM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 microM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 microM (EC100) L-glutamate with the rank order (EC50 in microM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole](101)>RX82 1002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding. In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10-12 microM at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are

SOMC-Designed Silica Supported Tungsten Oxo Imidazolin-2-iminato Methyl Precatalyst for Olefin Metathesis Reactions

KAUST Repository

Qureshi, Ziyauddin

2017-01-05

Synthesis, structure, and olefin metathesis activity of a surface complex [(≡Si-O-)W(═O)(CH3)2-ImDippN] (4) (ImDipp = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-iminato) supported on silica by a surface organometallic chemistry (SOMC) approach are reported. The reaction of N-silylated 2-iminoimidazoline with tungsten(VI) oxytetrachloride generated the tungsten oxo imidazolin-2-iminato chloride complex [ImDippNW(═O)Cl3] (2). This was grafted on partially dehydroxylated silica pretreated at 700 °C (SiO2-700) to afford a well-defined monopodal surface complex [(≡Si-O-)W(═O)Cl2-ImDippN] (3). 3 underwent alkylation by ZnMe2 to produce [(≡Si-O-)W(═O)(CH3)2-ImDippN] (4). The alkylated surface complex was thoroughly characterized by solid-state NMR, elemental microanalysis, Raman, FT-IR spectroscopies, and XAS analysis. 4 proved to be an active precatalyst for self-metathesis of terminal olefins such as propylene and 1-hexene.

SOMC-Designed Silica Supported Tungsten Oxo Imidazolin-2-iminato Methyl Precatalyst for Olefin Metathesis Reactions

KAUST Repository

Qureshi, Ziyauddin; Hamieh, Ali Imad Ali; Barman, Samir; Maity, Niladri; Samantaray, Manoja; Ould-Chikh, Samy; Abou-Hamad, Edy; Falivene, Laura; D’ Elia, Valerio; Rothenberger, Alexander; Llorens, Isabelle; Hazemann, Jean-Louis; Basset, Jean-Marie

2017-01-01

Synthesis, structure, and olefin metathesis activity of a surface complex [(≡Si-O-)W(═O)(CH3)2-ImDippN] (4) (ImDipp = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-iminato) supported on silica by a surface organometallic chemistry (SOMC) approach are reported. The reaction of N-silylated 2-iminoimidazoline with tungsten(VI) oxytetrachloride generated the tungsten oxo imidazolin-2-iminato chloride complex [ImDippNW(═O)Cl3] (2). This was grafted on partially dehydroxylated silica pretreated at 700 °C (SiO2-700) to afford a well-defined monopodal surface complex [(≡Si-O-)W(═O)Cl2-ImDippN] (3). 3 underwent alkylation by ZnMe2 to produce [(≡Si-O-)W(═O)(CH3)2-ImDippN] (4). The alkylated surface complex was thoroughly characterized by solid-state NMR, elemental microanalysis, Raman, FT-IR spectroscopies, and XAS analysis. 4 proved to be an active precatalyst for self-metathesis of terminal olefins such as propylene and 1-hexene.

Imidazoline and imidazolidine nitroxides as controlling agents in nitroxide-mediated pseudoliving radical polymerization

Science.gov (United States)

Edeleva, M. V.; Marque, S. R. A.; Bagryanskaya, E. G.

2018-04-01

Controlled, or pseudoliving, radical polymerization provides unique opportunities for the synthesis of structurally diverse polymers with a narrow molecular-weight distribution. These reactions occur under relatively mild conditions with broad tolerance to functional groups in the monomers. The nitroxide-mediated pseudoliving radical polymerization is of particular interest for the synthesis of polymers for biomedical applications. This review briefly describes one of the mechanisms of controlled radical polymerization. The studies dealing with the use of imidazoline and imidazolidine nitroxides as controlling agents for nitroxide-mediated pseudoliving radical polymerization of various monomers are summarized and analyzed. The publications addressing the key steps of the controlled radical polymerization in the presence of imidazoline and imidazolidine nitroxides and new approaches to nitroxide-mediated polymerization based on protonation of both nitroxides and monomers are considered. The bibliography includes 154 references.

An efficient solvent-free synthesis of imidazolines and benzimidazoles using K 4[Fe(CN 6] catalysis

Directory of Open Access Journals (Sweden)

Kabeer A. Shaikh

2012-01-01

Full Text Available Imidazolines and Benzimidazoles have been efficiently synthesized in high yields by treatment of 1,2-diamine with aldehydes using the metal co-ordinate complex K 4[Fe(CN 6] as a catalysis. The method was carried out under solvent free condition via oxidation of carbon-nitrogen bond. The process is green, mild and inexpensive.

Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction

Science.gov (United States)

Raasch, Walter; Schäfer, Ulrich; Qadri, Fatimunnisa; Dominiak, Peter

2002-01-01

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR.Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg−1, respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms.Agmatine reduces noradrenaline release in pithed SHR while α2-adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I1-binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate.Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR. PMID:11834614

Bis(imidazolin-2-iminato) rare earth metal complexes: synthesis, structural characterization, and catalytic application.

Science.gov (United States)

Trambitas, Alexandra G; Melcher, Daniel; Hartenstein, Larissa; Roesky, Peter W; Daniliuc, Constantin; Jones, Peter G; Tamm, Matthias

2012-06-18

Reaction of anhydrous rare earth metal halides MCl(3) with 2 equiv of 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-imine (Im(Dipp)NH) and 2 equiv of trimethylsilylmethyl lithium (Me(3)SiCH(2)Li) in THF furnished the complexes [(Im(Dipp)N)(2)MCl(THF)(n)] (M = Sc, Y, Lu). The molecular structures of all three compounds were established by single-crystal X-ray diffraction analyses. The coordination spheres around the pentacoordinate metal atoms are best described as trigonal bipyramids. Reaction of YbI(2) with 2 equiv of LiCH(2)SiMe(3) and 2 equiv of the imino ligand Im(Dipp)NH in tetrahydrofuran did not result in a divalent complex, but instead the Yb(III) complex [(Im(Dipp)N)(2)YbI(THF)(2)] was obtained and structurally characterized. Treatment of [(Im(Dipp)N)(2)MCl(THF)(n)] with 1 equiv of LiCH(2)SiMe(3) resulted in the formation of [(Im(Dipp)N)(2)M(CH(2)SiMe(3))(THF)(n)]. The coordination arrangement of these compounds in the solid state at the metal atoms is similar to that found for the starting materials, although the introduction of the neosilyl ligand induces a significantly greater distortion from the ideal trigonal-bipyramidal geometry. [(Im(Dipp)N)(2)Y(CH(2)SiMe(3))(THF)(2)] was used as precatalyst in the intramolecular hydroamination/cyclization reaction of various terminal aminoalkenes and of one aminoalkyne. The complex showed high catalytic activity and selectivity. A comparison with the previously reported dialkyl yttrium complex [(Im(Dipp)N)Y(CH(2)SiMe(3))(2)(THF)(3)] showed no clear tendency in terms of activity.

Diosmin, a Citrus Nutrient, Activates Imidazoline Receptors to Alleviate Blood Glucose and Lipids in Type 1-Like Diabetic Rats

Directory of Open Access Journals (Sweden)

Chia-Chen Hsu

2017-06-01

Full Text Available Diosmin is a nutrient that is widely contained in citrus and that has been indicated to improve glucose metabolism in diabetic disorders. Recently, we demonstrated that diosmin induces β-endorphin to lower hyperglycemia in diabetic rats. However, the mechanisms of diosmin in opioid secretion were unclear. Therefore, we focused on the secretion of opioids from isolated adrenal glands induced by diosmin. The changes in the released β-endorphin-like immunoreactivity (BER were determined using ELISA. Diosmin increased the BER level in a dose-dependent manner, and this effect was markedly reduced in the absence of calcium ions. Activation of the imidazoline I-2 receptor (I-2R has been introduced to induce opioid secretion. Interestingly, we observed that diosmin activates CHO cells expressing I-R. Additionally, diosmin-increased BER was inhibited by the blockade of I-2R in isolated adrenal glands. Additionally, an antagonist of I-2R blocked diosmin-induced effects, including the reduction in hyperglycemia and the increase in plasma BER in streptozotocin-induced diabetic rats (STZ-diabetic rats. Repeated treatment of STZ-diabetic rats with diosmin for one week induced changes in hepatic glycogen, lipid levels, and the expression of phosphoenolpyruvate carboxykinase (PEPCK. Furthermore, an antagonist of I-2R blocked the diosmin-induced changes. Additionally, plasma lipids modified by diosmin were also reversed by the blockade of I-2R in STZ-diabetic rats. Taken together, we suggest that diosmin may activate I-2R to enhance the secretion of β-endorphin from adrenal glands and to influence metabolic homeostasis, resulting in alleviation of blood glucose and lipids in STZ-diabetic rats.

Confirmation of the reaction pathway for obtaining 1-(stearamidoethyl-2-hepta-decyl-2-i midazoline

Directory of Open Access Journals (Sweden)

Ružić Nenad Lj.

2002-01-01

Full Text Available 2-lmidazolines are components of many products, used in industry and households. 1-(Stearamidoethyl-2-heptadecyl-2-imidazoline is a surface active compound, which after quaternization with dimethyl sulfate, is used in lubricants, detergents, shampoos, softeners and cosmetics products. Due to its importance, it was essential to establish the exact reaction pathway for obtaining this compound. Diethylene triamine and stearic acid were used as the starting components. Using titrimetric analysis, and IR and 1H NMR spectros-copic analysis, as well as UV-Vis spectrophotometry it was established that the main intermediate was the 1,3-diamide bis(stearamidoethylamine. Earlier investigations conducted by some authors, using exclusively titrimetric analysis, showed that the main intermediate was the 1,2-diamide. In this paper it was proved that the assumption of these authors that salicylaldehiyde would react only with the primary and not the secondary amine groups was wrong. 1,2-Diamide is the main product of the hydrolysis of 1-(stearamido-ethyl-2-heptadecyl-2-imidazoline. It was shown, in this paper that the reaction of diethylene triamine with stearic acid in xylene at the reflux temperature, yields the salt of 1-(stearamidoethyl-2-heptadecyl-2-imidazoline and stearic acid.

Involvement of α₂-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice.

Science.gov (United States)

Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil

2013-10-01

Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de

77 FR 73294 - Requirements for Child-Resistant Packaging: Products Containing Imidazolines Equivalent to 0.08...

Science.gov (United States)

2012-12-10

... injury or illness than the PPPA standard; and (2) the state or political subdivision applies to the... for Child-Resistant Packaging: Products Containing Imidazolines Equivalent to 0.08 Milligrams or More... Commission (CPSC, Commission, or we) is issuing a rule to require child-resistant (CR) packaging for any over...

Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism

DEFF Research Database (Denmark)

Olsen, Hervør L; Nørby, Peder L; Høy, Marianne

2003-01-01

We have previously demonstrated that the novel imidazoline compound (+)-2-(2-(4,5-dihydro-1H-imidazol-2-yl)-thiopene-2-yl-ethyl)-pyridine (NNC77-0074) increases insulin secretion from pancreatic beta-cells by stimulation of Ca(2+)-dependent exocytosis. Using capacitance measurements, we now show...... that NNC77-0074 stimulates exocytosis in clonal INS-1E cells. NNC77-0074-stimulated exocytosis was antagonised by the cytoplasmic phospholipase A(2) (cPLA(2)) inhibitors ACA and AACOCF(3) and in cells treated with antisense oligonucleotide against cPLA(2)alpha. NNC77-0074-evoked insulin secretion...... was likewise inhibited by ACA, AACOCF(3), and cPLA(2)alpha antisense oligonucleotide treatment. In pancreatic islets NNC77-0074 stimulated PLA(2) activity. We propose that cPLA(2)alpha plays an important role in the regulation of NNC77-0074-evoked exocytosis in insulin secreting beta-cells....

A novel imidazoline derivative as corrosion inhibitor for P110 carbon steel in hydrochloric acid environment

Directory of Open Access Journals (Sweden)

Lei Zhang

2015-09-01

Full Text Available A novel imidazoline derivative, 2-methyl-4-phenyl-1-tosyl-4, 5-dihydro-1H-imidazole (IMI, was prepared and investigated as corrosion inhibitor for P110 carbon steel in 1.0 M HCl solution by weight loss measurements, potentiodynamic polarization and electrochemical impedance spectroscopy (EIS tests. The inhibition efficiency increased with the rising concentration of IMI inhibitor. The test results and fitting data indicated that the IMI behaved as a mixed-type inhibitor and obeys the Langmuir adsorption isotherm. Scanning electron microscopy (SEM was carried out to investigate the surface of carbon steel specimens, showing great protection from aggressive solution. Finally, inhibition mechanism of IMI on metal surface was further discussed.

Study on the Synthesis and Corrosion Inhibition Performance of Mannich-Modified Imidazoline

Directory of Open Access Journals (Sweden)

Xiangjun Kong

2016-07-01

Full Text Available A novel Mannich-modified imidazoline (MMI as cationic emulsifier was synthesised for corrosion harm reduction, through three steps — acylation, cyclization, and Mannich reaction. The surface activity was characterized by determination of surface tensions and critical micelle concentration (CMC. The corrosion inhibition performance of five types of steels in the simulated corrosion solution in the presence of the MMI was investigated by static weight loss tests. The results showed that the MMI had good surface activities, with CMC of 19.8 μg g−1 and surface tension of 36.4 mN m−1. The corrosion test results indicated that the corrosion rates of different materials were decreased significantly, and degrees of corrosion inhibition were always higher than 80.0 %. The main inhibition mechanism was most likely due to the adsorption of the corrosion inhibitor on the steel surface, leading to the prevention of corrosion medium from the metal surface.

Orthosteric Binding of ρ-Da1a, a Natural Peptide of Snake Venom Interacting Selectively with the α1A-Adrenoceptor

Science.gov (United States)

Maïga, Arhamatoulaye; Merlin, Jon; Marcon, Elodie; Rouget, Céline; Larregola, Maud; Gilquin, Bernard; Fruchart-Gaillard, Carole; Lajeunesse, Evelyne; Marchetti, Charles; Lorphelin, Alain; Bellanger, Laurent; Summers, Roger J.; Hutchinson, Dana S.; Evans, Bronwyn A.; Servent, Denis; Gilles, Nicolas

2013-01-01

ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. PMID:23935897

Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling.

Science.gov (United States)

Maltsev, Alexander V; Kokoz, Yuri M; Evdokimovskii, Edward V; Pimenov, Oleg Y; Reyes, Santiago; Alekseev, Alexey E

2014-03-01

Evidence suggests that intracellular Ca(2+) levels and contractility of cardiomyocytes can be modulated by targeting receptors other than already identified adrenergic or non-adrenergic sarcolemmal receptors. This study uncovers the presence in myocardial cells of adrenergic α2 (α2-AR) and imidazoline I1 (I1R) receptors. In isolated left ventricular myocytes generating stationary spontaneous Ca(2+) transients in the absence of triggered action potentials, the prototypic agonist of both receptors agmatine can activate corresponding signaling cascades with opposing outcomes on nitric oxide (NO) synthesis and intracellular Ca(2+) handling. Specifically, activation of α2-AR signaling through PI3 kinase and Akt/protein kinase B stimulates NO production and abolishes Ca(2+) transients, while targeting of I1R signaling via phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) suppresses NO synthesis and elevates averaged intracellular Ca(2+). We identified that endothelial NO synthase (eNOS) is a major effector for both signaling cascades. According to the established eNOS transitions between active (Akt-dependent) and inactive (PKC-dependent) conformations, we suggest that balance between α2-AR and I1R signaling pathways sets eNOS activity, which by defining operational states of myocellular sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) can adjust Ca(2+) re-uptake and thereby cardiac inotropy. These results indicate that the conventional catalog of cardiomyocyte sarcolemmal receptors should be expanded by the α2-AR and I1R populations, unveiling previously unrecognized targets for endogenous ligands as well as for existing and potential pharmacological agents in cardiovascular medicine. Copyright © 2014 Elsevier Ltd. All rights reserved.

Imidazoline derivative templated synthesis of broccoli-like Bi2S3 and its electrocatalysis towards the direct electrochemistry of hemoglobin.

Science.gov (United States)

Chen, Xiaoqian; Wang, Qingxiang; Wang, Liheng; Gao, Feng; Wang, Wei; Hu, Zhengshui

2015-04-15

A broccoli-like bismuth sulfide (bBi2S3) was synthesized via a solvothermal method using a self-made imidazoline derivative of 2-undecyl-1-dithioureido-ethyl-imidazoline as the soft template. The morphology and chemical constitution of the product were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electrochemical characterization experiments show that the bBi2S3 has the higher specific surface area and standard heterogeneous electron transfer rate constant than the rod-like Bi2S3 (rBi2S3). Hemoglobin (Hb) was then chosen as a protein model to investigate the electrocatalytic property of the synthesized bBi2S3. The results show that Hb entrapped in the composite film of chitosan and bBi2S3 displays an excellent direct electrochemistry, and retains its biocatalytic activity toward the electro-reduction of hydrogen peroxide. The current response in the amperometry shows a linear response to H2O2 concentrations in the range from 0.4 to 4.8µM with high sensitivity (444µAmM(-1)) and low detection limit (0.096µM). The Michaelis-Menten constant (KM(app)) of the fabricated bioelectrode for H2O2 was determined as low as 1µM. These results demonstrate that the synthesized bBi2S3 offers a new path for the immobilization of redox-active protein and the construction of the third-generation biosensors. Copyright © 2014 Elsevier B.V. All rights reserved.

The influence of Desulfovibrio vulgaris on the efficiency of imidazoline as a corrosion inhibitor on low-carbon steel in seawater

Energy Technology Data Exchange (ETDEWEB)

Gonzalez-Rodriguez, Carlos A. [Facultad de Quimica UNAM, Ciudad Universitaria, C.P. 04510 Mexico, D.F. (Mexico)], E-mail: gorc74@yahoo.com; Rodriguez-Gomez, Francisco J.; Genesca-Llongueras, Joan [Facultad de Quimica UNAM, Ciudad Universitaria, C.P. 04510 Mexico, D.F. (Mexico)

2008-12-01

The action of Desulfovibrio vulgaris (Dv) during a corrosion process has been reported in literature, but the influence of imidazoline in the formation of biofilms is not clear, as well as the effect of bacteria on the efficiency of the corrosion inhibitors. The aim of this work is to determine the behavior of bacteria in the presence of imidazoline. Therefore, the growth of Dv, isolated and characterized from a morphological point of view, was monitored during 21 days, during which synthetic seawater was used as the culture medium, according to the ASTM D665-98 standard. Electrochemical noise (EN) was employed to establish the corrosion type generated by the microorganism on an AISI 1018 steel cylinder. The attack was observed using scanning electron microscopy (SEM). In order to evaluate the efficiency of the corrosion inhibitor, Tafel extrapolation was used; the optimum concentration of the inhibitor was used in the presence of sulphate-reducing bacteria (SRB). In general, two forms of corrosion were observed: localized corrosion (in the LAG phase) and mixed corrosion (in the LOG phase)

The influence of Desulfovibrio vulgaris on the efficiency of imidazoline as a corrosion inhibitor on low-carbon steel in seawater

International Nuclear Information System (INIS)

Gonzalez-Rodriguez, Carlos A.; Rodriguez-Gomez, Francisco J.; Genesca-Llongueras, Joan

2008-01-01

The action of Desulfovibrio vulgaris (Dv) during a corrosion process has been reported in literature, but the influence of imidazoline in the formation of biofilms is not clear, as well as the effect of bacteria on the efficiency of the corrosion inhibitors. The aim of this work is to determine the behavior of bacteria in the presence of imidazoline. Therefore, the growth of Dv, isolated and characterized from a morphological point of view, was monitored during 21 days, during which synthetic seawater was used as the culture medium, according to the ASTM D665-98 standard. Electrochemical noise (EN) was employed to establish the corrosion type generated by the microorganism on an AISI 1018 steel cylinder. The attack was observed using scanning electron microscopy (SEM). In order to evaluate the efficiency of the corrosion inhibitor, Tafel extrapolation was used; the optimum concentration of the inhibitor was used in the presence of sulphate-reducing bacteria (SRB). In general, two forms of corrosion were observed: localized corrosion (in the LAG phase) and mixed corrosion (in the LOG phase)

Efficient Hydrogen Storage and Production Using a Catalyst with an Imidazoline-Based, Proton-Responsive Ligand.

Science.gov (United States)

Wang, Lin; Onishi, Naoya; Murata, Kazuhisa; Hirose, Takuji; Muckerman, James T; Fujita, Etsuko; Himeda, Yuichiro

2017-03-22

A series of new imidazoline-based iridium complexes has been developed for hydrogenation of CO 2 and dehydrogenation of formic acid. One of the proton-responsive complexes bearing two -OH groups at ortho and para positions on a coordinating pyridine ring (3 b) can catalyze efficiently the chemical fixation of CO 2 and release H 2 under mild conditions in aqueous media without using organic additives/solvents. Notably, hydrogenation of CO 2 can be efficiently carried out under CO 2 and H 2 at atmospheric pressure in basic water by 3 b, achieving a turnover frequency of 106 h -1 and a turnover number of 7280 at 25 °C, which are higher than ever reported. Moreover, highly efficient CO-free hydrogen production from formic acid in aqueous solution employing the same catalyst under mild conditions has been achieved, thus providing a promising potential H 2 -storage system in water. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A useful PET probe [11C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I2-imidazoline receptors in the hypothalamus

International Nuclear Information System (INIS)

Kawamura, Kazunori; Shimoda, Yoko; Yui, Joji; Zhang, Yiding; Yamasaki, Tomoteru; Wakizaka, Hidekatsu; Hatori, Akiko; Xie, Lin; Kumata, Katsushi; Fujinaga, Masayuki; Ogawa, Masanao; Kurihara, Yusuke; Nengaki, Nobuki; Zhang, Ming-Rong

2017-01-01

Introduction: A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [ 11 C]BU99008, a more potent PET probe for I 2 -imidazoline receptors (I 2 Rs) imaging, with a conventional SA (mean 76 GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I 2 Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [ 11 C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I 2 Rs. Methods: [ 11 C]BU99008 was prepared by [ 11 C]methylation of N-desmethyl precursor with [ 11 C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats. Results: [ 11 C]BU99008 with ultra-high SA in the range of 5400–16,600 GBq/μmol were successfully synthesized (n = 7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [ 11 C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [ 11 C]BU99008 at 30 min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC 30–60 min ) in the hypothalamus of rats injected with [ 11 C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [ 11 C]BU99008 with ultra-high SA (86% of total binding) for I 2 R was higher than that of

硫代氨基咪唑啉盐缓蚀剂的合成及性能研究%Research on the synthesis and performances of thiocarbamates imidazoline salts corrosion inhibitor

Institute of Scientific and Technical Information of China (English)

杨根全; 李志元

2017-01-01

To solve the problem of comparatively poor compatibility of cationic imidazoline corrosion inhibitor and anionic scale inhibitor appeared in the gas-oil field,imidazoline has been synthesized,by using organic acid and triethylenetetramine as reaction raw materials.The water soluble anionic corrosion inhibitor can be obtained under the following conditions:n (imidazoline) ∶ n (CS2) ∶ n (NaOH) =1 ∶ 1 ∶ 1,ethanol as solvent,temperature 60 ℃,and reaction time 2 hours.The corrosion capacity of the corrosion inhibitor and its compatibility with scale inhibitor are investigated.The research results show that when the mass concentration of the dosed corrosion inhibitor is 50 mg/L,salt content 25％,pressure 0.5 MPa in corrosion media,and within 24 hours,the corrosion inhibiting rate of A3 carbon steel is higher than 92％.It has good compatibility with the anionic scale inhibitor.%针对油气田阳离子型咪唑啉类缓蚀剂与阴离子型阻垢剂配伍性较差的问题,以有机酸和三乙烯四胺为反应原料合成了咪唑啉,在n(咪唑啉)∶n(CS2)∶n(NaOH)为1∶1∶1、乙醇为溶剂、温度为60℃条件下反应2h,得到水溶性的阴离子缓蚀剂,并考察了该缓蚀剂的缓蚀性能及其与阻垢剂的配伍性.研究结果表明,在含盐25％、温度60℃、压力为0.5 MPa的腐蚀介质中,该缓蚀剂加药质量浓度为50 mg/L时,24 h内对A3碳钢的缓蚀率＞92％,与阴离子阻垢剂的配伍性良好.

Stimulatory effect of harmane and other beta-carbolines on locus coeruleus neurons in anaesthetized rats.

Science.gov (United States)

Ruiz-Durántez, E; Ruiz-Ortega JA; Pineda, J; Ugedo, L

2001-08-10

Harmane, harmaline and norharmane are beta-carboline related compounds which have been proposed to be endogenous ligands for imidazoline receptors. The effect of these compounds on the activity of locus coeruleus (LC) neurons was studied by extracellular recordings techniques. Intracerebroventricular administration of harmane and harmaline increased the firing rate of LC neurons. Systemic administration of efaroxan, a mixed alpha(2)-adrenoceptor/I(1)-imidazoline antagonist or vagotomy failed to modify the harmane effect. Furthermore, local applications of harmane and harmaline increased the firing rate of LC neurons in a dose-related manner. Finally, intravenous administration of norharmane also increased the activity of LC neurons. Our results demonstrate that beta-carbolines stimulate LC neuron activity and indicate that this stimulation occurs directly in the LC by a mechanism independent of I(1)- and I(2)-imidazoline receptors.

Evaluation of 11C-BU99008, a positron emission tomography ligand for the Imidazoline2 binding site in human brain.

Science.gov (United States)

Tyacke, Robin J; Myers, Jim F M; Venkataraman, Ashwin; Mick, Inge; Turton, Samuel; Passchier, Jan; Husbands, Stephen M; Rabiner, Eugenii Ilan A; Gunn, Roger N; Murphy, Philip S; Parker, Christine A; Nutt, David J

2018-03-09

The imidazoline 2 binding site (I 2 BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11 C-BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest reproducibility. Methods 14 healthy male volunteers underwent dynamic PET imaging with 11 C-BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I 2 BS/α 2 -adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80mg) and the mixed irreversible MAO A/B inhibitor, isocarboxazid (n=4; 50mg), respectively. Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure V T (regional total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results Brain uptake of 11 C-BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I 2 BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. V T estimates were high in the striatum (113±20 mL·cm -3 ), medium in cortex frontal lobe (55±9 mL·cm -3 ) and low in the cerebellum (47±7 mL·cm -3 ). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% ( V T = ~30 mL·cm -3 ) at the highest dose (80 mg). The ED 50 for idazoxan was calculated as 33.1 mg. Uptake was not blocked by pre-treatment with the MAO inhibitor, isocarboxazid. Conclusions In summary, 11 C

High non-specific binding of the {beta}{sub 1}-selective radioligand 2-{sup 125}I-ICI-H

Energy Technology Data Exchange (ETDEWEB)

Riemann, B. [Muenster Univ. (Germany). Department of Nuclear Medicine; Law, M.P. [Muenster Univ. (Germany). Department of Nuclear Medicine; Hammersmith Hospital, London (United Kingdom). MRC Clinical Sciences Centre; Kopka, K. [Muenster Univ. (DE). Department of Nuclear Medicine] [and others

2003-08-01

Aim: As results of cardiac biopsies suggest, myocardial {beta}{sub 1}-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac {beta}{sub 2}-adrenoceptors vary. With suitable radiopharmaceuticals single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess {beta}-adrenoceptors non-invasively. Among the novel racemic analogues of the established {beta}{sub 1}-selective adrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to {beta}{sub 1}-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative subtype selective {beta}{sub 1}-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac {beta}-adrenoceptors in mice and rats. In addition, the radiosynthesis of 2-{sup 125}I-ICI-H from the silylated precursor 2-SiMe{sub 3}-ICI-H was established. The specific activity was 80 GBq/{mu}mol, the radiochemical yield ranged from 70 to 80%. Results: The unlabelled compound 2-I-ICI-H showed high {beta}{sub 1}-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac {beta}-adrenoceptors. The radiolabelled counterpart 2-{sup 125}I-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac {beta}{sub 1}-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-{sup 125}I-ICI-H is no suitable radiotracer for imaging in vivo. (orig.)

Evidences for the agmatine involvement in antidepressant like effect of bupropion in mouse forced swim test.

Science.gov (United States)

Kotagale, Nandkishor R; Tripathi, Sunil J; Aglawe, Manish M; Chopde, Chandrabhan T; Umekar, Milind J; Taksande, Brijesh G

2013-06-01

Although bupropion has been widely used in the treatment of depression, the precise mechanism of its therapeutic actions is not fully understood. The present study investigated the role of agmatine in an antidepressant like effect of bupropion in mouse forced swim test. The antidepressant like effect of bupropion was potentiated by pretreatment with agmatine (10-20mg/kg, ip) and by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine (40 μg/mouse, icv), an agmatine biosynthetic precursor, ornithine decarboxylase inhibitor, dl-α-difluoromethyl ornithine hydrochloride, DFMO (12.5 μg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase inhibitor, arcaine (50 μg/mouse, icv) as well as imidazoline I1 receptor agonists, moxonidine (0.25mg/kg, ip) and clonidine (0.015 mg/kg, ip) and imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline hydrochloride, 2-BFI (5mg/kg, ip). Conversely, prior administration of I1 receptor antagonist, efaroxan (1mg/kg, ip) and I2 receptor antagonist, idazoxan (0.25mg/kg, ip) blocked the antidepressant like effect of bupropion and its synergistic combination with agmatine. These results demonstrate involvement of agmatine in the antidepressant like effect of bupropion and suggest agmatine and imidazoline receptors as a potential therapeutic target for the treatment of depressive disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

Generation and Characterization of Novel Human IRAS Monoclonal Antibodies

Directory of Open Access Journals (Sweden)

Bo Wang

2009-01-01

Full Text Available Imidazoline receptors were first proposed by Bousquet et al., when they studied antihypertensive effect of clonidine. A strong candidate for I1R, known as imidazoline receptor antisera-selected protein (IRAS, has been cloned from human hippocampus. We reported that IRAS mediated agmatine-induced inhibition of opioid dependence in morphine-dependent cells. To elucidate the functional and structure properties of I1R, we developed the newly monoclonal antibody against the N-terminal hIRAS region including the PX domain (10–120aa through immunization of BALB/c mice with the NusA-IRAS fusion protein containing an IRAS N-terminal (10–120aa. Stable hybridoma cell lines were established and monoclonal antibodies specifically recognized full-length IRAS proteins in their native state by immunoblotting and immunoprecipitation. Monoclonal antibodies stained in a predominantly punctate cytoplasmic pattern when applied to IRAS-transfected HEK293 cells by indirect immunofluorescence assays and demonstrated excellent reactivity in flow immunocytometry. These monoclonal antibodies will provide powerful reagents for the further investigation of hIRAS protein functions.

Pharmacological analysis of the inhibition produced by moxonidine and agmatine on the vasodepressor sensory CGRPergic outflow in pithed rats.

Science.gov (United States)

Rubio-Beltrán, Eloísa; Labastida-Ramírez, Alejandro; Hernández-Abreu, Oswaldo; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

2017-10-05

Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T 9 --T 12 ) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I 1 and I 2 receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i.v. with 25mg/kg gallamine and 2mg/kg⋅min hexamethonium) received i.v. continuous infusions of methoxamine (20μg/kg⋅min) followed by physiological saline (0.02ml/min), moxonidine (1, 3, 10 or 30μg/kg⋅min) or agmatine (1000 or 3000μg/kg⋅min). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V; 2ms) of the spinal cord (T 9 -T 12 ) produced frequency-dependent vasodepressor responses which were: (i) unchanged during saline infusion; and (ii) inhibited during the above infusions of moxonidine or agmatine. Moreover, using i.v. administrations, the inhibition by 3μg/kg⋅min moxonidine or 3000μg/kg⋅min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1-1µg/kg) was: (i) unaltered after saline (1ml/kg), rauwolscine (300μg/kg; α 2 -adrenoceptor antagonist) or BU224 (300μg/kg; imidazoline I 2 receptor antagonist); and (ii) reversed after AGN 192403 (3000μg/kg; imidazoline I 1 receptor antagonist). This reversion was relatively more pronounced after AGN 192403 plus rauwolscine. These blocking doses of antagonists lacked any effects on the electrically-induced vasodepressor responses. Therefore, the inhibition of the vasodepressor sensory CGRPergic outflow by moxonidine and agmatine is mainly mediated by prejunctional imidazoline I 1 receptors on perivascular sensory nerves. Copyright © 2017 Elsevier B.V. All rights reserved.

A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug.

Science.gov (United States)

Loeppky, Richard N; Shi, Jianzheng; Barnes, Charles L; Geddam, Sailaja

2008-02-01

Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-( N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 degrees C ( kobs = 6.25 x 10 (-5) s (-1) in 0.5 M acetate buffer with a 10 * [NO2(-)] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

Science.gov (United States)

Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. However, the actual cell number of both NK1.1+ and NK1.1− thymocytes in I-Ad/d mice (positive selecting background) was larger than that in I-Ab/d mice (negative selecting background). Markedly low but significant proportions of NK1.1+ Vα13/Vβ8.2+ cells were detected in the spleens from I-Ad/d and I-Ab/d mice. It was shown that the splenic NK1.1+ T cells of the I-Ab/d mice were anergized against stimulation through TCR. When (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice were given cOVA, extensive or intermediate elimination of NK1.1+α/βTCR+ thymocytes was induced in I-Ad/d or I-Ab/d mice, respectively. However, the clonal elimination was not as complete as that seen in the major NK1.1− thymocyte population. The present findings indicate that normal generation of NK1.1+α/βTCR+ thymocytes occurs in the absence of Vα14-Jα281 and that substantial negative selection operates on the NK1.1+α/βTCR+ cells. PMID:9653164

Evidence for the gastric cytoprotective effect of centrally injected agmatine.

Science.gov (United States)

Zádori, Zoltán S; Tóth, Viktória E; Fehér, Ágnes; Philipp, Kirsch; Németh, József; Gyires, Klára

2014-09-01

Agmatine (decarboxylated arginine) exerts cytoprotective action in several tissues, such as in the brain, heart or kidneys, but there is still controversy over the effects of agmatine on the gastric mucosa. The aim of the present study was to reveal the potential gastroprotective action of agmatine by using an acid-independent ulcer model to clarify which receptors and peripheral factors are involved in it. Gastric mucosal damage was induced by acidified ethanol. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. It was found that agmatine given intracerebroventricularly (i.c.v., 0.044-220 nmol/rat) significantly inhibited the development of ethanol-induced mucosal damage, while in the case of intraperitoneal injection (0.001-50mg/kg i.p.) it had only a minor effect. The central gastroprotective action of agmatine was completely antagonized by mixed alpha2-adrenoceptor and imidazoline I1 receptor antagonists (idazoxan, efaroxan), but only partially by yohimbine (selective alpha2-adrenoceptor antagonist) and AGN 192403 (selective I1 receptor ligand, putative antagonist). It was also inhibited by the non-selective opioid-receptor antagonist naloxone and the selective δ-opioid receptor antagonist naltrindole, but not by β-funaltrexamine and nor-Binaltorphimine (selective μ- and κ-opioid receptor antagonists, respectively). Furthermore, the effect of agmatine was antagonized by bilateral cervical vagotomy and by pretreatment with indomethacin and NG-nitro-l-arginine. Agmatine also reversed the ethanol-induced reduction of gastric mucosal CGRP and somatostatin content, but did not have any significant effect on gastric motor activity. These results indicate that agmatine given centrally induces gastric cytoprotection, which is mediated by central imidazoline I1 receptors, alpha2-adrenoceptors and δ-opioid receptors. Activation of

Identification of a domain within human TAF(I)48, a subunit of Selectivity Factor 1, that interacts with helix 2 of TBP.

Science.gov (United States)

Xu, Shuping; Hori, Roderick T

2004-09-01

RNA polymerase I transcription in human cells requires Selectivity Factor 1, a multisubunit complex composed of the TATA-box-binding protein (TBP) and three TBP-associated factors (TAFs) called TAF(I)48, TAF(I)63 and TAF(I)110. Each of the Selectivity Factor 1 subunits binds directly to the other three components, but these interactions have not been characterized. This study is the initial identification and analysis of a TBP-binding domain within a Selectivity Factor 1 TAF. The interaction between human TBP and human TAF(I)48 was initially examined using the yeast two-hybrid assay, and a TBP-binding domain was identified in the carboxyl-terminus of human (h)TAF(I)48. Consistent with this result, the hTAF(I)48 carboxyl-terminus was able to bind directly to TBP in protein-protein interaction assays. When mutations were introduced into the hTAF(I)48 carboxyl-terminus, we identified changes in uncharged and positive residues that affect its interaction with TBP. By examining TBP mutants, residues within and adjacent to helix 2 of TBP, previously demonstrated to interact with subunits of other TBP-containing complexes [Transcription Factor IID (TFIID) and TFIIIB] were also found to diminish its affinity for the carboxyl-terminus of hTAF(I)48. The regions of hTAF(I)48 and TBP that interact are compared to those identified within other complexes containing TBP.

Seismic safety margins research program. Phase I final report - Plant/site selection and data collection (Project I)

International Nuclear Information System (INIS)

Chuang, T.Y.

1981-07-01

Project I of Phase I of the Seismic Safety Margins Research Program (SSMRP) comprised two parts: the selection of a representative nuclear power plant/site for study in Phase I and the collection of data needed by the other SSMRP projects. Unit 1 of the Zion Nuclear Power Plant in Zion, Illinois, was selected for the SSMRP Phase I studies. Unit 1 of the Zion plant has been validated as a good choice for the Phase I study plant. Although no single nuclear power plant can represent all such plants equally well, selection criteria were developed to maximize the generic implications of Phase I of the SSMRP. On the basis of the selection criteria, the Zion plant and its site were found to be reasonably representative of operating and future plants with regard to its nuclear steam supply system; the type of containment structure (prestressed concrete); its electrical capacity (1100 MWe); its location (the Midwest); the peak seismic acceleration used for design (0.17g); and the properties of the underlying soil (the low-strain shear-wave velocity is 1650 ft/s in a 50- to 100-ft-thick layer of soil overlying sedimentary bedrock). (author)

Sequence diversity and natural selection at domain I of the apical membrane antigen 1 among Indian Plasmodium falciparum populations

Directory of Open Access Journals (Sweden)

Kumar Ashwani

2007-11-01

Full Text Available Abstract Background The Plasmodium falciparum apical membrane antigen 1 (AMA1 is a leading malaria vaccine candidate antigen. The complete AMA1 protein is comprised of three domains where domain I exhibits high sequence polymorphism and is thus named as the hyper-variable region (HVR. The present study describes the extent of genetic polymorphism and natural selection at domain I of the ama1 gene among Indian P. falciparum isolates. Methods The part of the ama1 gene covering domain I was PCR amplified and sequenced from 157 P. falciparum isolates collected from five different geographical regions of India. Statistical and phylogenetic analyses of the sequences were done using DnaSP ver. 4. 10. 9 and MEGA version 3.0 packages. Results A total of 57 AMA1 haplotypes were observed among 157 isolates sequenced. Forty-six of these 57 haplotypes are being reported here for the first time. The parasites collected from the high malaria transmission areas (Assam, Orissa, and Andaman and Nicobar Islands showed more haplotypes (H and nucleotide diversity π as compared to low malaria transmission areas (Uttar Pradesh and Goa. The comparison of all five Indian P. falciparum subpopulations indicated moderate level of genetic differentiation and limited gene flow (Fixation index ranging from 0.048 to 0.13 between populations. The difference between rates of non-synonymous and synonymous mutations, Tajima's D and McDonald-Kreitman test statistics suggested that the diversity at domain I of the AMA1 antigen is due to positive natural selection. The minimum recombination events were also high indicating the possible role of recombination in generating AMA1 allelic diversity. Conclusion The level of genetic diversity and diversifying selection were higher in Assam, Orissa, and Andaman and Nicobar Islands populations as compared to Uttar Pradesh and Goa. The amounts of gene flow among these populations were moderate. The data reported here will be valuable for the

Direct demonstration of D1 dopamine receptors in the bovine parathyroid gland using the D1 selective antagonist [125I]-SCH 23982

International Nuclear Information System (INIS)

Monsma, F.J. Jr.; Sibley, D.R.

1989-01-01

The presence of D1 dopamine receptors in the parathyroid gland has been proposed based on the demonstration of dopaminergic regulation of adenylate cyclase activity and parathyroid hormone release in dispersed bovine parathyroid cells. Using a radioiodinated D1 selective antagonist [125I]-SCH 23982, we have now directly labeled and characterized the D1 dopamine receptors in bovine parathyroid gland membranes. [125I]-SCH 23982 binds in a saturable manner with high affinity and low nonspecific binding to membranes prepared from bovine parathyroid glands. D1 dopamine receptors are present in this preparation at a concentration of approximately 130 fMoles/mg protein and [125I]-SCH 23982 binding increases with increasing protein concentration in a linear fashion. Determination of the Kd using the association (k1) and dissociation (k-1) rate constants revealed good agreement with the Kd determined by saturation analysis (390 pM vs. 682 pM, respectively). Inhibition of 0.3 nM [125I]-SCH 23982 binding by a series of dopaminergic antagonists verified the D1 nature of this binding site, exhibiting appropriate affinities and rank order of potency. The competition curves of all antagonists exhibited Hill coefficients that were not significantly different from 1. Inhibition of [125I]-SCH 23982 binding by dopamine and other dopaminergic agonists revealed the presence of high and low affinity agonist binding sites. Addition of 200 microM GppNHp effected a complete conversion of high affinity dopamine binding sites to a homogeneous population of low affinity dopamine sites. The D1 receptors identified in the parathyroid gland with [125I]-SCH 23982 appear to be pharmacologically identical with those previously characterized in the central nervous system

Effects of the beta-carbolines, harmane and pinoline, on insulin secretion from isolated human islets of Langerhans.

Science.gov (United States)

Cooper, E Jane; Hudson, Alan L; Parker, Christine A; Morgan, Noel G

2003-12-15

It is well known that certain imidazoline compounds can stimulate insulin secretion and this has been attributed to the activation of imidazoline I(3) binding sites in the pancreatic beta-cell. Recently, it has been proposed that beta-carbolines may be endogenous ligands having activity at imidazoline sites and we have, therefore, studied the effects of beta-carbolines on insulin secretion. The beta-carbolines harmane, norharmane and pinoline increased insulin secretion two- to threefold from isolated human islets of Langerhans. The effects of harmane and pinoline were dose-dependent (EC(50): 5 and 25 microM, respectively) and these agents also blocked the inhibitory effects of the potassium channel agonist, diazoxide, on glucose-induced insulin release. Stimulation of insulin secretion by harmane was glucose-dependent but, unlike the imidazoline I(3) receptor agonist efaroxan, it increased the rate of insulin release beyond that elicited by 20 mM glucose (20 mM glucose alone: 253+/-34% vs. basal; 20 mM glucose plus 100 microM harmane: 327+/-15%; P<0.01). Stimulation of insulin secretion by harmane was attenuated by the imidazoline I(3) receptor antagonist KU14R (2 (2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole) and was reduced when islets were treated with efaroxan for 18 h, prior to the addition of harmane. The results reveal that beta-carbolines can potentiate the rate of insulin secretion from human islets and suggest that these agents may be useful prototypes for the development of novel insulin secretagogues.

A calixarene-based ion-selective electrode for thallium(I) detection

International Nuclear Information System (INIS)

Chester, Ryan; Sohail, Manzar; Ogden, Mark I.; Mocerino, Mauro; Pretsch, Ernö; De Marco, Roland

2014-01-01

Highlights: • Tuning of metal binding cavities in thallium(I) calixarene ionophores. • Novel calixarene-based ionophores with improved selectivity for thallium(I). • Sandwich membrane characterization of thallium(I) binding in novel calixarenes. • Improved selectivity and sensitivity with novel thallium(I) calixarene ionophores. • Solid contact ion-selective electrodes for novel thallium(I) calixarene ionophores. - Abstract: Three new calixarene Tl + ionophores have been utilized in Tl + ion-selective electrodes (ISEs) yielding Nernstian response in the concentration range of 10 −2 –10 −6 M TlNO 3 with a non-optimized filling solution in a conventional liquid contact ISE configuration. The complex formation constants (log β IL ) for two of the calixarene derivatives with thallium(I) (i.e. 6.44 and 5.85) were measured using the sandwich membrane technique, with the other ionophore immeasurable due to eventual precipitation of the ionophore during these long-term experiments. Furthermore, the unbiased selectivity coefficients for these ionophores displayed excellent selectivity against Zn 2+ , Ca 2+ , Ba 2+ , Cu 2+ , Cd 2+ and Al 3+ with moderate selectivity against Pb 2+ , Li + , Na + , H + , K + , NH 4 + and Cs + , noting that silver was the only significant interferent with these calixarene-based ionophores. When optimizing the filling solution in a liquid contact ISE, it was possible to achieve a lower limit of detection of approximately 8 nM according to the IUPAC definition. Last, the new ionophores were also evaluated in four solid-contact (SC) designs leading to Nernstian response, with the best response noted with a SC electrode utilizing a gold substrate, a poly(3-octylthiophene) (POT) ion-to-electron transducer and a poly(methyl methacrylate)–poly(decyl methacrylate) (PMMA–PDMA) co-polymer membrane. This electrode exhibited a slope of 58.4 mV decade −1 and a lower detection limit of 30.2 nM. Due to the presence of an undesirable

Antihypertensive Action of Allantoin in Animals

Directory of Open Access Journals (Sweden)

Mei-Fen Chen

2014-01-01

Full Text Available The agonists of imidazoline I-1 receptors (I-1R are widely used to lower blood pressure. It has been indicated that guanidinium derivatives show an ability to activate imidazoline receptors. Also, allantoin has a chemical stricture similar to guanidinium derivatives. Thus, it is of special interest to characterize the effect of allantoin on I-1R. In conscious male spontaneous hypertensive rats (SHRs, mean blood pressure (MBP was recorded using the tail-cuff method. Furthermore, the hemodynamic analyses in catheterized rats were applied to measure the actions of allantoin in vivo. Allantoin decreased blood pressures in SHRs at 30 minutes, as the most effective time. Also, this antihypertensive action was shown in a dose-dependent manner from SHRs treated with allantoin. Moreover, in anesthetized rats, allantoin inhibited cardiac contractility and heart rate as showing in hemodynamic dP/dt max significantly. Also, the peripheral blood flow was markedly increased by allantoin. Both actions were diminished by efaroxan at the dose sufficient to block I-1R. Thus, we suggest that allantoin, as I-1R agonist, has the potential to develop as a new therapeutic agent for hypertension in the future.

Automated quantification of proliferation with automated hot-spot selection in phosphohistone H3/MART1 dual-stained stage I/II melanoma.

Science.gov (United States)

Nielsen, Patricia Switten; Riber-Hansen, Rikke; Schmidt, Henrik; Steiniche, Torben

2016-04-09

Staging of melanoma includes quantification of a proliferation index, i.e., presumed melanocytic mitoses of H&E stains are counted manually in hot spots. Yet, its reproducibility and prognostic impact increases by immunohistochemical dual staining for phosphohistone H3 (PHH3) and MART1, which also may enable fully automated quantification by image analysis. To ensure manageable workloads and repeatable measurements in modern pathology, the study aimed to present an automated quantification of proliferation with automated hot-spot selection in PHH3/MART1-stained melanomas. Formalin-fixed, paraffin-embedded tissue from 153 consecutive stage I/II melanoma patients was immunohistochemically dual-stained for PHH3 and MART1. Whole slide images were captured, and the number of PHH3/MART1-positive cells was manually and automatically counted in the global tumor area and in a manually and automatically selected hot spot, i.e., a fixed 1-mm(2) square. Bland-Altman plots and hypothesis tests compared manual and automated procedures, and the Cox proportional hazards model established their prognostic impact. The mean difference between manual and automated global counts was 2.9 cells/mm(2) (P = 0.0071) and 0.23 cells per hot spot (P = 0.96) for automated counts in manually and automatically selected hot spots. In 77 % of cases, manual and automated hot spots overlapped. Fully manual hot-spot counts yielded the highest prognostic performance with an adjusted hazard ratio of 5.5 (95 % CI, 1.3-24, P = 0.024) as opposed to 1.3 (95 % CI, 0.61-2.9, P = 0.47) for automated counts with automated hot spots. The automated index and automated hot-spot selection were highly correlated to their manual counterpart, but altogether their prognostic impact was noticeably reduced. Because correct recognition of only one PHH3/MART1-positive cell seems important, extremely high sensitivity and specificity of the algorithm is required for prognostic purposes. Thus, automated

Selective Thallium (I Ion Sensor Based on Functionalised ZnO Nanorods

Directory of Open Access Journals (Sweden)

Z. H. Ibupoto

2012-01-01

Full Text Available Well controlled in length and highly aligned ZnO nanorods were grown on the gold-coated glass substrate by hydrothermal growth method. ZnO nanorods were functionalised with selective thallium (I ion ionophore dibenzyldiaza-18-crown-6 (DBzDA18C6. The thallium ion sensor showed wide linear potentiometric response to thallium (I ion concentrations ( M to  M with high sensitivity of 36.87 ± 1.49 mV/decade. Moreover, thallium (I ion demonstrated fast response time of less than 5 s, high selectivity, reproducibility, storage stability, and negligible response to common interferents. The proposed thallium (I ion-sensor electrode was also used as an indicator electrode in the potentiometric titration, and it has shown good stoichiometric response for the determination of thallium (I ion.

The Creativity of Natural Selection? Part I: Darwin, Darwinism, and the Mutationists.

Science.gov (United States)

Beatty, John

2016-12-01

This is the first of a two-part essay on the history of debates concerning the creativity of natural selection, from Darwin through the evolutionary synthesis and up to the present. Here I focus on the mid-late nineteenth century to the early twentieth, with special emphasis on early Darwinism and its critics, the self-styled "mutationists." The second part focuses on the evolutionary synthesis and some of its critics, especially the "neutralists" and "neo-mutationists." Like Stephen Gould, I consider the creativity of natural selection to be a key component of what has traditionally counted as "Darwinism." I argue that the creativity of natural selection is best understood in terms of (1) selection initiating evolutionary change, and (2) selection being responsible for the presence of the variation it acts upon, for example by directing the course of variation. I consider the respects in which both of these claims sound non-Darwinian, even though they have long been understood by supporters and critics alike to be virtually constitutive of Darwinism.

Selection of Dogs for Land Mine and Booby Trap Detection Training. Volume I

Science.gov (United States)

1976-09-01

Sarcoptes scabier, the 12 causes of demodectic and sarcoptic mange , respectively, may be speci- fically diagnosed by microscopic examination of skin scrapings...8217 UNCLASSIFIED 10 - SELECTION OF DOGS FOR LAND MINE AND BOOBY TRAP DETECTION TRAINING (U) FINAL TECHNICAL REPORT VOLUME i by Daniel S. Mitchell...1 ...... I " SELECTION OF DOGS k- FOR LAND MINE AND OOlBY TRAP DETECTION TRAINING * Contract -3C p t DAA1WC.LYA by , /ODaniel S

Prostatic relaxation induced by agmatine is decreased in spontaneously hypertensive rats.

Science.gov (United States)

Lee, Liang-Ming; Tsai, Tsung-Chin; Chung, Hsien-Hui; Tong, Yat-Ching; Cheng, Juei-Tang

2012-09-01

What's known on the subject? and What does the study add? Neurotransmitters are known to control prostate contractility. Agmatine is one of them and induces relaxation through imidazoline receptors. The paper shows that the action of agmatine is reduced in hypertensive rats, and that this change is related to the decrease of ATP-sensitive potassium channels in the prostate. The findings can increase our understanding of the possible underlying mechanism for the development of clinical benign prostatic hyperplasia. To compare agmatine-induced prostatic relaxation in hypertensive and control rats. To investigate the responsible mechanism(s) and the role of the ATP-sensitive potassium channel. Prostate strips were isolated from male spontaneously hypertensive (SH) rats and normal Wistar-Kyoto (WKY) rats for measurement of isometric tension. The strips were precontracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. Dose-dependent relaxation of the prostatic strips was studied by cumulative administration of agmatine, 1 to 100 µmol/L, into the organ bath. Effects of specific antagonists on agmatine-induced relaxation were studied. Western blotting analysis was used to measure the gene expression of the ATP-sensitive potassium channel in the rat prostate. Prostatic relaxation induced by agmatine was markedly reduced in SH rats compared with WKY rats. The relaxation caused by agmatine was abolished by BU224, a selective imidazoline I(2)-receptor antagonist, but was not modified by efaroxan at a dose sufficient to block imidazoline I(1)-receptors. The relaxation induced by diazoxide at a concentration sufficient to activate ATP-sensitive potassium channels was markedly reduced in the SH rat prostate. Expressions of ATP-sensitive potassium channel sulphonylurea receptor and inwardly rectifying potassium channel (Kir) 6.2 subunits were both decreased in the prostate of SH rats. The decrease of agmatine-induced prostatic relaxation in SH rats is related to the change in

A calixarene-based ion-selective electrode for thallium(I) detection

Energy Technology Data Exchange (ETDEWEB)

Chester, Ryan [Nanochemistry Research Institute, Department of Chemistry, Curtin University, GPO Box U1987, Perth, Western Australia 6845 (Australia); Sohail, Manzar [Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Locked Bag 4, Maroochydore DC, Queensland 4556 (Australia); Ogden, Mark I.; Mocerino, Mauro [Nanochemistry Research Institute, Department of Chemistry, Curtin University, GPO Box U1987, Perth, Western Australia 6845 (Australia); Pretsch, Ernö [ETH Zürich, Institute of Biogeochemistry and Pollutant Dynamics (IBP), Universitätstrasse 16, CH-8092, Zürich (Switzerland); De Marco, Roland, E-mail: rdemarc1@usc.edu.au [Nanochemistry Research Institute, Department of Chemistry, Curtin University, GPO Box U1987, Perth, Western Australia 6845 (Australia); Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Locked Bag 4, Maroochydore DC, Queensland 4556 (Australia)

2014-12-03

Highlights: • Tuning of metal binding cavities in thallium(I) calixarene ionophores. • Novel calixarene-based ionophores with improved selectivity for thallium(I). • Sandwich membrane characterization of thallium(I) binding in novel calixarenes. • Improved selectivity and sensitivity with novel thallium(I) calixarene ionophores. • Solid contact ion-selective electrodes for novel thallium(I) calixarene ionophores. - Abstract: Three new calixarene Tl{sup +} ionophores have been utilized in Tl{sup +} ion-selective electrodes (ISEs) yielding Nernstian response in the concentration range of 10{sup −2}–10{sup −6} M TlNO{sub 3} with a non-optimized filling solution in a conventional liquid contact ISE configuration. The complex formation constants (log β{sub IL}) for two of the calixarene derivatives with thallium(I) (i.e. 6.44 and 5.85) were measured using the sandwich membrane technique, with the other ionophore immeasurable due to eventual precipitation of the ionophore during these long-term experiments. Furthermore, the unbiased selectivity coefficients for these ionophores displayed excellent selectivity against Zn{sup 2+}, Ca{sup 2+}, Ba{sup 2+}, Cu{sup 2+}, Cd{sup 2+} and Al{sup 3+} with moderate selectivity against Pb{sup 2+}, Li{sup +}, Na{sup +}, H{sup +}, K{sup +}, NH{sub 4}{sup +} and Cs{sup +}, noting that silver was the only significant interferent with these calixarene-based ionophores. When optimizing the filling solution in a liquid contact ISE, it was possible to achieve a lower limit of detection of approximately 8 nM according to the IUPAC definition. Last, the new ionophores were also evaluated in four solid-contact (SC) designs leading to Nernstian response, with the best response noted with a SC electrode utilizing a gold substrate, a poly(3-octylthiophene) (POT) ion-to-electron transducer and a poly(methyl methacrylate)–poly(decyl methacrylate) (PMMA–PDMA) co-polymer membrane. This electrode exhibited a slope of 58.4 mV decade

Obscured AGN at z ~ 1 from the zCOSMOS-Bright Survey. I. Selection and optical properties of a [Ne v]-selected sample

Science.gov (United States)

Mignoli, M.; Vignali, C.; Gilli, R.; Comastri, A.; Zamorani, G.; Bolzonella, M.; Bongiorno, A.; Lamareille, F.; Nair, P.; Pozzetti, L.; Lilly, S. J.; Carollo, C. M.; Contini, T.; Kneib, J.-P.; Le Fèvre, O.; Mainieri, V.; Renzini, A.; Scodeggio, M.; Bardelli, S.; Caputi, K.; Cucciati, O.; de la Torre, S.; de Ravel, L.; Franzetti, P.; Garilli, B.; Iovino, A.; Kampczyk, P.; Knobel, C.; Kovač, K.; Le Borgne, J.-F.; Le Brun, V.; Maier, C.; Pellò, R.; Peng, Y.; Perez Montero, E.; Presotto, V.; Silverman, J. D.; Tanaka, M.; Tasca, L.; Tresse, L.; Vergani, D.; Zucca, E.; Bordoloi, R.; Cappi, A.; Cimatti, A.; Koekemoer, A. M.; McCracken, H. J.; Moresco, M.; Welikala, N.

2013-08-01

Aims: The application of multi-wavelength selection techniques is essential for obtaining a complete and unbiased census of active galactic nuclei (AGN). We present here a method for selecting z ~ 1 obscured AGN from optical spectroscopic surveys. Methods: A sample of 94 narrow-line AGN with 0.65 advantage of the large amount of data available in the COSMOS field, the properties of the [Ne v]-selected type 2 AGN were investigated, focusing on their host galaxies, X-ray emission, and optical line-flux ratios. Finally, a previously developed diagnostic, based on the X-ray-to-[Ne v] luminosity ratio, was exploited to search for the more heavily obscured AGN. Results: We found that [Ne v]-selected narrow-line AGN have Seyfert 2-like optical spectra, although their emission line ratios are diluted by a star-forming component. The ACS morphologies and stellar component in the optical spectra indicate a preference for our type 2 AGN to be hosted in early-type spirals with stellar masses greater than 109.5 - 10 M⊙, on average higher than those of the galaxy parent sample. The fraction of galaxies hosting [Ne v]-selected obscured AGN increases with the stellar mass, reaching a maximum of about 3% at ≈2 × 1011 M⊙. A comparison with other selection techniques at z ~ 1, namely the line-ratio diagnostics and X-ray detections, shows that the detection of the [Ne v] λ3426 line is an effective method for selecting AGN in the optical band, in particular the most heavily obscured ones, but cannot provide a complete census of type 2 AGN by itself. Finally, the high fraction of [Ne v]-selected type 2 AGN not detected in medium-deep (≈100-200 ks) Chandra observations (67%) is suggestive of the inclusion of Compton-thick (i.e., with NH > 1024 cm-2) sources in our sample. The presence of a population of heavily obscured AGN is corroborated by the X-ray-to-[Ne v] ratio; we estimated, by means of an X-ray stacking technique and simulations, that the Compton-thick fraction in our

Agmatine Reduces Lipopolysaccharide-Mediated Oxidant Response via Activating PI3K/Akt Pathway and Up-Regulating Nrf2 and HO-1 Expression in Macrophages.

Directory of Open Access Journals (Sweden)

Jianshen Chai

Full Text Available Macrophages are key responders of inflammation and are closely related with oxidative stress. Activated macrophages can enhance oxygen depletion, which causes an overproduction of reactive oxygen species (ROS and leads to further excessive inflammatory response and tissue damage. Agmatine, an endogenous metabolite of L-arginine, has recently been shown to have neuroprotective effects based on its antioxidant properties. However, the antioxidant effects of agmatine in peripheral tissues and cells, especially macrophages, remain unclear. In this study we explored the role of agmatine in mediating antioxidant effects in RAW 264.7 cells and studied its antioxidant mechanism. Our data demonstrate that agmatine is an activator of Nrf2 signaling that markedly enhances Nrf2 nuclear translocation, increases nuclear Nrf2 protein level, up-regulates the expression of the Nrf2 downstream effector HO-1, and attenuates ROS generation induced by Lipopolysaccharide (LPS. We further demonstrated that the agmatine-induced activation of Nrf2 is likely through the PI3K/Akt pathway. LY294002, a specific PI3K/Akt inhibitor, abolished agmatine-induced HO-1 up-regulation and ROS suppression significantly. Inhibiting HO-1 pathway significantly attenuated the antioxidant effect of agmatine which the products of HO-1 enzymatic activity contributed to. Furthermore, the common membrane receptors of agmatine were evaluated, revealing that α2-adrenoceptor, I1-imidazoline receptor or I2-imidazoline receptor are not required by the antioxidant properties of agmatine. Taken together, our findings revealed that agmatine has antioxidant activity against LPS-induced ROS accumulation in RAW 264.7 cells involving HO-1 expression induced by Nrf2 via PI3K/Akt pathway activation.

Electrochemical and surface analysis studies on corrosion inhibition of Q235 steel by imidazoline derivative against CO2 corrosion

International Nuclear Information System (INIS)

Wang, B.; Du, M.; Zhang, J.; Gao, C.J.

2011-01-01

Research highlights: → The TAI inhibitor showed peak-value-phenomenon due to the change of adsorption mode. → The adsorption of TAI inhibitor made the PZC shift toward positive direction. → The adsorption film occurred by forming coordination bonds between heteroatom and Fe. → Bigger adhesive force owing to hydrophobic interaction was detected in TAI solution. → The long range-repulsive force reduced by screening effect of surface charges of TAI. - Abstract: The inhibition performance of a newly synthesized thioureido imidazoline inhibitor (TAI) in CO 2 corrosion was studied by using electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). Results show that the values of inhibition efficiency show peak-value-phenomenon at concentration of 0.15 mmol dm -3 owing to the change of adsorption mode. The adsorption of protonated TAI molecules on the negatively charged steel surface makes the potential of zero charge (PZC) shift to positive direction, and the long-range electrostatic exclusive forces between AFM tip and sample surface are reduced by screening effect of surface charges.

A habitat selection model for Javan deer (Rusa timorensis in Wanagama I Forest, Yogyakarta

Directory of Open Access Journals (Sweden)

DANANG WAHYU PURNOMO

2010-07-01

Full Text Available Purnomo DW. 2010. A Habitat selection model for Javan deer (Rusa timorensis in Wanagama I Forest, Yogyakarta. Nusantara Bioscience 2: 84-89. Wanagama I Forest is the natural breeding habitat of Javan deer (Rusa timorensis de Blainville, 1822. Habitat changes had affected Timor’s resource selection and caused the deer to move from undisturbed areas to developed areas with agriculture and human settlements. We suspected that this shift was caused by the degradation of natural habitat. The research aimed to identify factors that might influence future habitat selection. Habitat selection was analyzed by comparing proportions of sites actually used to sites that we considered available to use. The results of a logistic regression of site categories showed there are three habitat variables that influence resource selection: sum of tree species (expß=1.305, slope (expß=1.061, and distance to a water source (expß=1.002. The three variables influence the deer existing in a certain site of Wanagama Forest and arrange resource selection probability function (RSPF.

The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection.

Science.gov (United States)

Ramanathan, Anand; Devarkar, Swapnil C; Jiang, Fuguo; Miller, Matthew T; Khan, Abdul G; Marcotrigiano, Joseph; Patel, Smita S

2016-01-29

RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5' triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG-I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5'-ppp dsRNAs is ≈3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high katpase/Kd. We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from ≈3000 to 150 and 750, respectively. We propose that the CARD2-Hel2i interface is a 'gate' that prevents cellular RNAs from generating productive complexes that can signal. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. Structure-activity relationships and identification of potent and selective iGluR5 modulators

DEFF Research Database (Denmark)

Butini, Stefania; Pickering, Darryl S; Morelli, Elena

2008-01-01

(S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacolog...

H I-SELECTED GALAXIES IN THE SLOAN DIGITAL SKY SURVEY. I. OPTICAL DATA

International Nuclear Information System (INIS)

West, Andrew A.; Garcia-Appadoo, Diego A.; Dalcanton, Julianne J.; Ivezic, Zeljko; Bentz, Misty C.; Disney, Mike J.; Rockosi, Constance M.; Brinkmann, J.

2010-01-01

We present the optical data for 195 H I-selected galaxies that fall within both the Sloan Digital Sky Survey (SDSS) and the Parkes Equatorial Survey (ES). The photometric quantities have been independently recomputed for our sample using a new photometric pipeline optimized for large galaxies, thus correcting for SDSS's limited reliability for automatic photometry of angularly large or low surface brightness (LSB) galaxies. We outline the magnitude of the uncertainty in the SDSS catalog-level photometry and derive a quantitative method for correcting the over-sky subtraction in the SDSS photometric pipeline. The main thrust of this paper is to present the ES/SDSS sample and discuss the methods behind the improved photometry, which will be used in future scientific analysis. We present the overall optical properties of the sample and briefly compare to a volume-limited, optically selected sample. Compared to the optically selected SDSS sample (in the similar volume), H I-selected galaxies are bluer and more luminous (fewer dwarf ellipticals and more star formation). However, compared to typical SDSS galaxy studies, which have their own selection effect, our sample is bluer, fainter, and less massive.

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

New biphenyl derivatives of bis-imidazoline selones were synthesized in good yield and characterized by multinuclear (1D and 2D) NMR and UV-vis studies. The solid state structures of bis-imidazoline selones were further confirmed by single crystal X ray diffraction technique.

Staphylococcus hyicus exfoliative toxins selectively digest porcine desmoglein 1

DEFF Research Database (Denmark)

Fudaba, Y.; Nishifuji, K.; Andresen, Lars Ole

2005-01-01

. Recently, genes for ExhA, ExhB, ExhC and ExhD were cloned. Exfoliative toxins produced by S. aureus have been shown to selectively cleave human or mouse desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study, we attempted to identify the molecular target...... that Exh selectively degrade porcine desmoglein 1. In vitro incubation of the recombinant extracellular domains of desmoglein I and desmoglein 3 of human, mouse or canine origin demonstrated that only mouse desmogleins 1 alpha and 1 beta were cleaved by ExhA and ExhC at high concentration. Furthermore...

The calculation of 131I dose in second treatment for Graves' disease and the selection of patients

International Nuclear Information System (INIS)

Yang Jisheng; Wang Qiang; Hu Mingzao; Zuo Lei; Peng Xiaoyan

2001-01-01

Objective: To improve the method of 131 I dose calculation in second treatment for Graves' disease (GD) and to make a criterion for selection of patients. Methods: From 87 GD patients not recovered more than half a year after 131 I treatment, authors selected 41 cases (group A) whose thyroid weight were ≥30 g and gave them second 131 I treatment. The absorbed dose (d 2 ) of 131 I was calculated by the formula we designed: (m 1 /m 2 ):d 1 =(m 2 /m 3 ): d 2 ; i.e. d 2 (Gy) = d 1 m 2 2 /m 1 m 3 . The total dose (D) was calculated by the classical formula: D(37 KBq or μ Ci)= d 2 x 8 x m 2 (g)/1.6 x max. uptake % of 131 I x T 1/2eff (days). m 1 and m 2 was the thyroid weight before and after the first 131 I treatment respectively, m 3 was the pre-estimated thyroid weight after the second treatment, d 1 was the unit dose of the first treatment. Results were compared with 97 patients (group B) who had received second 131 I treatment before using this calculation method. The resting 46 cases (group C) whose thyroid weight were 131 I treatment of group A was 73.2% (30/41 cases), it was remarkably higher than that of group B (19.6%), but the early-permanent hypothyroidism rate was lower in group A. The recovery rate of group C was 91.3% (42/46 case) in two years (averaged 8.8 months). Conclusion: The calculating method can make the dose of second 131 I treatment for GD relatively optimal. Thyroid weight ≥30 g can be used as the main criterion for selection of patients 131 I treatment. Patients whose thyroid weight 131 I treatment and the therapeutic effect was poor

Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- <i>a> ]pyrazines as ATR Inhibitors

Energy Technology Data Exchange (ETDEWEB)

Barsanti, Paul A; Aversa, Robert J.; Jin, Xianming; Pan, Yue; Lu, Yipin; Elling, Robert; Jain, Rama; Knapp, Mark; Lan, Jiong; Lin, Xiaodong; Rudewicz, Patrick; Sim, Janet; Taricani, Lorena; Thomas, George; Xiao, Linda; Yue, Qin (Novartis)

2015-01-08

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.

Structural Basis for the Species-Selective Binding of N,C-Capped Dipeptides to the <i>Mycobacterium tuberculosisi> Proteasome

Energy Technology Data Exchange (ETDEWEB)

Hsu, Hao-Chi [Van Andel Research Institute, Grand Rapids, Michigan 49503, United States; Singh, Pradeep K.; Fan, Hao; Wang, Rong [NMR; Sukenick, George [NMR; Nathan, Carl; Lin, Gang; Li, Huilin [Van Andel Research Institute, Grand Rapids, Michigan 49503, United States

2016-12-27

The Mycobacterium tuberculosis (Mtb) 20S proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. To qualify for drug development, inhibitors targeting Mtb 20S must spare both the human constitutive proteasome (c-20S) and immunoproteasome (i-20S). We recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for Mtb 20S over human c-20S and i-20S. To understand the structural basis of their potency and selectivity, we have studied the structure–activity relationship of six derivatives and solved their cocrystal structures with Mtb 20S. The dipeptide inhibitors form an antiparallel β-strand with the active site β-strands. Selectivity is conferred by several features of Mtb 20S relative to its mouse counterparts, including a larger S1 pocket, additional hydrogen bonds in the S3 pocket, and hydrophobic interactions in the S4 pocket. Serine-20 and glutamine-22 of Mtb 20S interact with the dipeptides and confer Mtb-specific inhibition over c-20S and i-20S. The Mtb 20S and mammalian i-20S have a serine-27 that interacts strongly with the dipeptides, potentially explaining the higher inhibitory activity of the dipeptides toward i-20S over c-20S. This detailed structural knowledge will aid in optimizing the dipeptides as anti-tuberculosis drugs.

Selection dramatically reduces effective population size in HIV-1 infection

Directory of Open Access Journals (Sweden)

Mittler John E

2008-05-01

Full Text Available Abstract Background In HIV-1 evolution, a 100–100,000 fold discrepancy between census size and effective population size (Ne has been noted. Although it is well known that selection can reduce Ne, high in vivo mutation and recombination rates complicate attempts to quantify the effects of selection on HIV-1 effective size. Results We use the inbreeding coefficient and the variance in allele frequency at a linked neutral locus to estimate the reduction in Ne due to selection in the presence of mutation and recombination. With biologically realistic mutation rates, the reduction in Ne due to selection is determined by the strength of selection, i.e., the stronger the selection, the greater the reduction. However, the dependence of Ne on selection can break down if recombination rates are very high (e.g., r ≥ 0.1. With biologically likely recombination rates, our model suggests that recurrent selective sweeps similar to those observed in vivo can reduce within-host HIV-1 effective population sizes by a factor of 300 or more. Conclusion Although other factors, such as unequal viral reproduction rates and limited migration between tissue compartments contribute to reductions in Ne, our model suggests that recurrent selection plays a significant role in reducing HIV-1 effective population sizes in vivo.

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

OpenAIRE

Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. Ho...

Metformin selectively targets redox control of complex I energy transduction

Directory of Open Access Journals (Sweden)

Amy R. Cameron

2018-04-01

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

THE CLUSTERING CHARACTERISTICS OF H I-SELECTED GALAXIES FROM THE 40% ALFALFA SURVEY

Energy Technology Data Exchange (ETDEWEB)

Martin, Ann M. [NASA Postdoctoral Program, NASA Langley Research Center, Hampton, VA 23618 (United States); Giovanelli, Riccardo; Haynes, Martha P. [Center for Radiophysics and Space Research, Space Sciences Building, Cornell University, Ithaca, NY 14853 (United States); Guzzo, Luigi, E-mail: ann.m.martin@nasa.gov, E-mail: riccardo@astro.cornell.edu, E-mail: haynes@astro.cornell.edu, E-mail: luigi.guzzo@brera.inaf.it [INAF Osservatorio Astronomico di Brera, Milan (Italy)

2012-05-01

The 40% Arecibo Legacy Fast ALFA survey catalog ({alpha}.40) of {approx}10,150 H I-selected galaxies is used to analyze the clustering properties of gas-rich galaxies. By employing the Landy-Szalay estimator and a full covariance analysis for the two-point galaxy-galaxy correlation function, we obtain the real-space correlation function and model it as a power law, {xi}(r) = (r/r{sub 0}){sup -{gamma}}, on scales <10 h{sup -1} Mpc. As the largest sample of blindly H I-selected galaxies to date, {alpha}.40 provides detailed understanding of the clustering of this population. We find {gamma} = 1.51 {+-} 0.09 and r{sub 0} = 3.3 + 0.3, -0.2 h{sup -1} Mpc, reinforcing the understanding that gas-rich galaxies represent the most weakly clustered galaxy population known; we also observe a departure from a pure power-law shape at intermediate scales, as predicted in {Lambda}CDM halo occupation distribution models. Furthermore, we measure the bias parameter for the {alpha}.40 galaxy sample and find that H I galaxies are severely antibiased on small scales, but only weakly antibiased on large scales. The robust measurement of the correlation function for gas-rich galaxies obtained via the {alpha}.40 sample constrains models of the distribution of H I in simulated galaxies, and will be employed to better understand the role of gas in environmentally dependent galaxy evolution.

Selecting reference cities for i-Tree Streets

Science.gov (United States)

E.G. McPherson

2010-01-01

The i-Tree Streets (formerly STRATUM) computer program quantifies municipal forest structure, function, and value using tree growth and geographic data from sixteen U.S. reference cities, one for each of sixteen climate zones. Selecting the reference city that best matches a subject city is problematic when the subject city is outside the U.S., lays on the border...

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization.

Science.gov (United States)

Gully, Danielle; Geslin, Michel; Serva, Laurence; Fontaine, Evelyne; Roger, Pierre; Lair, Christine; Darre, Valerie; Marcy, Claudine; Rouby, Pierre-Eric; Simiand, Jacques; Guitard, Josette; Gout, Georgette; Steinberg, Regis; Rodier, Daniel; Griebel, Guy; Soubrie, Philippe; Pascal, Marc; Pruss, Rebecca; Scatton, Bernard; Maffrand, Jean-Pierre; Le Fur, Gerard

2002-04-01

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.

A solution to the vertical barΔI/sup →/vertical bar = 1/2 rule and other dynamical selection rules in particle physics

International Nuclear Information System (INIS)

Oneda, S.; Terasaki, K.

1984-01-01

Algebraic approach is developed in the framework of QCD and Electroweak theories. It is stressed that many seemingly different dynamical selection rules can share the same origin. In particular, derivation of vertical bar Δ I → vertical bar = 1/2 rule and explicit identification of its small violation are made for the Κ → 2 π decays, using new much milder soft-pion extrapolation. As a byproduct, the Β → ωπ decays are predicted to be predominantly λ = +-1 transitions in consistency with experiment

Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke.

Directory of Open Access Journals (Sweden)

Masahiko Ichijo

Full Text Available Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1 on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia.In C57Bl/6 mice (n = 133 subjected to unilateral common carotid occlusion (CCAO and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p. injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day; sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg; LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated.In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after

Radiodinated L-703,606: a potent selective antagonist to the human NK[sub 1] receptor

Energy Technology Data Exchange (ETDEWEB)

Francis, B E; Burns, H D [Merck Research Labs., West Point, PA (United States). Dept. of Radiopharmacology; Swain, C; Sabin, V [Merck Sharp and Dohme Research Labs., Harlow (United Kingdom). The Neuroscience Centre

1994-01-01

A new, radioiodinated, NK[sub 1] selective radiotracer ([[sup 125]I]L-703,606) was prepared. L-703,606 is an iodinated analog of the NK[sub 1] antagonist CP-96,345 in which the methoxy group has been replaced by an iodine substituent. [[sup 125]I]L-703,606 was made from the corresponding trimethylsilyl compound by treatment with no carrier added Na[sub 125]I and an Iodobead in TFA. The tracer was prepared at a specific activity of approx. 1100 Ci/mmol and preliminary binding studies demonstrated that [[sup 125]I]L=703,606 binds selectively to NK[sub 1] receptors. These results suggest that this radioligand will be useful for the biochemical and pharmacological characterization of the human NK[sub 1] receptor and, if labeled with I-123, may be useful for non-invasive NK[sub 1] receptor imaging via SPECT. (author).

Genetic trends of selection for pelt traits in Karakul sheep I. Direct ...

African Journals Online (AJOL)

Genetic trends of selection for pelt traits in Karakul sheep. I. Direct ... development in the Karakul Wereestimated with the Animal Model in four selection lines and in a control flock over ..... Selection experiments in laboratory and domestic.

Rationalization of the selectivity between 1,3- and 1,2-migration: a DFT study on gold(i)-catalyzed propargylic ester rearrangement.

Science.gov (United States)

Jiang, Jingxing; Liu, Yan; Hou, Cheng; Li, Yinwu; Luan, Zihong; Zhao, Cunyuan; Ke, Zhuofeng

2016-04-14

Gold catalyzed rearrangement of propargylic esters can undergo 1,3-acyloxy migration to form allenes, or undergo 1,2-acyloxy migration to access gold-carbenoids. The variation in migration leads to different reactivities and diverse cascade transformations. The effect of terminal substituents is very important for the rearrangement. However, it remains ambiguous how terminal substituents govern the selectivity of the rearrangement. This study presents a theoretical model based on the resonance structure of gold activated propargylic ester complexes to rationalize the rearrangement selectivity. Substrates with a major resonance contributor A prefer 5-exo-dig cyclization (1,2-migration), while those with a major resonance contributor B prefer 6-endo-dig cyclization (1,3-migration). This concise model would be helpful in understanding and tuning the selectivity of the metal catalyzed rearrangement of propargylic esters.

Development and Evaluation of a Barley 50k iSelect SNP Array

Directory of Open Access Journals (Sweden)

Micha M. Bayer

2017-10-01

Full Text Available High-throughput genotyping arrays continue to be an attractive, cost-effective alternative to sequencing based approaches. We have developed a new 50k Illumina Infinium iSelect genotyping array for barley, a cereal crop species of major international importance. The majority of SNPs on the array have been extracted from variants called in exome capture data of a wide range of European barley germplasm. We used the recently published barley pseudomolecule assembly to map the exome capture data, which allowed us to generate markers with accurate physical positions and detailed gene annotation. Markers from an existing and widely used barley 9k Infinium iSelect array were carried over onto the 50k chip for backward compatibility. The array design featured 49,267 SNP markers that converted into 44,040 working assays, of which 43,461 were scorable in GenomeStudio. Of the working assays, 6,251 are from the 9k iSelect platform. We validated the SNPs by comparing the genotype calls from the new array to legacy datasets. Rates of agreement averaged 98.1 and 93.9% respectively for the legacy 9k iSelect SNP set (Comadran et al., 2012 and the exome capture SNPs. To test the utility of the 50k chip for genetic mapping, we genotyped a segregating population derived from a Golden Promise × Morex cross (Liu et al., 2014 and mapped over 14,000 SNPs to genetic positions which showed a near exact correspondence to their known physical positions. Manual adjustment of the cluster files used by the interpreting software for genotype scoring improved results substantially, but migration of cluster files between sites led to a deterioration of results, suggesting that local adjustment of cluster files is required on a site-per-site basis. Information relating to the markers on the chip is available online at https://ics.hutton.ac.uk/50k.

Spectroscopic constants and potential energy curve of the iodine weakly bound 1u state correlating with the I(2P1/2) + I(2P1/2) dissociation limit

International Nuclear Information System (INIS)

Akopyan, M E; Baturo, V V; Lukashov, S S; Poretsky, S A; Pravilov, A M

2015-01-01

The stepwise three-step three-color laser population of the I 2 (β1 g , ν β , J β ) rovibronic states via the B0 u + , ν B , J B rovibronic states and rovibronic levels of the 1 u (bb) and 0 g + (bb) states mixed by hyperfine interaction is used for determination of rovibronic level energies of the weakly bound I 2 (1 u (bb)) state. Dunham coefficients of the state, Y i0 (i = 0–3), Y i1 (i = 0–2), Y 02 and Y 12 for the v 1 u  = 1–5, 8, 10, 15 and J 1 u  ≈ 9–87 ranges, the dissociation energy of the state, D e , and equilibrium I–I distance, R e , as well as the potential energy curve are determined. There are aperiodicities in the excitation spectrum corresponding to the β, ν β  = 23, J β  ← 1 u (bb), ν 1u  = 4, 5, J 1u progressions in the I 2  + Rg = He, Ar mixture, namely, a great number of lines which do not coincide with the R or P line progressions. Their positions conflict with the ΔJ-even selection rule. Furthermore, they do not correspond to the ΔJ-odd progression. (paper)

QSAR of adenosine receptor antagonists. Part 3: Exploring physicochemical requirements for selective binding of 1,2,4-triazolo[5,1-i]purine derivatives with human adenosine A3 receptor subtype.

Science.gov (United States)

Roy, Kunal; Leonard, J Thomas; Sengupta, Chandana

2004-07-16

Considering potential of selective adenosine A3 receptor antagonists in the development of prospective therapeutic agents, an attempt has been made to explore selectivity requirements of 1,2,4-triazolo[5,1-i]purine derivatives for binding with cloned human adenosine A3 receptor subtype. In this study, partition coefficient (logP) values of the molecules (calculated by Crippen's fragmentation method) and Wang-Ford charges of the common atoms of the triazolopurine nucleus (calculated from molecular electrostatic potential surface of energy minimized geometry using AM1 technique) were used as independent variables along with suitable dummy parameters. The best equation describing A3 binding affinity [n=29, Q2=0.796, Ra2=0.853, R2=0.874, R=0.935, s=0.342, F=41.5 (df 4,24), SDEP=0.396] showed parabolic relation with logP (optimum value being 4.134). Further, it was found that an aromatic substituent conjugated with the triazole nucleus should be present at R2 position for A3 binding affinity. Again, high negative charges on N2 and N4 are conducive to the binding affinity. While exploring selectivity requirements of the compounds for binding with A3 receptor over that with A2A receptor, the selectivity relation [n=23, Q2=0.909, Ra2=0.918, R2=0.933, R=0.966, s=0.401, F=62.4 (df 4,18), SDEP=0.412] showed that an aromatic R2 substituent conjugated with the triazole nucleus contributes significantly to the selectivity. Again, presence of a 4-substituted-phenyl ring (except 4-OH-phenyl and 4-CH3-phenyl) at R2 position also increases selectivity. Further, charge difference between N2 and N11 (negative charge on the former should be higher and that on the latter should be less) contributes significantly to the selectivity. In addition, negative charge on N7 is conducive while presence of substituents like propyl, butyl, pentyl or phenyl at R1 position is detrimental for the A3 selectivity.

Initial evaluation of 123I-5-I-R91150, a selective 5-HT2Aligand for single-photon emission tomography, in healthy human subjects

International Nuclear Information System (INIS)

Busatto, G.F.; Pilowsky, L.S.; Costa, D.C.; Mertens, J.; Terriere, D.; Ell, P.J.; Mulligan, R.; Travis, M.J.; Leysen, J.E.; Lui, D.; Gacinovic, S.; Waddington, W.; Lingford-Hughes, A.; Kerwin, R.W.

1997-01-01

The mapping of 5-HT 2 receptors in the brain using functional imaging techniques has been limited by a relative lack of selective radioligands. Iodine-123 labelled 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methox ybenzamide ( 123 I-5-I-R91150 or 123 I-R93274) is a new ligand for single-photon emission tomography (SPET), with high affinity and selectivity for 5-HT 2A receptors. This study reports on preliminary 123 I-5-I-R91150 SPET, whole-body and blood distribution findings in five healthy human volunteers. Maximal brain uptake was approximately 2% of total body counts at 180 min post injection (p.i.). Dynamic SPET sequences were acquired with the brain-dedicated, single-slice multi-detector system SME-810 over 200 min p.i. Early peak uptake (at 5 min p.i.) was seen in the cerebellum, a region free from 5HT 2A receptors. In contrast, radioligand binding in the frontal cortex increased steadily over time, up to a peak at approximately 100-120 min p.i. Frontal cortex-cerebellum activity ratios reached values of 1.4, and remained stable from approximately 100 min p.i. onwards. Multi-slice SPET sequences showed a pattern of regional variation of binding compatible with the autoradiographic data on the distribution of 5-HT 2A receptors in humans (cerebral cortex >striatum >cerebellum). These findings suggest that 123 I-5-I-R91150 may be used for the imaging of 5-HT 2A receptors in the living human brain with SPET. (orig.). With 4 figs., 2 tabs

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

Directory of Open Access Journals (Sweden)

Lydia Dmochewitz

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

Novel, potent, and radio-iodinatable somatostatin receptor 1 (sst1) selective analogues.

Science.gov (United States)

Erchegyi, Judit; Cescato, Renzo; Grace, Christy Rani R; Waser, Beatrice; Piccand, Véronique; Hoyer, Daniel; Riek, Roland; Rivier, Jean E; Reubi, Jean Claude

2009-05-14

The proposed sst(1) pharmacophore (J. Med. Chem. 2005, 48, 523-533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst(1) receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst(1)) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA(1,4-6,10,12,13)-[DTyr(2),DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (25) was radio-iodinated ((125)I-25) and specifically labeled sst(1)-expressing cells and tissues. 3D NMR structures were calculated for des-AA(1,4-6,10,12,13)-[DPhe(2),DTrp(8),IAmp(9)]-SRIF-Thr-NH(2) (16), des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9)]-SRIF-Thr-NH(2) (23), and des-AA(1,2,4-6,10,12,13)-[DAgl(NMe,2naphthoyl)(8),IAmp(9),Tyr(11)]-SRIF-NH(2) (27) in DMSO. Though the analogues have the sst(1) pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst(1) binding of these novel, less constrained sst(1)-selective family members.

Ethnic Related Selection for an ADH Class I Variant within East Asia

Science.gov (United States)

Li, Hui; Gu, Sheng; Cai, Xiaoyun; Speed, William C.; Pakstis, Andrew J.; Golub, Efim I.; Kidd, Judith R.; Kidd, Kenneth K.

2008-01-01

Background The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region. Methodology/Principal Findings Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best. Conclusions/Significance The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region

Ethnic related selection for an ADH Class I variant within East Asia.

Science.gov (United States)

Li, Hui; Gu, Sheng; Cai, Xiaoyun; Speed, William C; Pakstis, Andrew J; Golub, Efim I; Kidd, Judith R; Kidd, Kenneth K

2008-04-02

The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region. Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best. The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B diversities

Ethnic related selection for an ADH Class I variant within East Asia.

Directory of Open Access Journals (Sweden)

Hui Li

2008-04-01

Full Text Available The alcohol dehydrogenases (ADH are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region.Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian. The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH and relative EHH (REHH tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best.The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B

Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.

Science.gov (United States)

Hacker, Ulrich T; Schildhauer, Ines; Barroso, Margarita Céspedes; Kofler, David M; Gerner, Franz M; Mysliwietz, Josef; Buening, Hildegard; Hallek, Michael; King, Susan B S

2006-05-01

The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.

A calixarene-based ion-selective electrode for thallium(I) detection.

Science.gov (United States)

Chester, Ryan; Sohail, Manzar; Ogden, Mark I; Mocerino, Mauro; Pretsch, Ernö; De Marco, Roland

2014-12-03

Three new calixarene Tl(+) ionophores have been utilized in Tl(+) ion-selective electrodes (ISEs) yielding Nernstian response in the concentration range of 10(-2)-10(-6)M TlNO3 with a non-optimized filling solution in a conventional liquid contact ISE configuration. The complex formation constants (logβIL) for two of the calixarene derivatives with thallium(I) (i.e. 6.44 and 5.85) were measured using the sandwich membrane technique, with the other ionophore immeasurable due to eventual precipitation of the ionophore during these long-term experiments. Furthermore, the unbiased selectivity coefficients for these ionophores displayed excellent selectivity against Zn(2+), Ca(2+), Ba(2+), Cu(2+), Cd(2+) and Al(3+) with moderate selectivity against Pb(2+), Li(+), Na(+), H(+), K(+), NH4(+) and Cs(+), noting that silver was the only significant interferent with these calixarene-based ionophores. When optimizing the filling solution in a liquid contact ISE, it was possible to achieve a lower limit of detection of approximately 8nM according to the IUPAC definition. Last, the new ionophores were also evaluated in four solid-contact (SC) designs leading to Nernstian response, with the best response noted with a SC electrode utilizing a gold substrate, a poly(3-octylthiophene) (POT) ion-to-electron transducer and a poly(methyl methacrylate)-poly(decyl methacrylate) (PMMA-PDMA) co-polymer membrane. This electrode exhibited a slope of 58.4mVdecade(-1) and a lower detection limit of 30.2nM. Due to the presence of an undesirable water layer and/or leaching of redox mediator from the graphite redox buffered SC, a coated wire electrode on gold and graphite redox buffered SC yielded grossly inferior detection limits against the polypyrrole/PVC SC and POT/PMMA-PDMA SC ISEs that did not display signs of a water layer or leaching of SC ingredients into the membrane. Copyright © 2014 Elsevier B.V. All rights reserved.

Regio- and stereo-selective polymerization of 1,3-butadiene catalyzed by phosphorus–nitrogen PN3-pincer cobalt(ii) complexes

KAUST Repository

Gong, Dirong

2016-11-11

A new family of cobalt complexes (CoCl2-H, CoCl2-Me, CoCl2-iPr, CoBr2-H, CoBr2-Me, CoBr2-iPr, CoI2-H, CoI2-Me, and CoI2-iPr) supported by a PN3 ligand (6-(N,N′-di-t-butylphosphino)-2-pyrazol-yl-aminopyridine) have been prepared and fully characterized by FT-IR, elemental analysis, and X-ray analysis. The X-ray analysis reveals a trigonal bipyramidal conformation in the solid state for all representative complexes, CoCl2-H, CoBr2-H, CoBr2-iPr and CoI2-Me. The cobalt center is chelated by the PN3 ligand through the pyridinyl nitrogen, the pyrazol nitrogen and the phosphorus donor, with a long Co-P bond distance indicating a labile character. On activation with AlEt2Cl, Al2Et3Cl3, MAO, [Ph3C]+[B(C6F5)4]-/AliBu3 or AliBu3, cis-1,4 selective butadiene polymerization was achieved with up to 98.6% selectivity. The polymerization results show that the cis-1,4 selectivity is influenced by the steric hindrance, increasing with the bulkiness of the substituent groups (CoX2-iPr > CoX2-Me > CoX2-H) at the 3,5-positions of the pyrazole moiety, together with a slight decrease in activity. The activity changes in the order CoCl2L ≈ CoBr2L > CoI2L (for the same ligand L) when MAO is used as the activator, while the high level of cis-1,4 selectivity is maintained. It is possible to switch the selectivity from cis-1,4 to syndiotactic-1,2 by adding PPh3 © The Royal Society of Chemistry.

Vanadium NMR Chemical Shifts of (Imido)vanadium(V) Dichloride Complexes with Imidazolin-2-iminato and Imidazolidin-2-iminato Ligands: Cooperation with Quantum-Chemical Calculations and Multiple Linear Regression Analyses.

Science.gov (United States)

Yi, Jun; Yang, Wenhong; Sun, Wen-Hua; Nomura, Kotohiro; Hada, Masahiko

2017-11-30

The NMR chemical shifts of vanadium ( 51 V) in (imido)vanadium(V) dichloride complexes with imidazolin-2-iminato and imidazolidin-2-iminato ligands were calculated by the density functional theory (DFT) method with GIAO. The calculated 51 V NMR chemical shifts were analyzed by the multiple linear regression (MLR) analysis (MLRA) method with a series of calculated molecular properties. Some of calculated NMR chemical shifts were incorrect using the optimized molecular geometries of the X-ray structures. After the global minimum geometries of all of the molecules were determined, the trend of the observed chemical shifts was well reproduced by the present DFT method. The MLRA method was performed to investigate the correlation between the 51 V NMR chemical shift and the natural charge, band energy gap, and Wiberg bond index of the V═N bond. The 51 V NMR chemical shifts obtained with the present MLR model were well reproduced with a correlation coefficient of 0.97.

Selectivity switch in the synthesis of vinylgold(I) intermediates

KAUST Repository

Hashmi, A. Stephen K

2011-11-28

An unexpected regioselectivity reversal was observed in the synthesis of vinylgold(I) complexes from propargyl carboxamides. The use of [Au(IPr)(OH)] affords preferentially vinylgold(I) complexes resulting from a 5-exo-dig cyclization, whereas the use [Au(IPr)]+ species, generated in situ starting from [Au(IPr)(Cl)] and AgOTf, leads to vinylgold(I) complexes which form via a 6-endo-dig cyclization, This unexpected "selectivity switch" for this cyclization led us to propose two different reaction pathways enabling the formation of the two different products. One mechanism involves the [Au(IPr)]+ species with "classical" I activation of the alkyne framework of the carboxamides, and the second represents an "unusual" use of the basic Brønsted character of [Au(IPr)(OH)]. Mechanistic and DFT studies support the mechanistic hypotheses. © 2011 American Chemical Society.

Selectivity switch in the synthesis of vinylgold(I) intermediates

KAUST Repository

Hashmi, A. Stephen K; Schuster, Andreas M.; Gaillard, Sylvain; Cavallo, Luigi; Poater, Albert; Nolan, Steven P.

2011-01-01

An unexpected regioselectivity reversal was observed in the synthesis of vinylgold(I) complexes from propargyl carboxamides. The use of [Au(IPr)(OH)] affords preferentially vinylgold(I) complexes resulting from a 5-exo-dig cyclization, whereas the use [Au(IPr)]+ species, generated in situ starting from [Au(IPr)(Cl)] and AgOTf, leads to vinylgold(I) complexes which form via a 6-endo-dig cyclization, This unexpected "selectivity switch" for this cyclization led us to propose two different reaction pathways enabling the formation of the two different products. One mechanism involves the [Au(IPr)]+ species with "classical" I activation of the alkyne framework of the carboxamides, and the second represents an "unusual" use of the basic Brønsted character of [Au(IPr)(OH)]. Mechanistic and DFT studies support the mechanistic hypotheses. © 2011 American Chemical Society.

Selecting <i>Schizosaccharomyces pombei> diploids

DEFF Research Database (Denmark)

Ekwall, Karl; Thon, Genevieve

2017-01-01

Here we describe procedures for the selection of diploid Schizosaccharomyces pombe. ade6-M210/ade6-M216 heteroallelic complementation is widely used to select for Ade+ diploids. Such diploids will readily sporulate when starved of nitrogen. For some investigations, stable diploids are preferable (e.......g., for genetic complementation tests), and in these cases mating an h− strain with an h90 mat2-Pi-102 strain can be used to prevent sporulation. When ade6-M210/ade6-M216 mutations impact on, or show synthetic interactions with, the gene of interest, two different auxotrophic markers can be used to select...

Innovative Additive for Bitumen Based on Processed Fats

Science.gov (United States)

Babiak, Michał; Kosno, Jacek; Ratajczak, Maria; Zieliński, Krzysztof

2017-10-01

Various additives, admixtures and modifiers are used to improve technical properties and strength characteristics of building materials. Manufacturers of waterproofing materials, concrete, ceramics and bitumen have to use innovative, increasingly complex and costly additives, admixtures or modifiers. As a result, simple and inexpensive substances have been replaced by complex, long chain polymers, multi component resins or plastics. For economic and ecological reasons waste materials are more frequently used as additives, admixtures and modifiers. Nowadays the most commonly used physical modifiers of bitumen belong to the group of polymers - large molecular organic compounds of natural origin or being the result of planned chemical synthesis. Polymers are substances that do not chemically react with bitumen, they act as fillers or create a spatial network within bitumen (the so called physical cross-linking). The development of organic chemistry has allowed the synthesis of a number of substances chemically modifying bitumen. The most promising are heterocyclic organic compounds belonging to the group of imidazolines. The aim of the study presented in this paper was to demonstrate the suitability of processed natural and post-refining fat waste (diamidoamine dehydrate) as bitumen modifier. This paper discusses the impact of adding technical imidazoline on selected bitumen characteristics. Samples of bitumen 160/220, which is most commonly used for the production of waterproofing products, were analysed. For base bitumen and bitumen modified with technical imidazoline the following measurements were taken: measurement of the softening point by Ball and Ring method, determination of the breaking point by Fraass method and needle penetration measurement at 25°C. Later the samples were aged using TFOT laboratory method and the basic characteristics were determined again. The results showed that a small amount of imidazoline improved bitumen thermoplastic parameters at

Discovery of Clinical Candidate 2-((2<i>S>,6 <i>S>)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Energy Technology Data Exchange (ETDEWEB)

Ye, Xiang-Yang; Chen, Stephanie Y.; Wu, Shung; Yoon, David S.; Wang, Haixia; Hong, Zhenqiu; O’Connor, Stephen P.; Li, Jun; Li, James J.; Kennedy, Lawrence J.; Walker, Steven J.; Nayeem, Akbar; Sheriff, Steven; Camac, Daniel M.; Ramamurthy, Vidyhashankar; Morin, Paul E.; Zebo, Rachel; Taylor, Joseph R.; Morgan, Nathan N.; Ponticiello, Randolph P.; Harrity, Thomas; Apedo, Atsu; Golla, Rajasree; Seethala, Ramakrishna; Wang, Mengmeng; Harper, Timothy W.; Sleczka, Bogdan G.; He, Bin; Kirby, Mark; Leahy, David K.; Li, Jianqing; Hanson, Ronald L.; Guo, Zhiwei; Li, Yi-Xin; DiMarco, John D.; Scaringe, Raymond; Maxwell, Brad; Moulin, Frederick; Barrish, Joel C.; Gordon, David A.; Robl, Jeffrey A.

2017-06-05

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC₅₀ 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED₅₀ 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an “inhibition holiday” so that the potential for hypothalamic–pituitary–adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

Investigation of the mechanism of radioprotective action of adrenoceptor agonists

International Nuclear Information System (INIS)

Kulinskij, V.I.; Klimova, A.D.; Yashunskij, V.G.; Alpatova, T.V.; 4205700SU)

1986-01-01

α-Adrenoceptor agonists of both main groups, i.e. arylalkylamines and imidazolines, have a pronounced radioprotective effect. Their chemical analogs, which fail to stimulate α-adrenoceptors, do not protect mice. The effect of phenylephrine, adrenaline, and noradrenaline comes into play via α 1 -adrenoceptors and that of clonidine, via α 2 -adrenoceptors and also via α 1 -adrenoceptors. Adrenoceptor agonists can probably manifest their radioprotective action via both subtypes of α-adrenoceptors. Possible intracellular mechanisms of the radioprotective action are discussed

Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock.

Science.gov (United States)

Su, Fuhong; Huang, Hongchuan; Akieda, Kazuki; Occhipinti, Giovanna; Donadello, Katia; Piagnerelli, Michael; De Backer, Daniel; Vincent, Jean-Louis

2010-09-01

Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.

Range Selection and Median

DEFF Research Database (Denmark)

Jørgensen, Allan Grønlund; Larsen, Kasper Green

2011-01-01

and several natural special cases thereof. The rst special case is known as range median, which arises when k is xed to b(j 􀀀 i + 1)=2c. The second case, denoted prex selection, arises when i is xed to 0. Finally, we also consider the bounded rank prex selection problem and the xed rank range......Range selection is the problem of preprocessing an input array A of n unique integers, such that given a query (i; j; k), one can report the k'th smallest integer in the subarray A[i];A[i+1]; : : : ;A[j]. In this paper we consider static data structures in the word-RAM for range selection...... selection problem. In the former, data structures must support prex selection queries under the assumption that k for some value n given at construction time, while in the latter, data structures must support range selection queries where k is xed beforehand for all queries. We prove cell probe lower bounds...

Obscured AGN at z similar to 1 from the zCOSMOS-Bright Survey : I. Selection and optical properties of a [Ne v]-selected sample

NARCIS (Netherlands)

Mignoli, M.; Vignali, C.; Gilli, R.; Comastri, A.; Zamorani, G.; Bolzonella, M.; Bongiorno, A.; Lamareille, F.; Nair, P.; Pozzetti, L.; Lilly, S. J.; Carollo, C. M.; Contini, T.; Kneib, J. -P.; Le Fevre, O.; Mainieri, V.; Renzini, A.; Scodeggio, M.; Bardelli, S.; Caputi, K.; Cucciati, O.; de la Torre, S.; de Ravel, L.; Franzetti, P.; Garilli, B.; Iovino, A.; Kampczyk, P.; Knobel, C.; Kovac, K.; Le Borgne, J. -F.; Le Brun, V.; Maier, C.; Pello, R.; Peng, Y.; Montero, E. Perez; Presotto, V.; Silverman, J. D.; Tanaka, M.; Tasca, L.; Tresse, L.; Vergani, D.; Zucca, E.; Bordoloi, R.; Cappi, A.; Cimatti, A.; Koekemoer, A. M.; McCracken, H. J.; Moresco, M.; Welikala, N.

Aims. The application of multi-wavelength selection techniques is essential for obtaining a complete and unbiased census of active galactic nuclei (AGN). We present here a method for selecting z similar to 1 obscured AGN from optical spectroscopic surveys. Methods. A sample of 94 narrow-line AGN

Environment-based selection effects of <i>Planck> clusters

Energy Technology Data Exchange (ETDEWEB)

Kosyra, R.; Gruen, D.; Seitz, S.; Mana, A.; Rozo, E.; Rykoff, E.; Sanchez, A.; Bender, R.

2015-07-24

We investigate whether the large-scale structure environment of galaxy clusters imprints a selection bias on Sunyaev–Zel'dovich (SZ) catalogues. Such a selection effect might be caused by line of sight (LoS) structures that add to the SZ signal or contain point sources that disturb the signal extraction in the SZ survey. We use the Planck PSZ1 union catalogue in the Sloan Digital Sky Survey (SDSS) region as our sample of SZ-selected clusters. We calculate the angular two-point correlation function (2pcf) for physically correlated, foreground and background structure in the RedMaPPer SDSS DR8 catalogue with respect to each cluster. We compare our results with an optically selected comparison cluster sample and with theoretical predictions. In contrast to the hypothesis of no environment-based selection, we find a mean 2pcf for background structures of -0.049 on scales of ≲40 arcmin, significantly non-zero at ~4σ, which means that Planck clusters are more likely to be detected in regions of low background density. We hypothesize this effect arises either from background estimation in the SZ survey or from radio sources in the background. We estimate the defect in SZ signal caused by this effect to be negligibly small, of the order of ~10^-4 of the signal of a typical Planck detection. Analogously, there are no implications on X-ray mass measurements. However, the environmental dependence has important consequences for weak lensing follow up of Planck galaxy clusters: we predict that projection effects account for half of the mass contained within a 15 arcmin radius of Planck galaxy clusters. We did not detect a background underdensity of CMASS LRGs, which also leaves a spatially varying redshift dependence of the Planck SZ selection function as a possible cause for our findings.

Selection of chemical forms of iodine for transmutation of 129I

International Nuclear Information System (INIS)

Shirasu, Yoshiro; Minato, Kazuo

2003-01-01

To select suitable chemical forms of iodine for the target for transmutation of 129 I, the properties of iodine compounds of NaI, MgI 2 , CaI 2 , CuI and Ca(IO 3 ) 2 were compared and the out-of-reactor heating experiments of the pellets of CuI and Ca(IO 3 ) 2 with the cladding materials were carried out. CuI and Ca(IO 3 ) 2 are not deliquescent but stable in the air, which is of great advantage to construction, operation and maintenance of the processing plants. The cladding with Cu metal liner could be compatible with CuI though the compatibility of the stainless steel with CuI is not good. Ca(IO 3 ) 2 should be deleted from the list of the candidate target materials for the transmutation of 129 I due to the severe chemical reaction with the cladding materials

New Resin for the Selective Extraction of {sup 129}I

Energy Technology Data Exchange (ETDEWEB)

Bombard, A.; Happel, S. [TrisKem International, Bruz (France); Zulauf, A. [NUKEM Technologies GmbH, Alzenau (Germany); Streng, R. [Radiochemistry, Department of Chemistry, Philipps-University Marburg, Marburg (Germany)

2013-07-15

{sup 129}I is an ideal tracer of the marine environment. It has been used for some years particularly in the northeast Atlantic, Nordic seas and Arctic to determine its distribution after its discharges from La Hague and Sellafield reprocessing plants. Various methods for {sup 129}I determination exist. A new resin selective for iodine has been developed, characterized and tested on environmental samples. In order to allow {sup 129}I determination and to obtain accurate and precise results, the samples have to pass a number of sample preparation steps; among these steps are chemical separation and purification. The results of the analysis of seawater samples are presented. (author)

A new ion selective electrode for cesium (I) based on calix[4]arene-crown-6 compounds.

Science.gov (United States)

Ramanjaneyulu, P S; Kumar, Abha Naveen; Sayi, Y S; Ramakumar, K L; Nayak, S K; Chattopadhyay, S

2012-02-29

A polyvinylchloride (PVC) based liquid membrane ion selective electrode (ISE) for cesium has been developed. 25,27-Dihydroxycalix[4]arene-crown-6 (L1), 5,11,17,23-tetra-tert-butyl-25,27-dimethoxycalix[4]arene-crown-6 (L2) and 25,27-bis(1-octyloxy)calix[4]arene-crown-6 (L3) were investigated for their use as ionophores. The cation exchange resin DOWEX-50W was used to maintain low activity Cs+ in inner filling solution to improve the performance. The best response for cesium was observed with L3 along with optimized membrane constituents and composition. Excellent Nernstian response (56.6 mV/decade of Cs(I)) over the concentration range 10(-7) to 10(-2)M of Cs(I) was obtained with a fast response time of less than 10s. Detection limit for Cs(I) using the present ISE is 8.48×10(-8) M Cs(I). Separate solution method (SSM) was applied to ascertain the selectivity for Cs(I) over alkali, alkaline earth and transition metal ions. The response of ISE for Cs(I) was fairly constant over the pH range of 4-11. The lifetime of the electrode is 10 months which is the highest life for any membrane based Cs-ISE so far developed. The concentration of cesium ion in two simulated high level active waste streams was determined and results agreed well with those obtained independently employing AAS. Copyright © 2011 Elsevier B.V. All rights reserved.

Genetic variation and selection of MHC class I loci differ in two congeneric frogs.

Science.gov (United States)

Kiemnec-Tyburczy, Karen M; Tracy, Karen E; Lips, Karen R; Zamudio, Kelly R

2018-04-01

Major histocompatibility complex (MHC) genes encode proteins in the acquired immune response pathway that often show distinctive selection-driven patterns in wild vertebrate populations. We examined genetic variation and signatures of selection in the MHC class I alpha 1 (A1)- and alpha 2 (A2)-domain encoding exons of two frog congeners [Agalychnis callidryas (n = 20) and A. lemur (n = 20)] from a single locality in Panama. We also investigated how historical demographic processes may have impacted MHC genetic diversity by analyzing a neutral mitochondrial marker. We found that both MHC domains were highly variable in both species, with both species likely expressing three loci. Our analyses revealed different signatures of selection between the two species, most notably that the A. callidryas A2 domain had experienced positive selection while the A2 domain of A. lemur had not. Diversifying selection acted on the same number of A1 and A2 allelic lineages, but on a higher percentage of A1 sites compared to A2 sites. Neutrality tests of mitochondrial haplotypes predominately indicated that the two species were at genetic equilibrium when the samples were collected. In addition, two historical tests of demography indicated both species have had relatively stable population sizes over the past 100,000 years; thus large population size changes are unlikely to have greatly influenced MHC diversity in either species during this time period. In conclusion, our results suggest that the impact of selection on MHC diversity varied between these two closely related species, likely due to a combination of distinct ecological conditions and past pathogenic pressures.

Effect of agmatine on locus coeruleus neuron activity: possible involvement of nitric oxide

Science.gov (United States)

Ruiz-Durántez, Eduardo; Ruiz-Ortega, José A; Pineda, Joseba; Ugedo, Luisa

2002-01-01

To investigate whether agmatine (the proposed endogenous ligand for imidazoline receptors) controls locus coeruleus neuron activity and to elucidate its mechanism of action, we used single-unit extracellular recording techniques in anaesthetized rats. Agmatine (10, 20 and 40 μg, i.c.v.) increased in a dose-related manner the firing rate of locus coeruleus neurons (maximal increase: 95±13% at 40 μg). I1-imidazoline receptor ligands stimulate locus coeruleus neuron activity through an indirect mechanism originated in the paragigantocellularis nucleus via excitatory amino acids. However, neither electrolytic lesions of the paragigantocellularis nucleus nor pretreatment with the excitatory amino acid antagonist kynurenic acid (1 μmol, i.c.v.) modified agmatine effect (10 μg, i.c.v.). After agmatine administration (20 μg, i.c.v.), dose-response curves for the effect of clonidine (0.625 – 10 μg kg−1 i.v.) or morphine (0.3 – 4.8 mg kg−1 i.v.) on locus coeruleus neurons were not different from those obtained in the control groups. Pretreatment with the nitric oxide synthase inhibitors Nω-nitro-L-arginine (10 μg, i.c.v.) or Nω-nitro-L-arginine methyl ester (100 μg, i.c.v.) but not with the less active stereoisomer Nω-nitro-D-arginine methyl ester (100 μg, i.c.v.) completely blocked agmatine effect (10 and 40 μg, i.c.v.). Similarly, when agmatine (20 pmoles) was applied into the locus coeruleus there was an increase that was blocked by Nω-nitro-L-arginine methyl ester (100 μg, i.c.v.) in the firing rate of the locus coeruleus neurons (maximal increase 53±11% and 14±10% before and after nitric oxide synthase inhibition, respectively). This study demonstrates that agmatine stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase-dependent mechanism located in this nucleus. PMID:11877321

Surface passivation of mixed-halide perovskite CsPb(BrxI1-x)3 nanocrystals by selective etching for improved stability.

Science.gov (United States)

Jing, Qiang; Zhang, Mian; Huang, Xiang; Ren, Xiaoming; Wang, Peng; Lu, Zhenda

2017-06-08

In recent years, there has been an unprecedented rise in the research of halide perovskites because of their important optoelectronic applications, including photovoltaic cells, light-emitting diodes, photodetectors and lasers. The most pressing question concerns the stability of these materials. Here faster degradation and PL quenching are observed at higher iodine content for mixed-halide perovskite CsPb(Br x I 1-x ) 3 nanocrystals, and a simple yet effective method is reported to significantly enhance their stability. After selective etching with acetone, surface iodine is partially etched away to form a bromine-rich surface passivation layer on mixed-halide perovskite nanocrystals. This passivation layer remarkably stabilizes the nanocrystals, making their PL intensity improved by almost three orders of magnitude. It is expected that a similar passivation layer can also be applied to various other kinds of perovskite materials with poor stability issues.

ANALYSIS OF THE SECONDARY CURVES IN PATIENTS UNDERGOING SELECTIVE ARTHRODESIS LENKE I

Directory of Open Access Journals (Sweden)

TADEU GERVAZONI DEBOM

2015-12-01

Full Text Available Objective : To radiographically evaluate the behavior of the secondary curves in the coronal and sagittal planes in patients with AIS classified as Lenke I, who underwent surgical treatment of selective arthrodesis by posterior approach. Methods : Retrospective study which analyzed 40 patients with AIS, being 33 female. The measurement of the radiographic parameters used followed the recommendations by Cobb. Results : The average correction of the thoracic proximal, primary and lumbar curves was 34.73%, 75.06% and 64.64%, respectively. Conclusion : Surgical treatment by selective arthrodesis in cases of AIS Lenke type I provide correction of compensatory curves in the coronal and maintenance in the sagittal plane.

Critical role for invariant chain in CD1d-mediated selection and maturation of Vα14-invariant NKT cells.

Science.gov (United States)

Sillé, Fenna C M; Martin, Constance; Jayaraman, Pushpa; Rothchild, Alissa; Besra, Gurdyal S; Behar, Samuel M; Boes, Marianne

2011-09-30

The development and maturation of Vα14 invariant (i)NKT cells in mice requires CD1d-mediated lipid antigen presentation in the thymus and the periphery. Cortical thymocytes mediate positive selection, while professional APCs are involved in thymic negative selection and in terminal maturation of iNKT cells in the periphery. CD1d requires entry in the endosomal pathway to allow antigen acquisition for assembly as lipid/CD1d complexes for display to iNKT cells. This process involves tyrosine-based sorting motifs in the CD1d cytoplasmic tail and invariant chain (Ii) that CD1d associates with in the endoplasmic reticulum. The function of Ii in iNKT cell thymic development and peripheral maturation had not been fully understood. Using mice deficient in Ii and the Ii-processing enzyme cathepsin S (catS), we addressed this question. Ii(-/-) mice but not catS(-/-) mice developed significantly fewer iNKT cells in thymus, that were less mature as measured by CD44 and NK1.1 expression. Ii(-/-) mice but not catS(-/-) mice developed fewer Vβ7(+) cells in their iNKT TCR repertoire than WT counterparts, indicative of a change in endogenous glycolipid antigen/CD1d-mediated iNKT cell selection. Finally, using a Mycobacterium tuberculosis infection model in macrophages, we show that iNKT developed in Ii(-/-) but not catS(-/-) mice have defective effector function. Our data support a role for professional APCs expressing Ii, but no role for catS in the thymic development and peripheral terminal maturation of iNKT cells. Copyright © 2011 Elsevier B.V. All rights reserved.

Selective displacement of the tributylstannyl group to form [125I]phenylboronic acid derivatives

International Nuclear Information System (INIS)

Kinsey, B.M.; Kassis, A.I.

1990-01-01

Three radioiodinated phenylboronic acid derivatives (1a, 2a, 3a) were prepared at the no-carrier-added level by selective displacement of the corresponding tributylstannyl group. The tributylstannyl compounds 1b, 2b, and 3b were synthesized from the bromo derivatives 1c, 2c and 3c. Radioiodination was accomplished using Na 125 I and either Chloramine-T or peracetic acid to give 1a, 2a and 3a in radiochemical yields of 46, 26, and 67% respectively after HPLC purification. Compounds 1a, 2a and 3a were concentrated in vitro preferentially in HT-29 human colon carcinoma cells compared to V79 Chinese hamster lung fibroblasts, with 3a having the highest uptake

Selective recovery of Ag(I) coordination anion from simulate nickel electrolyte using corn stalk based adsorbent modified by ammonia–thiosemicarbazide

Energy Technology Data Exchange (ETDEWEB)

Xiong, Ying, E-mail: xiongying_1977@hotmail.com; Wan, Li; Xuan, Jing; Wang, Yongwei; Xing, Zhiqing; Shan, Weijun; Lou, Zhenning

2016-01-15

Highlights: • We developed a “green” corn stalk adsorbent treated by thiosemicarbazide–glutaraldehyde. • Adsorption mechanism of AgCl{sub i}{sup 1−i} could be electrostatic interaction with C−SH{sup +}−N and C=SH{sup +} group. • The gel could selectively adsorb AgCl{sub i}{sup 1−i} coordination anion from the Ag(I)–Cu(II)–Ni(II) simulate nickel electrolyte. - Abstract: In nickel electrolyte, Ag(I) was present at trace level concentration (10–20 mg L{sup −1}) and existed in the form of AgCl{sub i}{sup 1−i} coordination anion, instead of Ag{sup +} positive ion usually in several sources. In the present study, TSC-NH{sub 3}-OCS adsorbent based on natural corn stalk modified by ammonia (NH{sub 3})–thiosemicarbazide (TSC) was synthesized and characterized using some instrumental techniques. The TSC-NH{sub 3}-OCS adsorbent could selectively adsorb Ag(I) as AgCl{sub i}{sup 1−i} coordination anion from the Ag(I)–Cu(II)–Ni(II) simulate nickel electrolyte, especially in the case of the very high levels of Cu(II) and Ni(II), which significantly outperforms the commercial available resins. The adsorption mechanism was believed to be electrostatic interaction of the protonated bands of AgCl{sub 4}{sup 3−} with protonated thiol form of the thioamide units by FTIR and XPS analysis. The maximum adsorption capacity in the Ag(I) single and Ag(I)–Cu(II)–Ni(II) ternary system were obtained and calculated as 153.54 and 46.69 mg g{sup −1}, respectively. The reasons that the maximum adsorption capacity of AgCl{sub i}{sup 1−i} from the single and ternary system varied widely could be explained by adsorption kinetic and thermodynamic results. In addition, three successive sorption/desorption cycle runs from ternary system were performed which indicated that the TSC-NH{sub 3}-OCS adsorbent has a good performance for recovery Ag(I) from simulate nickel electrolyte.

PASS-predicted design, synthesis and biological evaluation of cyclic nitrones as nootropics.

Science.gov (United States)

Marwaha, Alka; Goel, R K; Mahajan, Mohinder P

2007-09-15

Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs).

2'-fluoro-2'-deoxy-1-β-D-arabinofuranosyl-5-[124I]iodouracil ([124I]FIAU)

International Nuclear Information System (INIS)

Chae, Min Jeong; Lee, Tae Sup; Kim, June Youp

2008-01-01

The HSV1-tk gene has been extensively studied as a type of reporter gene. In hepatocellular carcinoma (HCC), only a small proportion of patients are eligible for surgical resection and there is limitation in palliative options. Therefore, there is a need for the develoopement of new treatment modalities and gene therapy is a leading candidate. In the present study, we investigated the usefulness of substrate, 2'-fluoro-2'-deoxy-1-β -D-arabino-furanosyl-5-[ 124/125 I]iodo- uracil ([ 124/125 I]FIAU) as a non-invasive imaging agent for HSV1-tk gene therapy in hepatoma model using small animal PET. With the Morris hepatoma MCA cell line and MCA-tk cell line which was transduced with the HSV1-tk gene, in vitro uptake and correlation study between [ 125 I]FIAU uptake according to increasing numeric count of percentage of MCA-tk cell were performed. The biodistribution data and small animal PET images with [ 124 I]FIAU were obtained with Balb/c-nude mice bearing both MCA and MCA-tk tumors. Specific accumulation of [ 125 I]FIAU was observed in MCA-tk cells but uptake was low in MCA cells. Uptake in MCA-tk cells was 15 times higher than that of MCA cells at 480 min. [ 125 I]FIAU uptake was linearly correlated (R2=0.964, p=0.01) with increasing percentage of MCA-tk numeric cell count. Biodistribution results showed that [ 125 I]FIAU was mainly excreted via the renal system in the early phase. Ratios of MCA-tk tumor to blood acting were 10, 41, and 641 at 1 h, 4 h, and 24 h post-injection, respectively. The maximum ratio of MCA-tk to MCA tumor was 192.7 at 24 h. Ratios of MCA-tk tumor to liver were 13.8, 66.8, and 588.3 at 1 h, 4 h, and 24 h, respectively. On small aninal PET, [ 124 I]FIAU accumulated in substantial higher levels in MCA-tk tumor and liver than MCA tumor. FIAU shows selective accumulation to HSV1-tk expressing hepatoma cell tumors with minimal uptake in normal liver. Therefore, radiolabelled FIAU is expected to be a useful substrate for non-invasive imaging

Single-photon emission tomography imaging of serotonin transporters in the non-human primate brain with the selective radioligand [[sup 123]I]IDAM

Energy Technology Data Exchange (ETDEWEB)

Acton, P.D.; Kung Mei-Ping; Mu Mu; Ploessl, K.; Hou, C.; Siciliano, M.; Oya Shunichi (Department of Radiology, University of Pennsylvania, Philadelphia, PA (United States)); Kung, H.F. (Department of Radiology, University of Pennsylvania, Philadelphia, PA (United States) Department of Pharmacology, University of Pennsylvania, Philadelphia (United States))

1999-08-01

A new radioligand, 5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol ([[sup 123]I]IDAM), has been developed for selective single-photon emission tomography (SPET) imaging of SERT. In vitro binding studies suggest a high selectivity of IDAM for SERT (K[sub i]=0.097 nM), with considerably lower affinities for norepinephrine and dopamine transporters (NET K[sub i]= 234 nM and DAT K[sub i]>10 [mu]M, respectively). In this study the biodistribution of SERT in the baboon brain was investigated in vivo using [[sup 123]I]IDAM and SPET imaging. Dynamic sequences of SPET scans were performed on three female baboons (Papio anubis) after injection of 555 MBq of [[sup 123]I]IDAM. Displacing doses (1 mg/kg) of the selective SERT ligand (+)McN5652 were administered 90-120 min after injection of [[sup 123]I]IDAM. Similar studies were performed using a NET inhibitor, nisoxetine, and a DAT blocker, methylphenidate. After 60-120 min, the regional distribution of tracer within the brain reflected the characteristic distribution of SERT, with the highest uptake in the midbrain area (hypothalamus, raphe nucleus, substantia nigra), and the lowest uptake in the cerebellum (an area presumed free of SERT). Peak specific binding in the midbrain occurred at 120 min, with a ratio to the cerebellum of 1.80[+-]0.13. At 30 min, 85% of the radioactivity in the blood was metabolite. Following injection of a competing SERT ligand, (+)McN5652, the tracer exhibited rapid washout from areas with high concentrations of SERT (dissociation rate constant in the midbrain, averaged over three baboons, k[sub off]=0.025[+-]0.002 min[sup -1]), while the cerebellar activity distribution was undisturbed (washout rate 0.0059[+-] 0.0003 min[sup -1]). Calculation of tracer washout rate pixel-by-pixel enabled the generation of parametric images of the dissociation rate constant. Similar studies using nisoxetine and methylphenidate had no effect on the distribution of [[sup 123]I]IDAM in the brain

The Remarkable Similarity of Massive Galaxy Clusters from <i>z> ~ 0 to <i>z> ~ 1.9

Energy Technology Data Exchange (ETDEWEB)

McDonald, M.; Allen, S. W.; Bayliss, M.; Benson, B. A.; Bleem, L. E.; Brodwin, M.; Bulbul, E.; Carlstrom, J. E.; Forman, W. R.; Hlavacek-Larrondo, J.; Garmire, G. P.; Gaspari, M.; Gladders, M. D.; Mantz, A. B.; Murray, S. S.

2017-06-28

We present the results of a Chandra X-ray survey of the 8 most massive galaxy clusters at z>1.2 in the South Pole Telescope 2500 deg^2 survey. We combine this sample with previously-published Chandra observations of 49 massive X-ray-selected clusters at 01 and 90 SZ-selected clusters at 0.251.2 to constrain the evolution of the intracluster medium (ICM) over the past ~10 Gyr. We find that the bulk of the ICM has evolved self similarly over the full redshift range probed here, with the ICM density at r>0.2R500 scaling like E(z)^2. In the centers of clusters (r<0.1R500), we find significant deviations from self similarity (n_e ~ E(z)^{0.1+/-0.5}), consistent with no redshift dependence. When we isolate clusters with over-dense cores (i.e., cool cores), we find that the average over-density profile has not evolved with redshift -- that is, cool cores have not changed in size, density, or total mass over the past ~9-10 Gyr. We show that the evolving "cuspiness" of clusters in the X-ray, reported by several previous studies, can be understood in the context of a cool core with fixed properties embedded in a self similarly-evolving cluster. We find no measurable evolution in the X-ray morphology of massive clusters, seemingly in tension with the rapidly-rising (with redshift) rate of major mergers predicted by cosmological simulations. We show that these two results can be brought into agreement if we assume that the relaxation time after a merger is proportional to the crossing time, since the latter is proportional to H(z)^(-1).

Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid.

Science.gov (United States)

Chapman, A G; Talebi, A; Yip, P K; Meldrum, B S

2001-07-20

The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu(4alpha) receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED(50) 5.6 [2.9-10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED(50) 0.08 [0.01-0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED(50) 0.60 [0.29-1.2], nmol i.c.v.) and by the Group III antagonist, (RS)-alpha-methylserine-O-phosphate (MSOP) (ED(50) 49.3 [37.9-64.1], nmol i.c.v.). Another Group III agonist, (RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu(8) receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED(50) 3.7 [2.4-5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED(50) 40.2 [21.0-77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(4) receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20-50 nmol dose range. At doses of 50-200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu(8) receptor agonist PPG, is not

47 CFR 1.1604 - Post-selection hearings.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Post-selection hearings. 1.1604 Section 1.1604 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE Random Selection Procedures for Mass Media Services General Procedures § 1.1604 Post-selection hearings. (a) Following the random...

Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: a phase I study

International Nuclear Information System (INIS)

Order, Stanley E.; Siegel, Jeffry A.; Principato, Robert; Zeiger, Louis E.; Johnson, Elizabeth; Lang, Patricia; Lustig, Robert; Wallner, Paul E.

1996-01-01

Purpose: Selective high-dose radiation of solid tumors has been a goal of radiation oncology. The physiological barriers of solid tumors (high interstitial tumor pressure, reduced tumor vascularity, and poor perfusion) have been major barriers in achieving significant tumor dose of systemically infused radioconjugates. Direct tumor infusional brachytherapy overcomes these barriers and leads to selective high tumor doses. Methods and Materials: The development of interstitial tumor infusion of macroaggregated albumin (MAA) followed by colloidal chromic phosphate 32 P has overcome solid tumor obstacles in 47 patients with nonresectable pancreatic cancer in a Phase I dose escalation study. The colloidal 32 P infusion was followed by external radiation and five fluorouracil. Results: Of the 28 patients with cancer limited to the pancreas, 15 of 16 patients retained 86-100% (mean 96%) of the infused colloidal 32 P isotope. While the other 12 patients had partial shunting to the liver, shunting to the liver was due to high interstitial resistance with tumor dose deposition of 17-88% (mean 52%). Of the 19 patients with metastatic pancreas cancer, colloidal 32 P tumor deposition ranged from 22 to 100% of the infused dose (mean 79%). The less than optimal tumor deposition led to our increasing the MAA from 600,000 to 1.5-2.5 million particles. Interstitial dexamethasone 2 mg and later 4 mg was infused first and prevented liver shunting by somehow reducing tumor resistance. The median survival in 28 Phase I patients with nonresectable pancreas cancer without metastasis, was 12 months. No significant toxicity occurred when treatment was limited to two infusions with as much as 30 mCi each. The maximum tumor dose was 17,000 Gy (1.700,000 cGy). In 19 non-resectable pancreatic cancer patients with metastasis, a 6.9 months median survival was observed. Conclusions: Infusional brachytherapy is an outpatient procedure that delivers high-dose radiation selectively to pancreatic

The transport kinetics and selectivity of HpUreI, the urea channel from Helicobacter pylori†

Science.gov (United States)

Gray, Lawrence R; Gu, Sean X; Quick, Matthias; Khademi, Shahram

2017-01-01

Helicobacter pylori’s unique ability to colonize and survive in the acidic environment of the stomach is critically dependent on uptake of urea through the urea channel, HpUreI. Hence, HpUreI may represent a promising target for the development of specific drugs against this human pathogen. To obtain insight into the structure/function relationship of this channel, we have developed conditions for the high-yield expression and purification of stable recombinant HpUreI that allowed its detailed kinetic characterization in solubilized form and reconstituted into liposomes. Detergent-solubilized HpUreI forms homo-trimer, as determined by chemical cross-linking. Urea dissociation kinetics of purified HpUreI were determined by means of the scintillation proximity assay (SPA), whereas urea efflux was measured in HpUreI-containing proteoliposomes using stopped-flow spectrometry to determine the kinetics and selectivity of the urea channel. The kinetic analyses revealed that urea conduction in HpUreI is pH sensitive and saturable with a half-saturation concentration (or K0.5) of ~163 mM. Binding of urea by HpUreI was increased at lower pH; however, the apparent affinity of urea binding (~150 mM) was not significantly pH dependent. The solute selectivity analysis indicated that HpUreI is highly selective for urea and hydroxyurea. Removing either amino group of urea molecules diminishes their permeability through HpUreI. Similar to urea conduction, water diffusion through HpUreI is pH-dependent with low water permeability at neutral pH. PMID:21877689

25 CFR 26.10 - When will I find out if I have been selected for Job Placement and Training assistance?

Science.gov (United States)

2010-04-01

... INTERIOR HUMAN SERVICES JOB PLACEMENT AND TRAINING PROGRAM General Applicability § 26.10 When will I find out if I have been selected for Job Placement and Training assistance? (a) Your servicing office will notify you in writing within 30 calendar days once it receives a completed job training application...

Selective binding of 2-[125I]iodo-nisoxetine to norepinephrine transporters in the brain

International Nuclear Information System (INIS)

Kung, M.-P.; Choi, Seok-Rye; Hou, Catherine; Zhuang, Z.-P.; Foulon, Catherine; Kung, Hank F.

2004-01-01

A radioiodinated ligand, (R)-N-methyl-(2-[ 125 I]iodo-phenoxy)-3-phenylpropylamine, [ 125 I]2-INXT, targeting norepinephrine transporters (NET), was successfully prepared. A no-carrier-added product, [ 125 I]2-INXT, displayed a saturable binding with a high affinity (K d =0.06 nM) in the homogenates prepared from rat cortical tissues as well as from LLC-PK 1 cells expressing NET. A relatively low number of binding sties (B max =55 fmol/mg protein) measured with [ 125 I]2-INXT in rat cortical homogenates is consistent with the value reported for a known NET ligand, [ 3 H]nisoxetine. Competition studies with various compounds on [ 125 I]2-INXT binding clearly confirmed the pharmacological specificity and selectivity for NET binding sites. Following a tail-vein injection of [ 125 I]2-INXT in rats, a good initial brain uptake was observed (0.56% dose at 2 min) followed by a slow washout from the brain (0.2% remained at 3 hours post-injection). The hypothalamus (a NET-rich region) to striatum (a region devoid of NET) ratio was 1.5 at 3 hours post-i.v. injection. Pretreatment of rats with nisoxetine significantly inhibited the uptake of [ 125 I]2-INXT (70-100% inhibition) in locus coeruleus, hypothalamus and raphe nuclei, regions known to have a high density of NET; whereas escitalopram, a serotonin transporter ligand, did not show a similar effect. Ex vivo autoradiography of rat brain sections of [ 125 I]2-INXT (at 3 hours after an i.v. injection) displayed an excellent regional brain localization pattern corroborated to the specific NET distribution in the brain. The specific brain localization was significantly reduced by a dose of nisoxetine pretreatment. Taken together, the data suggest that [ 123 I]2-INXT may be useful for mapping NET binding sites in the brain

Subset selection from Type-I and Type-II generalized logistic populations

NARCIS (Netherlands)

Laan, van der M.J.; Laan, van der P.

1996-01-01

We give an introduction to the logistic and generalized logistic distributions. We obtain exact results for the probability of correct selection from Type-I and Type-II generalized logistic populations which only differ in their location parameter. Some open problems are formulated.

Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

Science.gov (United States)

Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

2008-10-01

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

MID-INFRARED SELECTION OF ACTIVE GALACTIC NUCLEI WITH THE WIDE-FIELD INFRARED SURVEY EXPLORER. I. CHARACTERIZING WISE-SELECTED ACTIVE GALACTIC NUCLEI IN COSMOS

International Nuclear Information System (INIS)

Stern, Daniel; Assef, Roberto J.; Eisenhardt, Peter; Benford, Dominic J.; Blain, Andrew; Cutri, Roc; Griffith, Roger L.; Jarrett, T. H.; Masci, Frank; Tsai, Chao-Wei; Yan, Lin; Dey, Arjun; Lake, Sean; Petty, Sara; Wright, E. L.; Stanford, S. A.; Harrison, Fiona; Madsen, Kristin

2012-01-01

The Wide-field Infrared Survey Explorer (WISE) is an extremely capable and efficient black hole finder. We present a simple mid-infrared color criterion, W1 – W2 ≥ 0.8 (i.e., [3.4]–[4.6] ≥0.8, Vega), which identifies 61.9 ± 5.4 active galactic nucleus (AGN) candidates per deg 2 to a depth of W2 ∼ 15.0. This implies a much larger census of luminous AGNs than found by typical wide-area surveys, attributable to the fact that mid-infrared selection identifies both unobscured (type 1) and obscured (type 2) AGNs. Optical and soft X-ray surveys alone are highly biased toward only unobscured AGNs, while this simple WISE selection likely identifies even heavily obscured, Compton-thick AGNs. Using deep, public data in the COSMOS field, we explore the properties of WISE-selected AGN candidates. At the mid-infrared depth considered, 160 μJy at 4.6 μm, this simple criterion identifies 78% of Spitzer mid-infrared AGN candidates according to the criteria of Stern et al. and the reliability is 95%. We explore the demographics, multiwavelength properties and redshift distribution of WISE-selected AGN candidates in the COSMOS field.

Fate of [14C]-zineb on lettuce plants

International Nuclear Information System (INIS)

Vonk, J.W.

1976-01-01

[1,2- 14 C]-zinc ethylenebisdithiocarbamate (zineb) was prepared and applied in droplets to leaves of lettuce plants. In aqueous suspension zineb decomposes mainly into ethylenethiourea (ETU) and 5,6-dihydro-3H-imidazo[2,1-C]-1,2,4-dithiazole-3-thione (DIDT). Lettuce plants were harvested 0,1,3,7,14 and 21 days after treatment and analysed. A high proportion of radioactivity remained on the surface of the plant and could be washed off. The following identified products were present: unchanged zineb, ETU, DIDT, 2-imidazoline and ethyleneurea. The ETU residue disappeared within 7 days, while 2-imidazoline and ethyleneurea were formed gradually. Radioactivity inside the plant consisted mostly of ethyleneurea: no ETU was present. (author)

Bond selective photochemistry in CH2BrI through electronic excitation at 210 nm

International Nuclear Information System (INIS)

Butler, L.J.; Hintsa, E.J.; Lee, Y.T.

1986-01-01

To explore the possibility of bond selective photochemistry in an excited electronic state, we have studied the photolysis of CH 2 BrI in a molecular beam at 210 nm. Following the direct local excitation of a repulsive transition on the C--Br bond at 210 nm, the fragments were detected by time-of-flight mass spectrometry. The dominant channel was found to be C--Br fission (60%) releasing an average of 15 kcal/mol into translation with the remainder reacting to form CH 2 +IBr and CH 2 +I+Br. There was no evidence for the primary fission of the C--I bond, making this the first clear example of the selective cleavage of a stronger bond in a molecule over the weakest one

(-)[125I]-iodopindolol, a new highly selective radioiodinated beta-adrenergic receptor antagonist: measurement of beta-receptors on intact rat astrocytoma cells

International Nuclear Information System (INIS)

Barovsky, K.; Brooker, G.

1980-01-01

(-)-Pindolol, one of the most potent beta-adrenergic receptor antagonists, was radioiodinated using chloramine-T oxidation of carrier-free Na 125I and separated from unreacted pindolol to yield 2200 Ci/mmole (-)-[125I]-iodopindolol ((-)-[125I]-IPin). Mass and ultraviolet spectra confirmed that the iodination occurred on the indole ring, presumably at the 3 position. The binding of radiolabeled (-)-[125I]-IPin to beta-adrenergic receptors has been studied using intact C6 rat astrocytoma cells (2B subclone) grown in monolayer cultures. Binding of (-)[125IPin was saturable with time and concentration. Using 13 pM (-)-[125I]IPin, binding equilibrium was reached in 90 min at 21-22 degrees C. The reverse rate constant was 0.026 min-1 at 21 0 C. Specific binding (expressed as 1 microM(-)-propranolol displaceable counts) of (-)-[125I]-IPin was 95% of total binding. Scatchard analysis of (-)-[125I]-I]Pin binding revealed approximately 4300 receptors/cell and a dissociation constant of 30 pM. This was in excellent agreement with the kinetically determined dissociation constant of 35 pM. Displacement by propranolol and isoproterenol showed that (-)-[125I]-IPin binding sites were pharmacologically and stereospecifically selective. These results indicate that (-)-[125I]-IPin, a pure (-)-stereoisomer, high specific activity radioligand, selectively binds to beta-adrenergic receptors in whole cells with a high percentage of specific binding and should therefore be useful in the study and measurement of cellular beta-adrenergic receptors

Preparation of O/I1-type Emulsions and S/I1-type Dispersions Encapsulating UV-Absorbing Agents.

Science.gov (United States)

Aramaki, Kenji; Kimura, Minami; Masuda, Kazuki

2015-01-01

Oil-in-cubic phase (O/I1) emulsions encapsulating the cosmetic UV absorbing agents 2-ethylhexyl 4-methoxycinnamate (EHMC), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, OCR) and 1-(4-tertbutylphenyl)-3-(4-methoxyphenyl)-1,3-propanedione (Avobenzone, TBMP) were prepared by vortex mixing accompanied by a heating-cooling process. A ternary phase diagram in a water/C12EO25/EHMC system at 25°C was constructed and the two-phase equilibrium of an oil phase and an I1 phase, which is necessary to prepare the O/I1-type emulsions, was confirmed. Also, the melting of the I1 phase into a fluid micellar solution phase was confirmed, allowing emulsification by a heating-cooling process. The O/I1-type emulsions were formulated in the ternary system as well as a quaternary system. The four-component system contained an additional cosolvent, isopropyl myristate (IPM). The use of the cosolvent allows the use of reduced amounts of EHMC, which is desirable because EHMC can cause temporary skin irritation. Formulation of the O/I1-type emulsions with other UV absorbing agents (OCR and TBMP) was also possible using the same emulsification method. When IPM was changed to tripalmitin, which has a melting point greater than room temperature, a solid-oil dispersion in I1 phase was formed. We have termed this a "solidin-cubic phase (S/I1) type dispersion". These novel emulsions have not been reported previously. The UV absorbability of the O/I1-type emulsions and S/I1-type dispersions that encapsulate the UV absorbing agents was confirmed by measurement of UV absorption spectra.

Theoretical study of structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some centrally acting antihypertensives

NARCIS (Netherlands)

Dr. Remko, M.; Swart, M.; Bickelhaupt, F.M.

2006-01-01

The methods of theoretical chemistry have been used to elucidate the molecular properties of the substituted imidazoline and oxazoline structures, a class of potent agonists and antagonists of imidazoline receptors. The geometries of various tautomers and isomers of 2-[2,6-dichlorophenylimino

Selective oxidation of methionine residues in apolipoprotein A-I and its potential biological consequences

International Nuclear Information System (INIS)

Panzenboeck, U.; Waldeck, R.; Rye, K.A.; Sloane, T.; Kritharides, L.; Stocker, R.

1998-01-01

The earliest stages of HDL oxidation are accompanied by the oxidation of specific Met residues in apolipoprotein AI and AII and the formation of Met sulfoxides (Met(O)) has been proposed to play a significant role in the reduction and hence detoxification of lipid hydroperoxides associated with HDL. Oxidation of HDL may generally decrease the anti-atherogenic properties of this lipoprotein, although both, the inhibition and the enhancement of cholesterol removal from cells has been reported for different types of oxidation. In light of these findings we have investigated the secondary structure, lipid affinity, LCAT activation and cholesterol-efflux promoting properties of native and selectively oxidized apo A-I(apo A-I +32 , containing Met(O) at Met l12 and Met l48 ) in purified or reconstituted forms. Data obtained by circular dichroism revealed that selective oxidation of Met residues 112 and 148 does not alter alpha helicity of the protein in solution, indicating that this oxidation is not sufficient to influence significantly this type of secondary structure of apo A-I in its 'lipid-free' form. The lipid affinity of native apo A-I and apo A-I +32 was determined as the rate of clearance of DMPC multilamellar to small unilamellar vesicles. Compared with the native protein, apo A-I +32 induced a 2-3 fold faster rate of clearance, suggesting that the increased hydrophilicity due Met(O) increased the rate for protein-lipid interactions. Met residues 112 and 148 reside in the hydrophobic faces of helices 5 and 7, and both these regions have been suggested to be important for both, LCAT activation and cholesterol efflux. Kinetic experiments have revealed that the affinity for LCAT is comparable for HDL reconstituted with either apo A-I or apo A-I +32 . Efflux of [ 3 H]-cholesterol from lipid-laden human monocytederived macrophages to isolated apolipoproteins was enhanced for apo A-I +32 compared with apo A-I, consistent with the DMPC clearance data. Together these

Synthesis and characterization of [{sup 125}I]N-(2-aminoethyl)-4-iodobenzamide as a selective monoamine oxidase B inhibitor

Energy Technology Data Exchange (ETDEWEB)

Rafii, Hamid; Chalon, Sylvie; Ombetta, Jean-Edouard; Frangin, Yves; Garreau, Lucette; Dognon, Anne-Marie; Lena, Isabelle; Bodard, Sylvie; Vilar, Marie-Paule; Besnard, Jean-Claude; Guilloteau, Denis

1995-07-01

We described the radiosynthesis of an analog of Ro 16-6491, [{sup 125}I]N-(2-aminoethyl)-4-iodobenzamide, for SPECT exploration of the monoamine oxidase B (MAO-B) in human brain. The radiolabelling was carried out by nucleophilic exchange of the brominated precursor at solid-state phase in presence of ammonium sulphate. The radiochemical purity of radioiodinated product was higher than 95%. In comparison with Ro 16-6491, the in vitro studies showed a good selectivity of stable N-(2-aminoethyl)-4-iodobenzamide for MAO-B but a slightly lower affinity. Biodistribution studies in the rat showed a high and selective uptake of this compound in the pineal gland 1 h after i.v. injection. The cerebral uptake was low, but the coupling of [{sup 125}I]N-(2-aminoethyl)-4-iodobenzamide with a lipophilic radical to enhance the passage through the blood-brain barrier can be envisaged.

47 CFR 1.1602 - Designation for random selection.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Designation for random selection. 1.1602 Section 1.1602 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE Random Selection Procedures for Mass Media Services General Procedures § 1.1602 Designation for random selection...

A radiolabeled peptide ligand of the hERG channel, [125I]-BeKm-1

DEFF Research Database (Denmark)

Angelo, Kamilla; Korolkova, Yuliya V; Grunnet, Morten

2003-01-01

The wild-type scorpion toxin BeKm-1, which selectively blocks human ether-a-go-go related (hERG) channels, was radiolabeled with iodine at tyrosine 11. Both the mono- and di-iodinated derivatives were found to be biologically active. In electrophysiological patch-clamp recordings mono-[127I]-BeKm-1...... had a concentration of half-maximal inhibition (IC50 value) of 27 nM, while wild-type BeKm-1 inhibited hERG channels with an IC50 value of 7 nM. Mono-[125I]-BeKm-1 was found to bind in a concentration-dependent manner and with picomolar affinity to hERG channel protein in purified membrane vesicles...... of [125I]-BeKm-1 to the hERG channel to an IC50 of 7 nM. In autoradiographic studies on rat hearts, binding of [125I]-BeKm-1 was dose-dependent and could partially be displaced by the addition of excess amounts of non-radioactive BeKm-1. The density of the radioactive signal was equally distributed...

47 CFR 1.1603 - Conduct of random selection.

Science.gov (United States)

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Conduct of random selection. 1.1603 Section 1.1603 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE Random Selection Procedures for Mass Media Services General Procedures § 1.1603 Conduct of random selection. The...

Contrasting patterns of selection between MHC I and II across populations of Humboldt and Magellanic penguins.

Science.gov (United States)

Sallaberry-Pincheira, Nicole; González-Acuña, Daniel; Padilla, Pamela; Dantas, Gisele P M; Luna-Jorquera, Guillermo; Frere, Esteban; Valdés-Velásquez, Armando; Vianna, Juliana A

2016-10-01

The evolutionary and adaptive potential of populations or species facing an emerging infectious disease depends on their genetic diversity in genes, such as the major histocompatibility complex (MHC). In birds, MHC class I deals predominantly with intracellular infections (e.g., viruses) and MHC class II with extracellular infections (e.g., bacteria). Therefore, patterns of MHC I and II diversity may differ between species and across populations of species depending on the relative effect of local and global environmental selective pressures, genetic drift, and gene flow. We hypothesize that high gene flow among populations of Humboldt and Magellanic penguins limits local adaptation in MHC I and MHC II, and signatures of selection differ between markers, locations, and species. We evaluated the MHC I and II diversity using 454 next-generation sequencing of 100 Humboldt and 75 Magellanic penguins from seven different breeding colonies. Higher genetic diversity was observed in MHC I than MHC II for both species, explained by more than one MHC I loci identified. Large population sizes, high gene flow, and/or similar selection pressures maintain diversity but limit local adaptation in MHC I. A pattern of isolation by distance was observed for MHC II for Humboldt penguin suggesting local adaptation, mainly on the northernmost studied locality. Furthermore, trans-species alleles were found due to a recent speciation for the genus or convergent evolution. High MHC I and MHC II gene diversity described is extremely advantageous for the long-term survival of the species.

Organic Ferroelectric-Based 1T1T Random Access Memory Cell Employing a Common Dielectric Layer Overcoming the Half-Selection Problem.

Science.gov (United States)

Zhao, Qiang; Wang, Hanlin; Ni, Zhenjie; Liu, Jie; Zhen, Yonggang; Zhang, Xiaotao; Jiang, Lang; Li, Rongjin; Dong, Huanli; Hu, Wenping

2017-09-01

Organic electronics based on poly(vinylidenefluoride/trifluoroethylene) (P(VDF-TrFE)) dielectric is facing great challenges in flexible circuits. As one indispensable part of integrated circuits, there is an urgent demand for low-cost and easy-fabrication nonvolatile memory devices. A breakthrough is made on a novel ferroelectric random access memory cell (1T1T FeRAM cell) consisting of one selection transistor and one ferroelectric memory transistor in order to overcome the half-selection problem. Unlike complicated manufacturing using multiple dielectrics, this system simplifies 1T1T FeRAM cell fabrication using one common dielectric. To achieve this goal, a strategy for semiconductor/insulator (S/I) interface modulation is put forward and applied to nonhysteretic selection transistors with high performances for driving or addressing purposes. As a result, high hole mobility of 3.81 cm 2 V -1 s -1 (average) for 2,6-diphenylanthracene (DPA) and electron mobility of 0.124 cm 2 V -1 s -1 (average) for N,N'-1H,1H-perfluorobutyl dicyanoperylenecarboxydiimide (PDI-FCN 2 ) are obtained in selection transistors. In this work, we demonstrate this technology's potential for organic ferroelectric-based pixelated memory module fabrication. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

IIIST1\\NTI-i\\III.

African Journals Online (AJOL)

guests in September 1914. (1) Major-General Sir Lothian Nicholson. KCB, CMG, and Major H 1. MacMullen, MC, History of the East Lancashire Regiment in the Great. War 1914-1918, Littlebury. Bros, Ltd. Liverpool,. 1936. p 114. Ti\\.~TI(~S-1\\ IIIST ••III. ~SI Til VI~V. I..•f :01 i\\. f~•• 10III.SOIl ~IIII~ 1~lt. The study of military tactics ...

Dopamine1 receptors in rat kidneys identified with 125I-Sch 23982

International Nuclear Information System (INIS)

Felder, R.A.; Jose, P.A.

1988-01-01

Dopamine1 receptors were studied in rat kidney using the selective dopamine1 antagonist 125I-labeled Sch 23982. The specific binding of 125I-Sch 23982 (defined by 5 microM Sch 23390) to renal cortical homogenates incubated at room temperature was rapid, saturable with time and ligand concentration, and reversible. Analysis of Rosenthal plots revealed a single class of receptors with an apparent dissociation constant of 12.2 +/- 1.9 nM and maximum receptor density of 1.03 +/- 0.15 pmol/mg protein (n = 6). However, competition experiments with the dopamine1 antagonist Sch 23390 revealed a low- and high-affinity binding site with inhibition constants of 1 x 10(-6) and 1 x 10(-8) M, respectively. The competition experiments were also indicative of dopamine1 receptors with stereoselectivity noted for dopamine1 but not for dopamine2 antagonists. The inhibition constants for dopamine1 antagonists and agonists were two orders of magnitude greater in renal cortical than striatal homogenates. Different buffers affected striatal but not renal cortical binding. Autoradiographic studies revealed 125I-Sch 23982 binding in renal cortical but not medullary tissue. These studies confirm the presence of dopamine1 receptors in the cortex of the rat kidney

N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance.

Directory of Open Access Journals (Sweden)

Soo-Huey Yap

2007-12-01

Full Text Available The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1 reverse transcriptase (RT consists of DNA polymerase, connection, and ribonuclease H (RNase H domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12. N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs M41L and T215Y/F (p < 0.001, the lamivudine resistance mutations M184V/I (p < 0.001, and non-nucleoside RTI (NNRTI resistance mutations K103N and Y181C/I (p < 0.001. The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81. The appearance of N348I was associated with a significant increase in viral load (p < 0.001, which

1 : 2 Adducts of copper(I) halides with 1,2-bis(di-2-pyridylphosphino)ethane: solid state and solution structural studies and antitumour activity.

Science.gov (United States)

Bowen, Richard J; Navarro, Maribel; Shearwood, Anne-Marie J; Healy, Peter C; Skelton, Brian W; Filipovska, Aleksandra; Berners-Price, Susan J

2009-12-28

The 1 : 2 adducts of copper(I) halides with 1,2-bis(2-pyridylphosphino)ethane (d2pype) have been synthesized and solution properties characterized by variable temperature (1)H, (31)P and (65)Cu NMR spectroscopy. Single-crystal structure determinations for the chloride, bromide and iodide complexes show these to crystallize from acetonitrile in the triclinic space group P1 as isostructural centrosymmetric dimers [(d2pype)Cu(mu-d2pype)(2)Cu(d2pype)]X(2).(solvent) with a approximately 12.6, b approximately 12.7, c approximately 15.3 A, alpha approximately 84, beta approximately 67, gamma approximately 84 degrees. In contrast to the analogous AuCl:2(d2pype) and AgNO(3):2(d2pype) adducts, in solution these CuX:2(d2pype) adducts (where X = Cl, Br and I) exist almost exclusively as bis-chelated monomeric [Cu(d2pype)(2)]X; evidence for an equilibrium between monomeric and dimeric forms is detected only for the CuCl adduct in methanol. Cytotoxicity studies in two human breast cancer lines and two matched liver progenitor cell lines indicate that [Cu(d2pype)(2)]Cl is non selectively toxic to both non-tumourigenic and tumourigenic cells. However, the analogous Au(I) compound [Au(d2pype)(2)]Cl, is toxic to highly tumourigenic cells and more selective in its toxicity to tumourigenic cells compared to non-tumourigenic cells. The significance of these results to the further development of selective, mitochondria-targeted, Au(I) antitumour complexes is discussed.

The active galactic nucleus population in X-ray-selected galaxy groups at 0.5 < Z < 1.1

International Nuclear Information System (INIS)

Oh, Semyeong; Woo, Jong-Hak; Matsuoka, Kenta; Mulchaey, John S.; Finoguenov, Alexis; Tanaka, Masayuki; Cooper, Michael C.; Ziparo, Felicia; Bauer, Franz E.

2014-01-01

We use Chandra data to study the incidence and properties of active galactic nuclei (AGNs) in 16 intermediate redshift (0.5 < z < 1.1) X-ray-selected galaxy groups in the Chandra Deep Field-South. We measure an AGN fraction of f(L X,H >10 42 ;M R <−20)=8.0 −2.3 +3.0 % at z-bar ∼0.74, approximately a factor of two higher than the AGN fraction found for rich clusters at comparable redshift. This extends the trend found at low redshift for groups to have higher AGN fractions than clusters. Our estimate of the AGN fraction is also more than a factor of three higher than that of low redshift X-ray-selected groups. Using optical spectra from various surveys, we also constrain the properties of emission-line selected AGNs in these groups. In contrast to the large population of X-ray AGNs (N(L X, H > 10 41 erg s –1 ) = 25), we find only four emission-line AGNs, three of which are also X-ray bright. Furthermore, most of the X-ray AGNs in our groups are optically dull (i.e., lack strong emission-lines), similar to those found in low redshift X-ray groups and clusters of galaxies. This contrasts with the AGN population found in low redshift optically selected groups which are dominated by emission-line AGNs. The differences between the optically and X-ray-selected AGNs populations in groups are consistent with a scenario where most AGNs in the densest environments are currently in a low accretion state.

Prolonging survival of corneal transplantation by selective sphingosine-1-phosphate receptor 1 agonist.

Directory of Open Access Journals (Sweden)

Min Gao

Full Text Available Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1 selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival.

Application of two-dimensional binary fingerprinting methods for the design of selective Tankyrase I inhibitors.

Science.gov (United States)

Muddukrishna, B S; Pai, Vasudev; Lobo, Richard; Pai, Aravinda

2017-11-22

In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I. Schematic representation of 2D QSAR work flow.

Selective binding of 2-[{sup 125}I]iodo-nisoxetine to norepinephrine transporters in the brain

Energy Technology Data Exchange (ETDEWEB)

Kung, M.-P.; Choi, Seok-Rye; Hou, Catherine; Zhuang, Z.-P.; Foulon, Catherine; Kung, Hank F. E-mail: kunghf@sunmac.spect.upenn.edu

2004-07-01

A radioiodinated ligand, (R)-N-methyl-(2-[{sup 125}I]iodo-phenoxy)-3-phenylpropylamine, [{sup 125}I]2-INXT, targeting norepinephrine transporters (NET), was successfully prepared. A no-carrier-added product, [{sup 125}I]2-INXT, displayed a saturable binding with a high affinity (K{sub d}=0.06 nM) in the homogenates prepared from rat cortical tissues as well as from LLC-PK{sub 1} cells expressing NET. A relatively low number of binding sties (B{sub max}=55 fmol/mg protein) measured with [{sup 125}I]2-INXT in rat cortical homogenates is consistent with the value reported for a known NET ligand, [{sup 3}H]nisoxetine. Competition studies with various compounds on [{sup 125}I]2-INXT binding clearly confirmed the pharmacological specificity and selectivity for NET binding sites. Following a tail-vein injection of [{sup 125}I]2-INXT in rats, a good initial brain uptake was observed (0.56% dose at 2 min) followed by a slow washout from the brain (0.2% remained at 3 hours post-injection). The hypothalamus (a NET-rich region) to striatum (a region devoid of NET) ratio was 1.5 at 3 hours post-i.v. injection. Pretreatment of rats with nisoxetine significantly inhibited the uptake of [{sup 125}I]2-INXT (70-100% inhibition) in locus coeruleus, hypothalamus and raphe nuclei, regions known to have a high density of NET; whereas escitalopram, a serotonin transporter ligand, did not show a similar effect. Ex vivo autoradiography of rat brain sections of [{sup 125}I]2-INXT (at 3 hours after an i.v. injection) displayed an excellent regional brain localization pattern corroborated to the specific NET distribution in the brain. The specific brain localization was significantly reduced by a dose of nisoxetine pretreatment. Taken together, the data suggest that [{sup 123}I]2-INXT may be useful for mapping NET binding sites in the brain.

Selective adsorption of silver(I) ions over copper(II) ions on a sulfoethyl derivative of chitosan.

Science.gov (United States)

Petrova, Yulia S; Pestov, Alexandr V; Usoltseva, Maria K; Neudachina, Ludmila K

2015-12-15

This study presents a simple and effective method of preparation of N-(2-sulfoethyl) chitosan (NSE-chitosan) that allows obtaining a product with a degree of modification up to 1.0. The chemical structure of the obtained polymers was confirmed by FT-IR and 1H NMR spectroscopies. Cross-linking of N-(2-sulfoethyl) chitosans by glutaraldehyde allows preparation of sorbents for removal and concentration of metal ions. Capacity of sorbents towards hydroxide ions was determined depending on the degree of sulfoethylation under static and dynamic conditions. Dissociation constants of functional amino groups of the analyzed sorbents were determined by potentiometric titration. It was shown that basicity of the amino groups decreased (wherein pKa decreased from 6.53 to 5.67) with increase in degree of sulfoethylation. It explains the significant influence of sulfo groups on selectivity of sorption of metal ions on N-(2-sulfoethyl) chitosan-based sorbents. The investigated substances selectively remove copper(II) and silver(I) ions from solutions of complex composition. Wherein the selectivity coefficient KAg/Cu increased to 20 (pH 6.5, ammonium acetate buffer solution) with increase in degree of sulfoethylation of the sorbent up to 1.0. Copyright © 2015 Elsevier B.V. All rights reserved.

Sphingosine-1-Phosphate (S1P) Impacts Presynaptic Functions by Regulating Synapsin I Localization in the Presynaptic Compartment.

Science.gov (United States)

Riganti, Loredana; Antonucci, Flavia; Gabrielli, Martina; Prada, Ilaria; Giussani, Paola; Viani, Paola; Valtorta, Flavia; Menna, Elisabetta; Matteoli, Michela; Verderio, Claudia

2016-04-20

Growing evidence indicates that sphingosine-1-P (S1P) upregulates glutamate secretion in hippocampal neurons. However, the molecular mechanisms through which S1P enhances excitatory activity remain largely undefined. The aim of this study was to identify presynaptic targets of S1P action controlling exocytosis. Confocal analysis of rat hippocampal neurons showed that S1P applied at nanomolar concentration alters the distribution of Synapsin I (SynI), a presynaptic phosphoprotein that controls the availability of synaptic vesicles for exocytosis. S1P induced SynI relocation to extrasynaptic regions of mature neurons, as well as SynI dispersion from synaptic vesicle clusters present at axonal growth cones of developing neurons. S1P-induced SynI relocation occurred in a Ca(2+)-independent but ERK-dependent manner, likely through the activation of S1P3 receptors, as it was prevented by the S1P3 receptor selective antagonist CAY1044 and in neurons in which S1P3 receptor was silenced. Our recent evidence indicates that microvesicles (MVs) released by microglia enhance the metabolism of endogenous sphingolipids in neurons and stimulate excitatory transmission. We therefore investigated whether MVs affect SynI distribution and whether endogenous S1P could be involved in the process. Analysis of SynI immunoreactivity showed that exposure to microglial MVs induces SynI mobilization at presynaptic sites and growth cones, whereas the use of inhibitors of sphingolipid cascade identified S1P as the sphingolipid mediating SynI redistribution. Our data represent the first demonstration that S1P induces SynI mobilization from synapses, thereby indicating the phosphoprotein as a novel target through which S1P controls exocytosis. Growing evidence indicates that the bioactive lipid sphingosine and its metabolite sphingosine-1-P (S1P) stimulate excitatory transmission. While it has been recently clarified that sphingosine influences directly the exocytotic machinery by activating the

CYP1A1 MspI Polymorphism and Cervical Carcinoma Risk in the Multi-Ethnic Population of Malaysia: a Case-Control Study.

Science.gov (United States)

Tan, Yee Hock; Sidik, Shiran Mohd; Syed Husain, Sharifah Noor Akmal; Lye, Munn Sann; Chong, Pei Pei

2016-01-01

Tobacco smoking is considered a risk factor for cervical cancer development due to the presence of tobacco based carcinogenic metabolites in cervical cells of female smokers. In this study, we investigated the role of the T3801C (MspI) polymorphism of CYP1A1, a gene encoding an enzyme necessary for the initiation of tobacco based carcinogen metabolism, on cervical cancer risk. The T to C substitution may alter CYP1A1 activities, potentially elevating cervical cancer risk. Since results of gene-disease association studies vary according to the study population, the multi-ethnic population of Malaysia provides an excellent representative cohort for identifying and comparing the cervical cancer risk among the 3 major ethnics in Southeast Asia in relation to CYP1A1 MspI polymorphism. A total of 195 Thin Prep Pap smear samples from HPV negative and cancer free females were randomly selected as controls while 106 formalin fixed paraffin embedded samples from females with invasive cervical cancer were randomly selected for the cases group. The polymorphisms were identified using restriction fragment length polymorphism (RFLP) PCR. We found no significant associations between CYP1A1 MspI polymorphism and cervical cancer in the general Malaysian female population. However, upon ethnic stratification, the variant C/C genotype was significantly associated with a 4.66-fold increase in cervical cancer risk in Malay females (95% CI= 1.21-17.9; p=0.03). No significant association was observed in the Chinese and Indian females. Additionally, there were no significant associations in the dominant model and allele frequency model analysis in both the general and ethnically stratified female population of Malaysia. Our findings suggest that the C/C genotype of CYP1A1 MspI polymorphism is associated with the development of cervical carcinoma in the Malay females of Malaysia.

I-1 General; I-1 Opsti deo

Energy Technology Data Exchange (ETDEWEB)

NONE

1960-07-01

General part of the regulations and instructions for operation of the RA reactor includes fundamental data about the reactor properties, biological shields, purpose of reactor operation, organizational scheme, rights and responsibilities of the head of laboratory, leaders of the working teams and all the staff of the laboratory for RA reactor exploitation. Opsti deo knjige propisa i uputstva za rad reaktora sadrzi osnovne podatke o reaktoru, biloskoj zastiti, nameni reaktora, prava i duznosti nacelnika, sefova smena i osoblja laboratorije za eksploataciju reaktora RA.

Sexual Selection of Protamine 1 in Mammals.

Science.gov (United States)

Lüke, Lena; Tourmente, Maximiliano; Roldan, Eduardo R S

2016-01-01

Protamines have a crucial role in male fertility. They are involved in sperm chromatin packaging and influence the shape of the sperm head and, hence, are important for sperm performance. Protamine structure is basic with numerous arginine-rich DNA-binding domains. Postcopulatory sexual selection is thought to play an important role in protamine sequence evolution and expression. Here, we analyze patterns of evolution and sexual selection (in the form of sperm competition) acting on protamine 1 gene sequence in 237 mammalian species. We assessed common patterns as well as differences between the major mammalian subclasses (Eutheria, Metatheria) and clades. We found that a high arginine content in protamine 1 associates with a lower sperm head width, which may have an impact on sperm swimming velocity. Increase in arginine content in protamine 1 across mammals appears to take place in a way consistent with sexual selection. In metatherians, increase in sequence length correlates with sexual selection. Differences in selective pressures on sequences and codon sites were observed between mammalian clades. Our study revealed a complex evolutionary pattern of protamine 1, with different selective constraints, and effects of sexual selection, between mammalian groups. In contrast, the effect of arginine content on head shape, and the possible involvement of sperm competition, was identified across all mammals. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Molecular dynamics simulations and quantum chemical calculations ...

African Journals Online (AJOL)

Molecular dynamic simulation results indicate that the imidazoline derivative molecules uses the imidazoline ring to effectively adsorb on the surface of iron, with the alkyl hydrophobic tail forming an n shape (canopy like covering) at geometry optimization and at 353 K. The n shape canopy like covering to a large extent may ...

Phosphorene as a Superior Gas Sensor: Selective Adsorption and Distinct I-V Response.

Science.gov (United States)

Kou, Liangzhi; Frauenheim, Thomas; Chen, Changfeng

2014-08-07

Recent reports on the fabrication of phosphorene, that is, mono- or few-layer black phosphorus, have raised exciting prospects of an outstanding two-dimensional (2D) material that exhibits excellent properties for nanodevice applications. Here, we study by first-principles calculations the adsorption of CO, CO2, NH3, NO, and NO2 gas molecules on a monolayer phosphorene. Our results predict superior sensing performance of phosphorene that rivals or even surpasses that of other 2D materials such as graphene and MoS2. We determine the optimal adsorption positions of these molecules on the phosphorene and identify molecular doping, that is, charge transfer between the molecules and phosphorene, as the driving mechanism for the high adsorption strength. We further calculated the current-voltage (I-V) relation using the nonequilibrium Green's function (NEGF) formalism. The transport features show large (1-2 orders of magnitude) anisotropy along different (armchair or zigzag) directions, which is consistent with the anisotropic electronic band structure of phosphorene. Remarkably, the I-V relation exhibits distinct responses with a marked change of the I-V relation along either the armchair or the zigzag directions depending on the type of molecules. Such selectivity and sensitivity to adsorption makes phosphorene a superior gas sensor that promises wide-ranging applications.

Evidence of differential HLA class I-mediated viral evolution in functional and accessory/regulatory genes of HIV-1.

Directory of Open Access Journals (Sweden)

Zabrina L Brumme

2007-07-01

Full Text Available Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT, Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of "escape maps," which identify known and putative cytotoxic T lymphocyte (CTL epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4(+ T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other

Three-energy focusing Laue monochromator for the diamond light source x-ray pair distribution function beamline I15-1

Energy Technology Data Exchange (ETDEWEB)

Sutter, John P., E-mail: john.sutter@diamond.ac.uk; Chater, Philip A.; Hillman, Michael R.; Keeble, Dean S.; Wilhelm, Heribert [Diamond Light Source Ltd, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE (United Kingdom); Tucker, Matt G. [Diamond Light Source Ltd, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE (United Kingdom); ISIS Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0QX (United Kingdom)

2016-07-27

The I15-1 beamline, the new side station to I15 at the Diamond Light Source, will be dedicated to the collection of atomic pair distribution function data. A Laue monochromator will be used consisting of three silicon crystals diffracting X-rays at a common Bragg angle of 2.83°. The crystals use the (1 1 1), (2 2 0), and (3 1 1) planes to select 40, 65, and 76 keV X-rays, respectively, and will be bent meridionally to horizontally focus the selected X-rays onto the sample. All crystals will be cut to the same optimized asymmetry angle in order to eliminate image broadening from the crystal thickness. Finite element calculations show that the thermal distortion of the crystals will affect the image size and bandpass.

Three-energy focusing Laue monochromator for the diamond light source x-ray pair distribution function beamline I15-1

International Nuclear Information System (INIS)

Sutter, John P.; Chater, Philip A.; Hillman, Michael R.; Keeble, Dean S.; Wilhelm, Heribert; Tucker, Matt G.

2016-01-01

The I15-1 beamline, the new side station to I15 at the Diamond Light Source, will be dedicated to the collection of atomic pair distribution function data. A Laue monochromator will be used consisting of three silicon crystals diffracting X-rays at a common Bragg angle of 2.83°. The crystals use the (1 1 1), (2 2 0), and (3 1 1) planes to select 40, 65, and 76 keV X-rays, respectively, and will be bent meridionally to horizontally focus the selected X-rays onto the sample. All crystals will be cut to the same optimized asymmetry angle in order to eliminate image broadening from the crystal thickness. Finite element calculations show that the thermal distortion of the crystals will affect the image size and bandpass.

Selective coupling reaction between 2,6-diiodoanisoles and terminal alkynes catalyzed by Pd(PPh32Cl2 and CuI

Directory of Open Access Journals (Sweden)

Allan F. C. Rossini

2012-06-01

Full Text Available The cross-coupling reaction between aryl halides and terminal alkynes, catalyzed by palladium complexes and copper (I salts, consists in an efficient synthetic tool for the formation of C-C bonds, resulting in disubstituted acetylenic compounds. Accordingly, in this work we present our preliminary results involving the selective cross-coupling reaction between 2,6-diiodoanisoles and terminal alkynes, catalyzed by Pd(PPh32Cl2 and CuI, in the formation of 2-iodo-alkynylanisoles (scheme 1.

Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

Science.gov (United States)

Potter, Adam S; Casa, Angelo J; Lee, Adrian V

2012-01-01

The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses. Copyright © 2011 Wiley Periodicals, Inc.

Dual monitoring using 124I-FIAU and bioluminescence for HSV1-tk suicide gene therapy

International Nuclear Information System (INIS)

Lee, T. S.; Kim, J. H.; Kwon, H. C.

2007-01-01

Herpes simplex virus type I thymidine kinase (HSV-tk) is the most common reporter gene and is used in cancer gene therapy with a prodrug nucleoside analog, ganciclovir (GCV). The aim of this study is to evaluate therapeutic efficacy of suicide gene therapy with 2'-fluoro-2'-deoxy-1-D-arabinofuranosyl-5-[ 124 I] iodouracil ( 124 I - FIAU) and bioluminescence in retrovirally HSV -tk and firefly luciferase transduced hepatoma model. The HSV -tk and firefly luciferase (Luc) was retrovirally transduced and expressed in MCA rat Morris hepatoma cells. Nude mice with subcutaneous tumors, MCA and MCA-TK-Luc, were subjected to GCV treatment (50mg/Kg/d intraperitoneally) for 5 day. PET imaging and biodistribution with ( 124 I-FIAU) were performed at before and after initiation of therapy with GCV. Bioluminescent signal was also measured during GCV treatment. Before GCV treatment, no significant difference in tumor volume was found in tumors between MCA and MCA-TK-Luc. After GCV treatment, tumor volume of MCA-TK-Luc markedly reduced compared to that of MCA. In biodistribution study, 124 I-FIAU uptake after GCV therapy significantly decreased compared with pretreatment levels (34.8 13.67 %ID/g vs 7.6 2.59 %ID/g) and bioluminescent signal was also significantly decreased compared with pretreatment levels. In small animal PET imaging, 124 I-FIAU selectively localized in HSV -tk expressing tumor and the therapeutic efficacy of GCV treatment was evaluated by 124 I-FIAU PET imaging. 124 I-FIAU PET and bioluminescence imaging in HSV-tk suicide gene therapy were effective to evaluate the therapeutic response. 124 I-FIAU may serve as an efficient and selective agent for monitoring of transduced HSV1-tk gene expression in vivo in clinical trials

Positive Selection on Hemagglutinin and Neuraminidase Genes of H1N1 Influenza Viruses

LENUS (Irish Health Repository)

Li, Wenfu

2011-04-21

Abstract Background Since its emergence in March 2009, the pandemic 2009 H1N1 influenza A virus has posed a serious threat to public health. To trace the evolutionary path of these new pathogens, we performed a selection-pressure analysis of a large number of hemagglutinin (HA) and neuraminidase (NA) gene sequences of H1N1 influenza viruses from different hosts. Results Phylogenetic analysis revealed that both HA and NA genes have evolved into five distinct clusters, with further analyses indicating that the pandemic 2009 strains have experienced the strongest positive selection. We also found evidence of strong selection acting on the seasonal human H1N1 isolates. However, swine viruses from North America and Eurasia were under weak positive selection, while there was no significant evidence of positive selection acting on the avian isolates. A site-by-site analysis revealed that the positively selected sites were located in both of the cleaved products of HA (HA1 and HA2), as well as NA. In addition, the pandemic 2009 strains were subject to differential selection pressures compared to seasonal human, North American swine and Eurasian swine H1N1 viruses. Conclusions Most of these positively and\\/or differentially selected sites were situated in the B-cell and\\/or T-cell antigenic regions, suggesting that selection at these sites might be responsible for the antigenic variation of the viruses. Moreover, some sites were also associated with glycosylation and receptor-binding ability. Thus, selection at these positions might have helped the pandemic 2009 H1N1 viruses to adapt to the new hosts after they were introduced from pigs to humans. Positive selection on position 274 of NA protein, associated with drug resistance, might account for the prevalence of drug-resistant variants of seasonal human H1N1 influenza viruses, but there was no evidence that positive selection was responsible for the spread of the drug resistance of the pandemic H1N1 strains.

A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels.

Science.gov (United States)

Petitjean, Dimitri; Kalstrup, Tanja; Zhao, Juan; Blunck, Rikard

2015-09-02

The mutation F184C in Kv1.1 leads to development of episodic ataxia type I (EA1). Although the mutation has been said to alter activation kinetics and to lower expression, we show here that the underlying molecular mechanisms may be more complex. Although F184 is positioned in the "peripheral" S1 helix, it occupies a central position in the 3D fold. We show in cut-open oocyte voltage-clamp recordings of gating and ionic currents of the Shaker Kv channel expressed in Xenopus oocytes that F184 not only interacts directly with the gating charges of the S4, but also creates a functional link to the selectivity filter of the neighboring subunit. This link leads to impaired fast and slow inactivation. The effect on fast inactivation is of an allosteric nature considering that fast inactivation is caused by a linked cytosolic ball peptide. The extensive effects of F184C provide a new mechanism underlying EA. Episodic ataxia (EA) is an inherited disease that leads to occasional loss of motor control in combination with variable other symptoms such as vertigo or migraine. EA type I (EA1), studied here, is caused by mutations in a voltage-gated potassium channel that contributes to the generation of electrical signals in the brain. The mechanism by which mutations in voltage-gated potassium channels lead to EA is still unknown and there is no consistent pharmacological treatment. By studying in detail one disease-causing mutation in Kv1.1, we describe a novel molecular mechanism distinct from mechanisms described previously. This mechanism contributes to the understanding of potassium channel function in general and might lead to a better understanding of how EA develops. Copyright © 2015 the authors 0270-6474/15/3512198-09$15.00/0.

Blanket comparison and selection study. Volume I

International Nuclear Information System (INIS)

1983-10-01

The objectives of the Blanket Comparison and Selection Study (BCSS) can be stated as follows: (1) Define a small number (approx. 3) of blanket design concepts that should be the focus of the blanket R and D program. A design concept is defined by the selection of all materials (e.g., breeder, coolant, structure and multiplier) and other major characteristics that significantly influence the R and D requirements. (2) Identify and prioritize the critical issues for the leading blanket concepts. (3) Provide the technical input necessary to develop a blanket R and D program plan. Guidelines for prioritizing the R and D requirements include: (a) critical feasibility issues for the leading blanket concepts will receive the highest priority, and (b) for equally important feasibility issues, higher R and D priority will be given to those that require minimum cost and short time

Relative quantum yield of I-asterisk(2P1/2) in the tunable laser UV photodissociation of i-C3F7I and n-C3F7I - Effect of temperature and exciplex emission

Science.gov (United States)

Smedley, J. E.; Leone, S. R.

1983-01-01

Wavelength-specific relative quantum yields of metastable I from pulsed laser photodissociation of i-C3F7I and n-C3F7I in the range 265-336 nm are determined by measuring the time-resolved infrared emission from the atomic I(P-2(1/2) P-2(3/2) transition. It is shown that although this yield appears to be unity from 265 to 298 nm, it decreases dramatically at longer wavelengths. Values are also reported for the enhancement of emission from metastable I due to exciplex formation at several temperatures. The exciplex formation emission increases linearly with parent gas pressure, but decreases with increasing temperature. Absorption spectra of i- and n-C3F7I between 303 and 497 K are presented, and the effect of temperature on the quantum yields at selected wavelengths greater than 300 nm, where increasing the temperature enhances the absorption considerably, are given. The results are discussed in regard to the development of solar-pumped iodine lasers.

H I-SELECTED GALAXIES IN THE SLOAN DIGITAL SKY SURVEY. II. THE COLORS OF GAS-RICH GALAXIES

International Nuclear Information System (INIS)

West, Andrew A.; Garcia-Appadoo, Diego A.; Dalcanton, Julianne J.; Ivezic, Zeljko; Disney, Mike J.; Rockosi, Constance M.

2009-01-01

We utilize color information for an H I-selected sample of 195 galaxies to explore the star formation histories and physical conditions that produce the observed colors. We show that the H I selection creates a significant offset toward bluer colors that can be explained by enhanced recent bursts of star formation. There is also no obvious color bimodality, because the H I selection restricts the sample to bluer, actively star-forming systems, diminishing the importance of the red sequence. Rising star formation rates are still required to explain the colors of galaxies bluer than g - r< 0.3. We also demonstrate that the colors of the bluest galaxies in our sample are dominated by emission lines and that stellar population synthesis models alone (without emission lines) are not adequate for reproducing many of the galaxy colors. These emission lines produce large changes in the r - i colors but leave the g - r color largely unchanged. In addition, we find an increase in the dispersion of galaxy colors at low masses that may be the result of a change in the star formation process in low-mass galaxies.

Synthesis of (Ga _1–<i>x> Zn _<i>x> )(N _1–<i>x> O _<i>x> ) with Enhanced Visible-Light Absorption and Reduced Defects by Suppressing Zn Volatilization

Energy Technology Data Exchange (ETDEWEB)

Chen, Dennis P.; Skrabalak, Sara E.

2016-04-18

(Ga_1–<i>x>)(N_1–<i>x> O _<i>x>) (GZNO) particles with enhanced optical absorption were synthesized by topotactic transformation of Zn²⁺/Ga³⁺ layered double hydroxides. This outcome was achieved by suppressing Zn volatilization during nitridation by maintaining a low partial pressure of O₂ (p_O2). Zn-rich (x > 1/3) variants of GZNO were achieved and compared to those prepared by conventional ammonoylsis conditions. The optical absorption and structural properties of these samples were compared to those prepared in the absence of O₂ by diffuse-reflectance spectroscopy and powder X-ray diffraction methods. Notably, suppression of Zn volatilization leads to smaller-band-gap materials (2.30 eV for x = 0.42 versus 2.71 eV for x = 0.21) and reduced structural defects. This synthetic route and set of characterizations provide useful structure–property studies of GZNO and potentially other oxynitrides of interest as photocatalysts.

Antibody-directed lentiviral gene transduction for live-cell monitoring and selection of human iPS and hES cells.

Directory of Open Access Journals (Sweden)

Dai-tze Wu

Full Text Available The identification of stem cells within a mixed population of cells is a major hurdle for stem cell biology--in particular, in the identification of induced pluripotent stem (iPS cells during the reprogramming process. Based on the selective expression of stem cell surface markers, a method to specifically infect stem cells through antibody-conjugated lentiviral particles has been developed that can deliver both visual markers for live-cell imaging as well as selectable markers to enrich for iPS cells. Antibodies recognizing SSEA4 and CD24 mediated the selective infection of the iPS cells over the parental human fibroblasts, allowing for rapid expansion of these cells by puromycin selection. Adaptation of the vector allows for the selective marking of human embryonic stem (hES cells for their removal from a population of differentiated cells. This method has the benefit that it not only identifies stem cells, but that specific genes, including positive and negative selection markers, regulatory genes or miRNA can be delivered to the targeted stem cells. The ability to specifically target gene delivery to human pluripotent stem cells has broad applications in tissue engineering and stem cell therapies.

Pre- and postsynaptic effects of brimonidine on isolated rabbit iris dilator muscles

Directory of Open Access Journals (Sweden)

Tatsui S

2016-05-01

Full Text Available Sonoko Tatsui,1 Hitoshi Ishikawa,2 Kimiya Shimizu,1 Kimiyo Mashimo1 1Department of Ophthalmology, School of Medicine, Kitasato University, 2Department of Orthoptics and Visual Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan Purpose: Brimonidine is an imidazoline compound used for the treatment of glaucoma, but having very little effect on pupil diameter. Like para-aminoclonidine, most imidazoline compounds interact with postsynaptic α-adrenoceptors and cause pupil dilatation. Therefore, as part of an investigation of the mechanism of action of brimonidine on pupil diameter, the present study was initiated to measure, in vitro, the relative potency of brimonidine on the pre- and postsynaptic α-adrenoceptors of rabbit iris dilator muscle. Methods: The contractile activity of brimonidine and its effect on twitch contraction evoked by electrical field stimulation were studied in isolated rabbit iris dilator muscles by isometric tension recording. Results: Brimonidine significantly inhibited the twitch contraction of the dilator muscle caused by field stimulation, without affecting the response to exogenously applied phenylephrine. Compared to phenylephrine, brimonidine caused only a small contractile response with % maximum contraction values of<10%. Conclusion: These results suggest that brimonidine may act on nerve endings to inhibit adrenergic neurotransmission with very little effect on postsynaptic α-adrenoceptors. This may indicate that brimonidine reduced the pupil diameter just a little, thus improving night vision. Keywords: brimonidine, rabbit iris dilator, electrical field stimulation, presynaptic α2-adrenoceptor, postsynaptic α1-adrenoceptor, imidazolin

A new fluorescent pyrene–pyridine dithiocarbamate probe: A chemodosimeter to detect Hg2+ in pure aqueous medium and in live cells

International Nuclear Information System (INIS)

Singh, Vikram; Srivastava, Priyanka; PrakashVerma, Shiv; Misra, Arvind; Das, Parimal; Singh, Nanhai

2014-01-01

A new pyrene–pyridine dithiocarbamate based fluorescent chemodosimeter, potassium (pyren-1-ylmethyl)(pyridin-2-ylmethyl)dithiocarbamate (L1) has been designed and synthesized. The chemodosimeter shows high selectivity and sensitivity (5.2 ppb) for Hg 2+ in pure aqueous medium in which emission intensity was quenched by ≈80% due to the formation of new cyclized species, 1. The probe behaves as a chemodosimeter for Hg 2+ ions and forms Hg 2+ triggered cyclised imidazoline species with approximate detection time of 50 s and exhibits both colorimetric and fluorometric changes on detection of Hg 2+ ion. Color of the probe (L1) changed from green to colorless visible to the naked eye and from green to dark blue upon the addition of Hg 2+ ions under UV light. The Hg 2+ triggered cyclization reaction was confirmed by spectral data analysis and a single crystal structure determination of the cyclised entity 2 obtained from the model compound potassium benzyl(pyridin-2-ylmethyl) dithiocarbamate (L2). L1 finds its application for detection of Hg 2+ ions on paper strips, and in BSA (bovine serum albumin) medium. L1 is also applicable for the monitoring of Hg 2+ ion in NIH3T3 live cells. - Highlights: • Efficient chemodosimeter to detect Hg 2+ ions in pure aqueous medium. • Hg 2+ triggered cyclisation and formation of imidazoline species. • Probe exhibit both colorimetric and fluorometric changes • Probe is applicable to detect Hg 2+ in live cells and on cellulose paper strips

A new fluorescent pyrene–pyridine dithiocarbamate probe: A chemodosimeter to detect Hg{sup 2+} in pure aqueous medium and in live cells

Energy Technology Data Exchange (ETDEWEB)

Singh, Vikram; Srivastava, Priyanka [Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005 (India); PrakashVerma, Shiv [Centre for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi-221005 (India); Misra, Arvind [Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005 (India); Das, Parimal [Centre for Genetic Disorders, Faculty of Science, Banaras Hindu University, Varanasi-221005 (India); Singh, Nanhai, E-mail: nsinghbhu@gmail.com [Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005 (India)

2014-10-15

A new pyrene–pyridine dithiocarbamate based fluorescent chemodosimeter, potassium (pyren-1-ylmethyl)(pyridin-2-ylmethyl)dithiocarbamate (L1) has been designed and synthesized. The chemodosimeter shows high selectivity and sensitivity (5.2 ppb) for Hg{sup 2+} in pure aqueous medium in which emission intensity was quenched by ≈80% due to the formation of new cyclized species, 1. The probe behaves as a chemodosimeter for Hg{sup 2+} ions and forms Hg{sup 2+} triggered cyclised imidazoline species with approximate detection time of 50 s and exhibits both colorimetric and fluorometric changes on detection of Hg{sup 2+} ion. Color of the probe (L1) changed from green to colorless visible to the naked eye and from green to dark blue upon the addition of Hg{sup 2+} ions under UV light. The Hg{sup 2+} triggered cyclization reaction was confirmed by spectral data analysis and a single crystal structure determination of the cyclised entity 2 obtained from the model compound potassium benzyl(pyridin-2-ylmethyl) dithiocarbamate (L2). L1 finds its application for detection of Hg{sup 2+} ions on paper strips, and in BSA (bovine serum albumin) medium. L1 is also applicable for the monitoring of Hg{sup 2+} ion in NIH3T3 live cells. - Highlights: • Efficient chemodosimeter to detect Hg{sup 2+} ions in pure aqueous medium. • Hg{sup 2+} triggered cyclisation and formation of imidazoline species. • Probe exhibit both colorimetric and fluorometric changes • Probe is applicable to detect Hg{sup 2+} in live cells and on cellulose paper strips.

ACTHsub(1-24) and lysine vasopressin selectively activate dopamine synthesis in frontal cortex

Energy Technology Data Exchange (ETDEWEB)

Delanoy, R L; Kramarcy, N R; Dunn, A J [Florida Univ., Gainesville (USA). Coll. of Medicine

1982-01-07

The accumulation of (/sup 3/H)catecholamines from (/sup 3/H)tyrosine in frontal cortical, septal, striatal and hippocampal slices was examined following intracerebroventricular (i.c.v.) injections of ACTHsub(1-24), lysine vasopressin (LVP) and saline. Both ACTHsub(1-24) and LVP (1..mu..g) selectively increased the accumulation of (/sup 3/H)dopamine (DA) in frontal cortical slices, but did not affect that of (/sup 3/H)norepinephrine (NE). LVP but not ACTHsub(1-24) also inhibited the accumulation of (/sup 3/H)DA in striatal slices. ACTHsub(1-24) did not alter the accumulation of (/sup 3/H)NE in hippocampal slices, nor did LVP alter the accumulation of either catecholamine (CA) in septal slices. In vitro incubations with ACTH analogs or LVP failed to alter the rate of accumulation of (/sup 3/H)CAs in striatal, substantia nigral and frontal cortical slices, except for an inhibitory effect at high doses. This effect is believed to be an artifact of precursor dilution caused by release of tyrosine following degradation of the peptides. Neither peptide modified the increased (/sup 3/H)CA accumulation stimulated by 26 mM K/sup +/, nor did ACTHsub(1-24) modify the inhibition of (/sup 3/H)CA accumulation caused by 3 X 10/sup -6/ M Haloperidol or 3 X 10/sup -7/ M apomorphine. Selective activation of the mesocortical DA system has also been reported to occur in response to footshock, suggesting the possibility that endogenous ACTH and/or LVP might mediate the stress-induced activation of mesocortical DA synthesis. Alternatively, i.c.v. injections of these peptides may themselves be stressful and thus indirectly elicit the response.

Development of a calibration system for airborne "1"3"1I monitoring devices

International Nuclear Information System (INIS)

Zhao, C.; Tang, F.; He, L.; Xu, Y.; Lu, X.

2016-01-01

A prototype calibration system for airborne "1"3"1I monitoring devices was developed at the Shanghai Institute of Measurement and Testing Technology (SIMT). This system consists of a gaseous "1"3"1I_2 generator, an airborne storage chamber, an airborne iodine sampler, and an HPGe spectrometer. With this system, "1"3"1I reference samples in the form of charcoal filters and charcoal cartridges, with activities ranging from 100 to 10,000 Bq, were produced with overall relative standard uncertainties of 2.8% (for filter samples) and 3.5% (for cartridge samples); the activities range could be extended according to need. - Highlights: • Original calibration system for airborne "1"3"1I monitoring devices was developed. • Two types of "1"3"1I reference samples was prepared. • The activity of the produced "1"3"1I reference sample could be easily controlled. • The influence of uneven distribution of "1"3"1I in cartridge samples was considered.

Cosmic clocks: a tight radius-velocity relationship for H I-selected galaxies

Science.gov (United States)

Meurer, Gerhardt R.; Obreschkow, Danail; Wong, O. Ivy; Zheng, Zheng; Audcent-Ross, Fiona M.; Hanish, D. J.

2018-05-01

H I-selected galaxies obey a linear relationship between their maximum detected radius Rmax and rotational velocity. This result covers measurements in the optical, ultraviolet, and H I emission in galaxies spanning a factor of 30 in size and velocity, from small dwarf irregulars to the largest spirals. Hence, galaxies behave as clocks, rotating once a Gyr at the very outskirts of their discs. Observations of a large optically selected sample are consistent, implying this relationship is generic to disc galaxies in the low redshift Universe. A linear radius-velocity relationship is expected from simple models of galaxy formation and evolution. The total mass within Rmax has collapsed by a factor of 37 compared to the present mean density of the Universe. Adopting standard assumptions, we find a mean halo spin parameter λ in the range 0.020-0.035. The dispersion in λ, 0.16 dex, is smaller than expected from simulations. This may be due to the biases in our selection of disc galaxies rather than all haloes. The estimated mass densities of stars and atomic gas at Rmax are similar (˜0.5 M⊙ pc-2), indicating outer discs are highly evolved. The gas consumption and stellar population build time-scales are hundreds of Gyr, hence star formation is not driving the current evolution of outer discs. The estimated ratio between Rmax and disc scalelength is consistent with long-standing predictions from monolithic collapse models. Hence, it remains unclear whether disc extent results from continual accretion, a rapid initial collapse, secular evolution, or a combination thereof.

Dual monitoring using {sup 124}I-FIAU and bioluminescence for HSV1-tk suicide gene therapy

Energy Technology Data Exchange (ETDEWEB)

Lee, T. S.; Kim, J. H.; Kwon, H. C. [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

2007-07-01

Herpes simplex virus type I thymidine kinase (HSV-tk) is the most common reporter gene and is used in cancer gene therapy with a prodrug nucleoside analog, ganciclovir (GCV). The aim of this study is to evaluate therapeutic efficacy of suicide gene therapy with 2'-fluoro-2'-deoxy-1-D-arabinofuranosyl-5-[{sup 124}I] iodouracil ({sup 124}I - FIAU) and bioluminescence in retrovirally HSV -tk and firefly luciferase transduced hepatoma model. The HSV -tk and firefly luciferase (Luc) was retrovirally transduced and expressed in MCA rat Morris hepatoma cells. Nude mice with subcutaneous tumors, MCA and MCA-TK-Luc, were subjected to GCV treatment (50mg/Kg/d intraperitoneally) for 5 day. PET imaging and biodistribution with ({sup 124}I-FIAU) were performed at before and after initiation of therapy with GCV. Bioluminescent signal was also measured during GCV treatment. Before GCV treatment, no significant difference in tumor volume was found in tumors between MCA and MCA-TK-Luc. After GCV treatment, tumor volume of MCA-TK-Luc markedly reduced compared to that of MCA. In biodistribution study, {sup 124}I-FIAU uptake after GCV therapy significantly decreased compared with pretreatment levels (34.8 13.67 %ID/g vs 7.6 2.59 %ID/g) and bioluminescent signal was also significantly decreased compared with pretreatment levels. In small animal PET imaging, {sup 124}I-FIAU selectively localized in HSV -tk expressing tumor and the therapeutic efficacy of GCV treatment was evaluated by {sup 124}I-FIAU PET imaging. {sup 124}I-FIAU PET and bioluminescence imaging in HSV-tk suicide gene therapy were effective to evaluate the therapeutic response. {sup 124}I-FIAU may serve as an efficient and selective agent for monitoring of transduced HSV1-tk gene expression in vivo in clinical trials.

Effects of an endurance cycling competition on resting serum insulin-like growth factor I (IGF-I) and its binding proteins IGFBP-1 and IGFBP-3

Science.gov (United States)

Chicharro, J; Lopez-Calderon, A; Hoyos, J; Martin-Velasco, A; Villa, G; Villanua, M; Lucia, A

2001-01-01

Objectives—To determine whether consecutive bouts of intense endurance exercise over a three week period alters serum concentrations of insulin-like growth factor I (IGF-I) and/or its binding proteins. Methods—Seventeen professional cyclists (mean (SEM) VO2MAX, 74.7 (2.1) ml/kg/min; age, 27 (1) years) competing in a three week tour race were selected as subjects. Blood samples were collected at each of the following time points: t0 (control, before the start of competition), t1 (end of first week), and t3 (end of third week). Serum levels of both total and free IGF-I and IGF binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured in each of the samples. Cortisol levels were measured in nine subjects. Results—A significant (p<0.01) increase was found in total IGF-I and IGFBP-1 at both t1 and t3 compared with to (IGF-I: 110.9 (17.7), 186.8 (12.0), 196.9 (14.7) ng/ml at t0, t1, and t3 respectively; IGFBP-1: 54.6 (6.6), 80.6 (8.0), and 89.2 (7.9) ng/ml at t0, t1, and t3 respectively). A significant (p<0.01) decrease was noted in free IGF-I at t3 compared with both to and t1 (t0: 0.9 (0.1) ng/ml; t1: 0.9 (0.1) ng/ml; t3: 0.7 (0.1) ng/ml); in contrast, IGFBP-3 levels remained stable throughout the race. Conclusions—It would appear that the increase in circulating levels of both IGF-I and its binding protein IGFBP-1 is a short term (one week) endocrine adaptation to endurance exercise. After three weeks of training, total IGF-I and IGFBP-1 remained stable, whereas free IGF-I fell below starting levels. Key Words: cycling; insulin-like growth factor; exercise; endurance; binding proteins PMID:11579061

Supplier Selection within the Process of Analytical Hierarchy in a Business Bir Üretim İşletmesinde Analitik Hiyerarşi Süreci İle Tedarikçi Seçimi

Directory of Open Access Journals (Sweden)

Kezban KAPAR

2013-09-01

Full Text Available Supplier selection is one of the most critical activities in today's competitive businessworld. Selecting the supplier is a very difficult task to carry out. For determining the bestsupplier selection while assessing all the cases to choose the best approach, the AnalyticalHierarchy Process (AHP is used.AHP is a method used for systematic comparison, evaluation and selection of theoptions via determining the strengths and weaknesses of options. In this study, AHP methodwas utilized in the supplier selection and Expert Choice 11.5 was used while utilizing AHPmethod. The suppliers' superiorities were determined by Expert Choice and they werecompared systematically.Tedarikçi seçimi, günümüz rekabetçi iş dünyasında en kritik faaliyetlerden biridir. Birtedarikçi seçiminde en iyi olanı seçmek zor bir iştir. En iyi tedarikçi seçiminin belirlenmesiiçin çok amaçlı karar verme tekniklerinden birisi olan ve alternatif tedarikçilerdeğerlendirilerek bütün durumlar içinden en iyi olanı seçebilen Analitik Hiyerarşi Süreci(AHS, tedarikçi seçiminde yaygın olarak kullanılan bir yöntemdir.AHS, seçim aşamasında seçeneklerin üstünlüklerinin belirlenmesi ve sistematik olarakkarşılaştırılıp değerlendirilmesini sağlayan bir yöntemdir. Bu çalışmada, bir işletmenintedarikçi seçiminde AHS yönteminden yararlanılmış ve AHS yönteminin kullanılmasındaExpert Choice 11.5 programı kullanılmıştır. Expert Choice ile tedarikçilerin üstünlükleribelirlenmiştir ve sistematik olarak karşılaştırılmıştır.

The SPECT tracer [123I]ADAM binds selectively to serotonin transporters: a double-blind, placebo-controlled study in healthy young men

International Nuclear Information System (INIS)

Giessen, Elsmarieke van de; Booij, Jan

2010-01-01

The tracer 123 I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([ 123 I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [ 123 I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [ 123 I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [ 123 I]ADAM binds selectively to SERTs. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [ 123 I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate. Our preliminary findings suggest that [ 123 I]ADAM binds selectively to SERTs in human brain. (orig.)

FILOSOFIA THEORETICA VoI. 1 No. 1 Dec. 2011 MENTAL ...

African Journals Online (AJOL)

JONATHAN CHIMAKONAM OKEKE

2011-12-01

Dec 1, 2011 ... investigate the problem of personal identity (Furman and Avila, 146). Others include, Thomas Reid ... disembodied thoughts and memories are the bastion of personal identity. This does not suggest the .... may make a little sense to me when I say that I'm what I think I am, but how far does this go? How do I ...

Identification of recently selected mutations driven by artificial selection in hanwoo (korean cattle).

Science.gov (United States)

Lim, Dajeong; Gondro, Cedric; Park, Hye Sun; Cho, Yong Min; Chai, Han Ha; Seong, Hwan Hoo; Yang, Bo Suk; Hong, Seong Koo; Chang, Won Kyung; Lee, Seung Hwan

2013-05-01

Hanwoo have been subjected over the last seventy years to intensive artificial selection with the aim of improving meat production traits such as marbling and carcass weight. In this study, we performed a signature of selection analysis to identify recent positive selected regions driven by a long-term artificial selection process called a breeding program using whole genome SNP data. In order to investigate homozygous regions across the genome, we estimated iES (integrated Extended Haplotype Homozygosity SNP) for the each SNPs. As a result, we identified two highly homozygous regions that seem to be strong and/or recent positive selection. Five genes (DPH5, OLFM3, S1PR1, LRRN1 and CRBN) were included in this region. To go further in the interpretation of the observed signatures of selection, we subsequently concentrated on the annotation of differentiated genes defined according to the iES value of SNPs localized close or within them. We also described the detection of the adaptive evolution at the molecular level for the genes of interest. As a result, this analysis also led to the identification of OLFM3 as having a strong signal of selection in bovine lineage. The results of this study indicate that artificial selection which might have targeted most of these genes was mainly oriented towards improvement of meat production.

Identification of Recently Selected Mutations Driven by Artificial Selection in Hanwoo (Korean Cattle

Directory of Open Access Journals (Sweden)

Dajeong Lim

2013-05-01

Full Text Available Hanwoo have been subjected over the last seventy years to intensive artificial selection with the aim of improving meat production traits such as marbling and carcass weight. In this study, we performed a signature of selection analysis to identify recent positive selected regions driven by a long-term artificial selection process called a breeding program using whole genome SNP data. In order to investigate homozygous regions across the genome, we estimated iES (integrated Extended Haplotype Homozygosity SNP for the each SNPs. As a result, we identified two highly homozygous regions that seem to be strong and/or recent positive selection. Five genes (DPH5, OLFM3, S1PR1, LRRN1 and CRBN were included in this region. To go further in the interpretation of the observed signatures of selection, we subsequently concentrated on the annotation of differentiated genes defined according to the iES value of SNPs localized close or within them. We also described the detection of the adaptive evolution at the molecular level for the genes of interest. As a result, this analysis also led to the identification of OLFM3 as having a strong signal of selection in bovine lineage. The results of this study indicate that artificial selection which might have targeted most of these genes was mainly oriented towards improvement of meat production.

Astrophysical s-factor measurements for {sup 1}20Te(p,{gamma}){sup 1}21I and {sup 1}20Te(p,n){sup 1}20I reactions; {sup 1}20Te(p,{gamma}){sup 1}21I ve {sup 1}20Te(p,n){sup 1}20I reaksiyonlarinin astrofiziksel s-factor oelcuemleri

Energy Technology Data Exchange (ETDEWEB)

Gueray, R T; Oezkan, N; Yalcin, C [Kocaeli University, Kocaeli (Turkey); Goerres, J; DeBoer, R; Palumbo, A; Tan, W P; Wiescher, M [University of Notre Dame, (United States); Fueloep, Zs; Somorjai, E [Institute of Nuclear Research ATOMKI (Hungary); Lee, H Y [Argonne National Laboratory (United States)

2009-07-01

Astrophysical S-factors for the {sup 1}20Te(p,{gamma}){sup 1}21I and {sup 1}20Te(p,n){sup 1}20I reactions have been measured in the effective center-of-mass energies between 2.47 MeV and 7.93 MeV. Experimental data have been compared with the Hauser-Fesbach statistical model calculations obtained with the model codes NON-SMOKER and TALYS. The discrepancies between the experimental results and calculations can mainly be attributed to the optical model potentials used in the codes.

Preparation and biodistribution of 131I labeled 3-Amino-1-hydroxypropylidene-1, 1-bisphosphonate

International Nuclear Information System (INIS)

Lin Rushan; Yang Yuanyou; Liu Ning; Liao Jiali; Jin Jiannan; Pu Manfei

2008-01-01

3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (ABP) was synthesized and labeled with 131 I using N-succinimidyl-5-(tri-butylstannyl)-3-pyridinecarboxylate (SPC) as a bi-functional linker. 131 I could be coupled to ABP via a 131 I-SIPC intermediate with a labeling yield of more than 64%, and a radiochemical purity of more than 99% after HPLC purification. After 72 h at room temperature, the radiochemical purity was still more than 98.8%, implying that the 131 I-SIPC-ABP is stable in vitro. Biodistribution experiments in mice show that 131 I-SIPC-ABP has high affinity to bone and high stability in vivo as well as in vitro. (authors)

Complete primary structure of rainbow trout type I collagen consisting of alpha1(I)alpha2(I)alpha3(I) heterotrimers.

Science.gov (United States)

Saito, M; Takenouchi, Y; Kunisaki, N; Kimura, S

2001-05-01

The subunit compositions of skin and muscle type I collagens from rainbow trout were found to be alpha1(I)alpha2(I)alpha3(I) and [alpha1(I)](2)alpha2(I), respectively. The occurrence of alpha3(I) has been observed only for bonyfish. The skin collagen exhibited more susceptibility to both heat denaturation and MMP-13 digestion than the muscle counterpart; the former had a lower denaturation temperature by about 0.5 degrees C than the latter. The lower stability of skin collagen, however, is not due to the low levels of imino acids because the contents of Pro and Hyp were almost constant in both collagens. On the other hand, some cDNAs coding for the N-terminal and/or a part of triple-helical domains of proalpha(I) chains were cloned from the cDNA library of rainbow trout fibroblasts. These cDNAs together with the previously cloned collagen cDNAs gave information about the complete primary structure of type I procollagen. The main triple-helical domain of each proalpha(I) chain had 338 uninterrupted Gly-X-Y triplets consisting of 1014 amino acids and was unique in its high content of Gly-Gly doublets. In particular, the bonyfish-specific alpha(I) chain, proalpha3(I) was characterized by the small number of Gly-Pro-Pro triplets, 19, and the large number of Gly-Gly doublets, 38, in the triple-helical domain, compared to 23 and 22, respectively, for proalpha1(I). The small number of Gly-Pro-Pro and the large number of Gly-Gly in proalpha3(I) was assumed to partially loosen the triple-helical structure of skin collagen, leading to the lower stability of skin collagen mentioned above. Finally, phylogenetic analyses revealed that proalpha3(I) had diverged from proalpha1(I). This study is the first report of the complete primary structure of fish type I procollagen.

Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity

Energy Technology Data Exchange (ETDEWEB)

Xie, Xiaoling; Baird, Daniel; Bowen, Kimberly; Capka, Vladimir; Chen, Jinyun; Chenail, Gregg; Cho, YoungShin; Dooley, Julia; Farsidjani, Ali; Fortin, Pascal; Kohls, Darcy; Kulathila, Raviraj; Lin, Fallon; McKay, Daniel; Rodrigues, Lindsey; Sage, David; Touré, B. Barry; van der Plas, Simon; Wright, Kirk; Xu, Ming; Yin, Hong; Levell, Julian; Pagliarini, Raymond A. (Novartis)

2017-03-01

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 “regulatory segment,” which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

Energy Technology Data Exchange (ETDEWEB)

Smith, Adrian L.; D’Angelo, Noel D.; Bo, Yunxin Y.; Booker, Shon K.; Cee, Victor J.; Herberich, Brad; Hong, Fang-Tsao; Jackson, Claire L.M.; Lanman, Brian A.; Liu, Longbin; Nishimura, Nobuko; Pettus, Liping H.; Reed, Anthony B.; Tadesse, Seifu; Tamayo, Nuria A.; Wurz, Ryan P.; Yang, Kevin; Andrews, Kristin L.; Whittington, Douglas A.; McCarter, John D.; Miguel, Tisha San; Zalameda, Leeanne; Jiang, Jian; Subramanian, Raju; Mullady, Erin L.; Caenepeel, Sean; Freeman, Daniel J.; Wang, Ling; Zhang, Nancy; Wu, Tian; Hughes, Paul E.; Norman, Mark H. (Amgen)

2012-09-17

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

Influenza A virus NS1 gene mutations F103L and M106I increase replication and virulence

Directory of Open Access Journals (Sweden)

Ping Jihui

2011-01-01

Full Text Available Abstract Background To understand the evolutionary steps required for a virus to become virulent in a new host, a human influenza A virus (IAV, A/Hong Kong/1/68(H3N2 (HK-wt, was adapted to increased virulence in the mouse. Among eleven mutations selected in the NS1 gene, two mutations F103L and M106I had been previously detected in the highly virulent human H5N1 isolate, A/HK/156/97, suggesting a role for these mutations in virulence in mice and humans. Results To determine the selective advantage of these mutations, reverse genetics was used to rescue viruses containing each of the NS1 mouse adapted mutations into viruses possessing the HK-wt NS1 gene on the A/PR/8/34 genetic backbone. Both F103L and M106I NS1 mutations significantly enhanced growth in vitro (mouse and canine cells and in vivo (BALB/c mouse lungs as well as enhanced virulence in the mouse. Only the M106I NS1 mutation enhanced growth in human cells. Furthermore, these NS1 mutations enhanced early viral protein synthesis in MDCK cells and showed an increased ability to replicate in mouse interferon β (IFN-β pre-treated mouse cells relative to rPR8-HK-NS-wt NS1. The double mutant, rPR8-HK-NS-F103L + M106I, demonstrated growth attenuation late in infection due to increased IFN-β induction in mouse cells. We then generated a rPR8 virus possessing the A/HK/156/97 NS gene that possesses 103L + 106I, and then rescued the L103F + I106M mutant. The 103L + 106I mutations increased virulence by >10 fold in BALB/c mice. We also inserted the avian A/Ck/Beijing/1/95 NS1 gene (the source lineage of the A/HK/156/97 NS1 gene that possesses 103L + 106I, onto the A/WSN/33 backbone and then generated the L103F + I106M mutant. None of the H5N1 and H9N2 NS containing viruses resulted in increased IFN-β induction. The rWSN-A/Ck/Beijing/1/95-NS1 gene possessing 103L and 106I demonstrated 100 fold enhanced growth and >10 fold enhanced virulence that was associated with increased tropism for lung

(D-Pen2,4 prime -125I-Phe4,D-Pen5)enkephalin: A selective high affinity radioligand for delta opioid receptors with exceptional specific activity

Energy Technology Data Exchange (ETDEWEB)

Knapp, R.J.; Sharma, S.D.; Toth, G.; Duong, M.T.; Fang, L.; Bogert, C.L.; Weber, S.J.; Hunt, M.; Davis, T.P.; Wamsley, J.K. (Department of Pharmacology, University of Arizona, College of Medicine, Tucson (United States))

1991-09-01

(D-Pen2,4{prime}-125I-Phe4,D-Pen5)enkephalin ((125I)DPDPE) is a highly selective radioligand for the delta opioid receptor with a specific activity (2200 Ci/mmol) that is over 50-fold greater than that of tritium-labeled DPDPE analogs. (125I)DPDPE binds to a single site in rat brain membranes with an equilibrium dissociation constant (Kd) value of 421 {plus minus} 67 pM and a receptor density (Bmax) value of 36.4 {plus minus} 2.7 fmol/mg protein. The high affinity of this site for delta opioid receptor ligands and its low affinity for mu or kappa receptor-selective ligands are consistent with its being a delta opioid receptor. The distribution of these sites in rat brain, observed by receptor autoradiography, is also consistent with that of delta opioid receptors. Association and dissociation binding kinetics of 1.0 nM (125I) DPDPE are monophasic at 25 degrees C. The association rate (k + 1 = 5.80 {plus minus} 0.88 {times} 10(7) M-1 min-1) is about 20- and 7-fold greater than that measured for 1.0 nM (3H) DPDPE and 0.8 nM (3H) (D-Pen2,4{prime}-Cl-Phe4, D-Pen5)enkephalin, respectively. The dissociation rate of (125I)DPDPE (0.917 {plus minus} 0.117 {times} 10(-2) min-1) measured at 1.0 nM is about 3-fold faster than is observed for either of the other DPDPE analogs. The rapid binding kinetics of (125I)DPDPE is advantageous because binding equilibrium is achieved with much shorter incubation times than are required for other cyclic enkephalin analogs. This, in addition to its much higher specific activity, makes (125I)DPDPE a valuable new radioligand for studies of delta opioid receptors.

Supplier Selection Process Using ELECTRE I Decision Model and an Application in the Retail Sector

Directory of Open Access Journals (Sweden)

Oğuzhan Yavuz

2013-12-01

Full Text Available Supplier selection problem is one of the main topic for the today’s businesses. The supplier selection problem within the supply chain management activities is very important for the businesses, particularly operating in the retail sector. Thus, in this study, the supplier selection problem was discussed in order of importance between energy drinks suppliers of food business in the retail sector. Costs, delivery, quality and flexibility variables were used to select suppliers, and ELECTRE I Method, one of the multiple decision methods, was used to ranking suppliers according to this variables. Which suppliers are more important for the food company was determined by ranking suppliers according to computing net superior values and net inferior values. Results obtained werepresented in tables and certain steps

Selective changes in expression of HLA class I polymorphic determinants in human solid tumors

International Nuclear Information System (INIS)

Natali, P.G.; Nicotra, M.R.; Bigotti, A.; Venturo, I.; Giacomini, P.; Marcenaro, L.; Russo, C.

1989-01-01

Analysis of surgical biopsies with monoclonal antibodies (mAbs) to framework determinants of major histocompatibility complex class I antigens has shown that malignant transformation is frequently associated with a marked loss of these cell surface molecules. The present study sought to determine whether more selective losses of major histocompatibility complex class I expression occur. Multiple specimens from 13 different types of primary and metastatic tumors were tested utilizing mAb BB7.2, which recognizes a polymorphic HLA-A2 epitope. In each case, expression of HLA-A,B,C molecules was determined by testing with mAb W6/32 directed to a framework HLA class I determinant. The authors have found that in HLA-A2-positive patients, HLA-A2 products are not detectable or are reduced in their expression in 70-80% of endometrial, colorectal, mammary, and renal tumors; in 40-60% of soft-tissue, skin, ovary, urinary bladder, prostate, and stomach tumors; and in 25-30% of melanomas and lung carcinomas tested. All tumors expressed the framework HLA-A,B.C determinant. The HLA-A2 epitope recognized by mAb BB7.2 is located in a portion of the HLA-A2 molecule postulated to react with the T-cell receptor. The selective loss of an HLA class I polymorphic epitope shown in this study may explain the mechanism by which tumor cells escape both T-cell recognition and natural killer cell surveillance

Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation

International Nuclear Information System (INIS)

Quirion, R.; Chabot, J.-G.; Dore, S.; Seto, D.; Kar, S.

1997-01-01

Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [ 125 I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [ 125 I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [ 125 I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [ 125 I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [ 125 I]insulin receptor binding was noted at all time points in the molecular layer of the

Construction of a new selective coated disk electrode for Ag (I) based on modified polypyrrole-carbon nanotubes composite with new lariat ether.

Science.gov (United States)

Abbaspour, A; Tashkhourian, J; Ahmadpour, S; Mirahmadi, E; Sharghi, H; Khalifeh, R; Shahriyari, M R

2014-01-01

A poly (vinyl chloride) (PVC) matrix membrane ion-selective electrode for silver (I) ion is fabricated based on modified polypyrrole - multiwalled carbon nanotubes composite with new lariat ether. This sensor has a Nernstian slope of 59.4±0.5mV/decade over a wide linear concentration range of 1.0×10(-7) to 1.0×10(-1)molL(-1) for silver (I) ion. It has a short response time of about 8.0s and can be used for at least 50days. The detection limit is 9.3×10(-8)molL(-1) for silver (I) ion, and the electrode was applicable in the wide pH range of 1.6 -7.7. The electrode shows good selectivity for silver ion against many cations such as Hg (II), which usually imposes serious interference in the determination of silver ion concentration. The use of multiwalled carbon nanotubes (MWCNTs) in a polymer matrix improves the linear range and sensitivity of the electrode. In addition by coating the solid contact with a layer of the polypyrrole (Ppy) before coating the membrane on it, not only did it reduce the drift in potential, but a shorter response time was also resulted. The proposed electrode was used as an indicator electrode for potentiometric titration of silver ions with chloride anions and in the titration of mixed halides. This electrode was successfully applied for the determination of silver ions in silver sulphadiazine as a burning cream. © 2013.

MEDYCYNA, PŁYWANIE I SPRAWNOŚĆ FIZYCZNA, WYBRANE ASPEKTY = MEDICINE, SWIMMING AND PHYSICAL EFFICIENCY, SELECTED ASPECTS

OpenAIRE

Ahmad El-Essa; Ewa Zieliński; Kinga Grobelska; Dariusz Skalski

2018-01-01

MEDYCYNA, PŁYWANIE I SPRAWNOŚĆ FIZYCZNA, WYBRANE ASPEKTY = MEDICINE, SWIMMING AND PHYSICAL EFFICIENCY, SELECTED ASPECTS Stan zdrowia populacji oraz systemu opieki zdrowotnej w krajach rozwijających się na przykładzie Ghany = Health status and healthcare system condition in developing countries on the Ghana’s example Zarys anatomii i fizjologii narządu wzroku = Outline of anatomy and phisiology of the organ of eyesight Mechaniczne urazy gałki ocznej i ich możliwe powikłania = Mecha...

Artificial Photosystem I and II: Highly Selective solar fuels and tandem photocatalysis

Science.gov (United States)

Ding, Yuchen; Castellanos, Ignacio; Cerkovnik, Logan; Nagpal, Prashant

2014-03-01

Artificial photosynthesis, or generation of solar fuels from CO2/H2O, can provide an important alternative for rising CO2 emission and renewable energy generation. In our recent work, composite photocatalysts (CPCs) made from widebandgap nanotubes and different QDs were used to mimic Photosystem II (PS680) and I (PS700), respectively. By tuning the redox potentials using the size, composition and energy band alignment of QDs, we demonstrate highly selective (>90%) and efficient production of ethane, ethanol and acetaldehyde as solar fuels with different wavelengths of light. We also show that this selectivity is a result of precise energy band alignments (using cationic/anionic doping of nanotubes, QD size etc.), confirmed using measurements of electronic density of states, and alignment of higher redox potentials with hot-carriers can also lead to hot-carrier photocatalysis. This wavelength-selective CPCs can have important implications for inexpensive production of solar fuels including alkanes, alcohols, aldehydes and hydrogen, and making tandem structures (red, green, blue) with three CPCs, allowing almost full visible spectrum (410 ~ 730nm) utilization with different fuels produced simultaneously.

Selective electronalysis of peracetic acid in the presence of a large excess of H2O2 at Au(1 1 1)-like gold electrode

International Nuclear Information System (INIS)

Awad, M.I.

2012-01-01

Highlights: ► Analysis of peracetic acid in the presence of a large excess of H 2 O 2 is introduced. ► Au(1 1 1)-like gold electrode serves as an ideal for this purpose. ► The analysis is characterized by high selectivity and sensitivity. - Abstract: Peracetic acid (PAA) has been selectively electroanalyzed in the presence of a large excess of hydrogen peroxide (H 2 O 2 ), about 500 fold that of PAA, using Au (1 1 1)-like gold electrode in acetate buffer solutions of pH 5.4. Au(1 1 1)-like gold electrode was prepared by a controlled reductive desorption of a previously assembled thiol, typically cysteine, monolayer onto the polycrystalline gold (poly-Au) electrode. Cysteine molecules were selectively removed from the Au(1 1 1) facets of the poly-Au electrode, keeping the other two facets (i.e., Au(1 1 0) and Au(1 0 0)) under the protection of the adsorbed cysteine. It has been found that Au(1 1 1)-like gold electrode positively shifts the reduction peak of PAA, while, fortunately, shifts the reduction peak of H 2 O 2 negatively, achieving a large potential separation (around 750 mV) between the two reduction peaks as compared with that (around 450 mV) obtained at the poly-Au electrode. This large potential separation between the two reduction peaks enabled the analysis of PAA in the presence of a large excess of H 2 O 2 . In addition, the positive shift of the reduction peak of PAA gives the present method a high immunity against the interference of the dissolved oxygen.

Selective labelling of apolipoproteins A-I and C-I at methionine residues by (TH) methyl exchange

Energy Technology Data Exchange (ETDEWEB)

Hancock, W.S.; Harding, D.R.K.; Barling, P.M.; Sparrow, J.T.

1985-01-01

Apolipoproteins C-I and A-I were radioactively labelled with tritium by (TH)-methyl exchange. The methionine residues were first methylated with (TH)-methyl iodide at pH4 and the reaction products were purified by gel filtration and cation exchange chromatography. The products were then demethylated with 2-mercaptoethanol (6 M) at pH 8.6 to regenerate the apolipoproteins in an unmodified but tritiated form. The specific radioactivity for apolipoprotein C-I and A-I was 3.5 x 10W and 1.5 x 10X dpm/pmol respectively. The properties of (TH)-apolipoprotein C-I were examined by reversed phase HPLC and by incorporation into very low density lipoproteins (VLDL).

Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.

Science.gov (United States)

Bollinger, Stefan; Hübner, Harald; Heinemann, Frank W; Meyer, Karsten; Gmeiner, Peter

2010-10-14

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT(1A) binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT(2), α(1), and α(2)-adrenergic as well as D(1)-D(4) dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT(1A) were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K(i) value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

Synthesis, Characterization, and Variable-Temperature NMR Studies of Silver(I) Complexes for Selective Nitrene Transfer.

Science.gov (United States)

Huang, Minxue; Corbin, Joshua R; Dolan, Nicholas S; Fry, Charles G; Vinokur, Anastasiya I; Guzei, Ilia A; Schomaker, Jennifer M

2017-06-05

An array of silver complexes supported by nitrogen-donor ligands catalyze the transformation of C═C and C-H bonds to valuable C-N bonds via nitrene transfer. The ability to achieve high chemoselectivity and site selectivity in an amination event requires an understanding of both the solid- and solution-state behavior of these catalysts. X-ray structural characterizations were helpful in determining ligand features that promote the formation of monomeric versus dimeric complexes. Variable-temperature 1 H and DOSY NMR experiments were especially useful for understanding how the ligand identity influences the nuclearity, coordination number, and fluxional behavior of silver(I) complexes in solution. These insights are valuable for developing improved ligand designs.

Development of a Two-Piece Mask and Lens and Mold for Same.

Science.gov (United States)

1980-05-01

standard and imidazoline- modified 6150C vulcanizates. In another attempt, the imidazoline was first masterbatched in Nordel (95% Nordel 1320 and 5...cure, which improves the surface characteristics of the vulcanizate (less dust pick- up), attempts have been made to masterbatch these ingredients in a...high Mooney EPDM (for better dispersion) first, later diluting the masterbatch with Nordel 1320. Two such higher Mooney EPDM polymers have been tried

GAP1, a novel selection and counter-selection marker for multiple gene disruptions in Saccharomyces cerevisiae

DEFF Research Database (Denmark)

Regenberg, Birgitte; Hansen, J.

2000-01-01

the GAP1 gene. This is caused by recombination between two Salmonella typuimurium hisG direct repeats embracing GAP1, and will result in a sub-population of gap1 cells. Such cells are selected on a medium containing D-histidine, and may subsequently be used for a second gene disruption. Hence, multiple...... flanked by short (60 bp) stretches of the gene in question. Through homologous recombination, the cassette will integrate into the target gene, which is thus replaced by GAP1, and mutants are selected for on minimal L-citrulline medium. When propagated under non-selective conditions, some cells will lose...... gene disruptions can be made fast, cheaply and easily in a gap1 strain, with two positive selection steps for each disruption. Copyright (C) 2000 John Wiley & Sons, Ltd....

Formula I(1 and I(2: Race Tracks for Likelihood Maximization Algorithms of I(1 and I(2 Cointegrated VAR Models

Directory of Open Access Journals (Sweden)

Jurgen A. Doornik

2017-11-01

Full Text Available This paper provides some test cases, called circuits, for the evaluation of Gaussian likelihood maximization algorithms of the cointegrated vector autoregressive model. Both I(1 and I(2 models are considered. The performance of algorithms is compared first in terms of effectiveness, defined as the ability to find the overall maximum. The next step is to compare their efficiency and reliability across experiments. The aim of the paper is to commence a collective learning project by the profession on the actual properties of algorithms for cointegrated vector autoregressive model estimation, in order to improve their quality and, as a consequence, also the reliability of empirical research.

C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C-H Activation.

Science.gov (United States)

Tran, Gaël; Confair, Danielle; Hesp, Kevin D; Mascitti, Vincent; Ellman, Jonathan A

2017-09-01

Herein, we report a Rh(I)/bisphosphine/K 3 PO 4 catalytic system allowing for the first time the selective branched C-H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and -poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles.

More insight into the interplay of response selection and visual attention in dual-tasks: masked visual search and response selection are performed in parallel.

Science.gov (United States)

Reimer, Christina B; Schubert, Torsten

2017-09-15

Both response selection and visual attention are limited in capacity. According to the central bottleneck model, the response selection processes of two tasks in a dual-task situation are performed sequentially. In conjunction search, visual attention is required to select the items and to bind their features (e.g., color and form), which results in a serial search process. Search time increases as items are added to the search display (i.e., set size effect). When the search display is masked, visual attention deployment is restricted to a brief period of time and target detection decreases as a function of set size. Here, we investigated whether response selection and visual attention (i.e., feature binding) rely on a common or on distinct capacity limitations. In four dual-task experiments, participants completed an auditory Task 1 and a conjunction search Task 2 that were presented with an experimentally modulated temporal interval between them (Stimulus Onset Asynchrony, SOA). In Experiment 1, Task 1 was a two-choice discrimination task and the conjunction search display was not masked. In Experiment 2, the response selection difficulty in Task 1 was increased to a four-choice discrimination and the search task was the same as in Experiment 1. We applied the locus-of-slack method in both experiments to analyze conjunction search time, that is, we compared the set size effects across SOAs. Similar set size effects across SOAs (i.e., additive effects of SOA and set size) would indicate sequential processing of response selection and visual attention. However, a significantly smaller set size effect at short SOA compared to long SOA (i.e., underadditive interaction of SOA and set size) would indicate parallel processing of response selection and visual attention. In both experiments, we found underadditive interactions of SOA and set size. In Experiments 3 and 4, the conjunction search display in Task 2 was masked. Task 1 was the same as in Experiments 1 and 2

Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes.

Science.gov (United States)

Bizy, Alexandra; Guerrero-Serna, Guadalupe; Hu, Bin; Ponce-Balbuena, Daniela; Willis, B Cicero; Zarzoso, Manuel; Ramirez, Rafael J; Sener, Michelle F; Mundada, Lakshmi V; Klos, Matthew; Devaney, Eric J; Vikstrom, Karen L; Herron, Todd J; Jalife, José

2013-11-01

Applications of human induced pluripotent stem cell derived-cardiac myocytes (hiPSC-CMs) would be strengthened by the ability to generate specific cardiac myocyte (CM) lineages. However, purification of lineage-specific hiPSC-CMs is limited by the lack of cell marking techniques. Here, we have developed an iPSC-CM marking system using recombinant adenoviral reporter constructs with atrial- or ventricular-specific myosin light chain-2 (MLC-2) promoters. MLC-2a and MLC-2v selected hiPSC-CMs were purified by fluorescence-activated cell sorting and their biochemical and electrophysiological phenotypes analyzed. We demonstrate that the phenotype of both populations remained stable in culture and they expressed the expected sarcomeric proteins, gap junction proteins and chamber-specific transcription factors. Compared to MLC-2a cells, MLC-2v selected CMs had larger action potential amplitudes and durations. In addition, by immunofluorescence, we showed that MLC-2 isoform expression can be used to enrich hiPSC-CM consistent with early atrial and ventricular myocyte lineages. However, only the ventricular myosin light chain-2 promoter was able to purify a highly homogeneous population of iPSC-CMs. Using this approach, it is now possible to develop ventricular-specific disease models using iPSC-CMs while atrial-specific iPSC-CM cultures may require additional chamber-specific markers. © 2013.

26 CFR 1.6050I-0 - Table of contents.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Table of contents. 1.6050I-0 Section 1.6050I-0...) INCOME TAXES Information Returns § 1.6050I-0 Table of contents. This section lists the major captions... transaction. (i) In general. (ii) Example. (e) Time, manner, and form of reporting. (1) Time of reporting. (2...

The tumbling rotational state of 1I/`Oumuamua

Science.gov (United States)

Fraser, Wesley C.; Pravec, Petr; Fitzsimmons, Alan; Lacerda, Pedro; Bannister, Michele T.; Snodgrass, Colin; Smolić, Igor

2018-05-01

The discovery1 of 1I/2017 U1 (1I/`Oumuamua) has provided the first glimpse of a planetesimal born in another planetary system. This interloper exhibits a variable colour within a range that is broadly consistent with local small bodies, such as the P- and D-type asteroids, Jupiter Trojans and dynamically excited Kuiper belt objects2-7. 1I/`Oumuamua appears unusually elongated in shape, with an axial ratio exceeding 5:1 (refs 1,4,5,8). Rotation period estimates are inconsistent and varied, with reported values between 6.9 and 8.3 h (refs 4-6,9). Here, we analyse all the available optical photometry data reported to date. No single rotation period can explain the exhibited brightness variations. Rather, 1I/`Oumuamua appears to be in an excited rotational state undergoing non-principal axis rotation, or tumbling. A satisfactory solution has apparent lightcurve frequencies of 0.135 and 0.126 h-1 and implies a longest-to-shortest axis ratio of ≳5:1, although the available data are insufficient to uniquely constrain the true frequencies and shape. Assuming a body that responds to non-principal axis rotation in a similar manner to Solar System asteroids and comets, the timescale to damp 1I/`Oumuamua's tumbling is at least one billion years. 1I/`Oumuamua was probably set tumbling within its parent planetary system and will remain tumbling well after it has left ours.

Evaluation and metabolite studies of {sup 125}I- and {sup 123}I-labelled E-(R,R)-IQNP: potential radioligands for visualization of M{sub 1} muscarinic acetylcholine receptors in brain

Energy Technology Data Exchange (ETDEWEB)

Bergstroem, Kim A.; Halldin, Christer; Hiltunen, Jukka; Swahn, Carl-Gunnar; Ito, Hiroshi; Ginovart, Nathalie; Hall, Haakan; McPherson, Daniel W.; Knapp, F. F. (Russ); Larsson, Stig; Schnell, Per-Olof; Farde, Lars

1998-04-01

A new ligand for the M{sub 1} muscarinic receptor subtype, E-(R,R)-1-azabicyclo[2.2.2]oct-3-yl {alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (E-IQNP), was labelled with {sup 125}I and {sup 123}I for autoradiographic studies on human whole-brain cryosections and SPET studies, respectively, in Cynomolgus monkey. Autoradiography demonstrated E-[{sup 125}I]IQNP binding in M{sub 1} receptor-rich regions such as the neocortex and the striatum. The binding was displaceable by the selective M{sub 1} antagonist biperiden. In vivo single photon emission tomography (SPET) studies with E-[{sup 123}I]IQNP demonstrated a high accumulation of radioactivity in the monkey neocortex. Rapid hydrolysis of the quinuclidinyl ester to the free acid was found to be a major biotransformation route for E-[{sup 123}I]IQNP. The free acid of E-[{sup 123}I]IQNP does not pass the blood-brain barrier, but the plasma concentration was high as compared to the total radioactivity in brain. It is thus necessary to correct for the high concentration of radioactive metabolites in parenchymal blood (CBV) to obtain accurate values for E-[{sup 123}I]IQNP binding in brain.

Pharmacological analysis of the cardiac sympatho-inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats.

Science.gov (United States)

Cobos-Puc, Luis E; Sánchez-López, Araceli; Centurión, David

2016-11-15

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3μg/kgmin); (2) partially inhibited by B-HT 933 (30μg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100μg/kgmin), moxonidine (10μg/kgmin) or agmatine (1000 and 3000μg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000μg/kgmin agmatine. In SHR, 300μg/kg rauwolscine failed to block the sympatho-inhibition to 100μg/kgmin B-HT 933 or 10μg/kgmin moxonidine, but 1000μg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000μg/kg AGN 192403 or 300μg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α 2 -adrenoceptors and to a lesser extent by I 1 -imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α 2 -adrenoceptors and I 1 -imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α 2 -adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats. Copyright © 2016 Elsevier B.V. All rights reserved.

The SPECT tracer [{sup 123}I]ADAM binds selectively to serotonin transporters: a double-blind, placebo-controlled study in healthy young men

Energy Technology Data Exchange (ETDEWEB)

Giessen, Elsmarieke van de [University of Amsterdam, Academic Medical Center, Graduate School Neurosciences Amsterdam, Department of Nuclear Medicine, Amsterdam (Netherlands); Booij, Jan [University of Amsterdam, Academic Medical Center, Graduate School Neurosciences Amsterdam, Department of Nuclear Medicine, Amsterdam (Netherlands); University of Amsterdam, Academic Medical Center, Department of Nuclear Medicine, F2-236, Amsterdam (Netherlands)

2010-08-15

The tracer {sup 123}I-2-([2-({l_brace}dimethylamino{r_brace}methyl)phenyl]thio)-5-iodophenylamine ([{sup 123}I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [{sup 123}I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [{sup 123}I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [{sup 123}I]ADAM binds selectively to SERTs. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [{sup 123}I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate. Our preliminary findings suggest that [{sup 123}I]ADAM binds selectively to SERTs in human brain. (orig.)

A Cognitive Model of Document Use during a Research Project. Study I. Document Selection.

Science.gov (United States)

Wang, Peiling; Soergel, Dagobert

1998-01-01

Proposes a model of document selection by real users of a bibliographic retrieval system. Reports on Part I of a longitudinal study of decision making on document use by academics (25 faculty and graduate students in Agricultural Economics). Examines what components are relevant to the users' decisions and what cognitive process may have occurred…

Conformational stability analyses of alpha subunit I domain of LFA-1 and Mac-1.

Directory of Open Access Journals (Sweden)

Debin Mao

Full Text Available β₂ integrin of lymphocyte function-associated antigen-1 (LFA-1 or macrophage-1 antigen (Mac-1 binds to their common ligand of intercellular adhesion molecule-1 (ICAM-1 and mediates leukocyte-endothelial cell (EC adhesions in inflammation cascade. Although the two integrins are known to have distinct functions, the corresponding micro-structural bases remain unclear. Here (steered-molecular dynamics simulations were employed to elucidate the conformational stability of α subunit I domains of LFA-1 and Mac-1 in different affinity states and relevant I domain-ICAM-1 interaction features. Compared with low affinity (LA Mac-1, the LA LFA-1 I domain was unstable in the presence or absence of ICAM-1 ligand, stemming from diverse orientations of its α₇-helix with different motifs of zipper-like hydrophobic junction between α₁- and α₇-helices. Meanwhile, spontaneous transition of LFA-1 I domain from LA state to intermediate affinity (IA state was first visualized. All the LA, IA, and high affinity (HA states of LFA-1 I domain and HA Mac-1 I domain were able to bind to ICAM-1 ligand effectively, while LA Mac-1 I domain was unfavorable for binding ligand presumably due to the specific orientation of S144 side-chain that capped the MIDAS ion. These results furthered our understanding in correlating the structural bases with their functions of LFA-1 and Mac-1 integrins from the viewpoint of I domain conformational stability and of the characteristics of I domain-ICAM-1 interactions.

Photoaffinity cross-linking of a radioiodinated probe, 125I-A55453, into alpha 1-adrenergic receptors

International Nuclear Information System (INIS)

Dickinson, K.E.; Leeb-Lundberg, L.M.; Heald, S.L.; Wikberg, J.E.; DeBernardis, J.F.; Caron, M.G.; Lefkowitz, R.J.

1984-01-01

We have synthesized and characterized a high-affinity alpha 1-adrenergic receptor probe, 4-amino-6,7-dimethoxy-2[4'- [5''(3'''- 125 I-iodo-4'''-aminophenyl)pentanoyl]-1'-piperazinyl] quinazoline ( 125 I-A55453). This ligand binds reversibly to rat hepatic plasma membranes with high affinity (KD . 77 +/- 6 pM), and it labels the same number of specific prazosin-competable sites as the alpha 1-adrenergic receptor-selective radioligand [ 125 I] iodo-2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone. Specific binding is stereoselective and competed for by alpha-adrenergic agents with an alpha 1-adrenergic receptor specificity. 125 I-A55453 can be covalently photoincorporated into peptides of rat hepatic and splenic membranes using the bifunctional photoactive cross-linker, N-succinimidyl-6- (4'-azido-2'-nitrophenylamino)hexanoate. Following photolysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of labeled hepatic membranes reveals a major specifically labeled peptide of Mr . 82,000 (+/- 1,000) with minor peptides at Mr . 50,000 (+/- 500), and 40,000 (+/- 300). Covalent incorporation of 125 I-A55453 into the Mr . 82,000 peptide is inhibited by adrenergic drugs with an alpha 1-adrenergic receptor specificity. Labeled splenic membranes demonstrate a broad band of photoincorporated radioactivity centered at Mr . 82,000, and covalent incorporation into this peptide is also attenuated with an alpha 1-adrenergic receptor specificity. This new high-affinity radioiodinated probe has features which should make it useful for the molecular characterization of alpha 1-adrenergic receptors in tissues

Correlations fo Sc, rare earths and other elements in selected rock samples from Arrua-i

Energy Technology Data Exchange (ETDEWEB)

Facetti, J F; Prats, M [Asuncion Nacional Univ. (Paraguay). Inst. de Ciencias

1972-01-01

The Sc and Eu contents in selected rocks samples from the stock of Arrua-i have been determined and correlations established with other elements and with the relative amount of some rare earths. These correlations suggest metasomatic phenomena for the formation of the rock samples.

Correlations fo Sc, rare earths and other elements in selected rock samples from Arrua-i

International Nuclear Information System (INIS)

Facetti, J.F.; Prats, M.

1972-01-01

The Sc and Eu contents in selected rocks samples from the stock of Arrua-i have been determined and correlations established with other elements and with the relative amount of some rare earths. These correlations suggest metasomatic phenomena for the formation of the rock samples

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

Science.gov (United States)

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

2017-02-17

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

Blocking S1P interaction with S1P1 receptor by a novel competitive S1P1-selective antagonist inhibits angiogenesis

International Nuclear Information System (INIS)

Fujii, Yasuyuki; Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi; Igarashi, Yasuyuki; Goitsuka, Ryo

2012-01-01

Highlights: ► The effect of a newly developed S1P 1 -selective antagonist on angiogenic responses. ► S1P 1 is a critical component of VEGF-related angiogenic responses. ► S1P 1 -selective antagonist showed in vitro activity to inhibit angiogenesis. ► S1P 1 -selective antagonist showed in vivo activity to inhibit angiogenesis. ► The efficacy of S1P 1 -selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P 1 ) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P 1 and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P 1 -selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P 1 antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P 1 is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

Identification and characterization of alpha 1 adrenergic receptors in the canine prostate using [125I]-Heat

International Nuclear Information System (INIS)

Lepor, H.; Baumann, M.; Shapiro, E.

1987-01-01

We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [ 125 I]-Heat, a selective and high affinity ligand with high specific activity (2200 Ci/mmole) has been used to characterize alpha 1 adrenergic receptors in the brain. In this study alpha 1 adrenergic receptors in the dog prostate were characterized using [ 125 I]-Heat. The Scatchard plots were linear indicating homogeneity of [ 125 I]-Heat binding sites. The mean alpha 1 adrenergic receptor density determined from these Scatchard plots was 0.61 +/- 0.07 fmol/mg. wet wt. +/- S.E.M. The binding of [ 125 I]-Heat to canine prostate alpha 1 adrenergic binding sites was of high affinity (Kd = 86 +/- 19 pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [ 125 I]-Heat for alpha 1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [ 125 I]-Heat binding at a single ligand concentration. [ 125 I]-Heat is an ideal ligand for studying alpha 1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha 1 adrenergic receptors in the prostate

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

Science.gov (United States)

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

2017-10-19

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

A pyrazolyl-based thiolato single-source precursor for the selective synthesis of isotropic copper-deficient copper(I) sulfide nanocrystals: synthesis, optical and photocatalytic activity

Energy Technology Data Exchange (ETDEWEB)

Mondal, Gopinath; Santra, Ananyakumari; Bera, Pradip; Acharjya, Moumita [Vidyasagar University, Post Graduate Department of Chemistry, Panskura Banamali College (India); Jana, Sumanta [Indian Institute of Engineering Science and Technology (IIEST), Department of Chemistry (India); Chattopadhyay, Dipankar [University of Calcutta, Department of Polymer Science and Technology (India); Mondal, Anup [Indian Institute of Engineering Science and Technology (IIEST), Department of Chemistry (India); Seok, Sang Il [Korea Research Institute of Chemical Technology, KRICT-EPFL Global Research Laboratory, Division of Advanced Materials (Korea, Republic of); Bera, Pulakesh, E-mail: pbera.pbc.chem@gmail.com [Vidyasagar University, Post Graduate Department of Chemistry, Panskura Banamali College (India)

2016-10-15

Hexagonal copper-deficient copper(I) sulfide (Cu{sub 2-x}S, x = 0.03, 0.2) nanocrystals (NCs) are synthesized from a newly prepared single-source precursor (SP), [Cu(bdpa){sub 2}][CuCl{sub 2}], where bdpa is benzyl 3,5-dimethyl-pyrazole-1-carbodithioate. The SP is crystallized with space group Pī and possesses a distorted tetrahedron structure with a CuN{sub 2}S{sub 2} chromophore where the central copper is in +1 oxidation state. Distortion in copper(I) structure and the low decomposition temperature of SP make it favorable for the low-temperature solvent-assisted selective growth of high-copper content sulfides. The nucleation and growth of Cu{sub 2-x}S (x = 0.03, 0.2) are effectively controlled by the SP and the solvent in the solvothermal decomposition process. During decomposition, fragment benzyl thiol (PhCH{sub 2}SH) from SP effectively passivates the nucleus leading to spherical nanocrystals. Further, solvent plays an important role in the selective thermochemical transformation of Cu{sup I}-complex to Cu{sub 2-x}S (x = 0.03, 0.2) NCs. The chelating binders (solvent) like ethylene diamine (EN) and ethylene glycol (EG) prefer to form spherical Cu{sub 1.97}S nanoparticles (djurleite), whereas nonchelating hydrazine hydrate (HH) shows the tendency to furnish hexagonal platelets of copper-deficient Cu{sub 1.8}S. The optical band gap values (2.25–2.50 eV) show quantum confinement effect in the structure. The synthesized NCs display excellent catalytic activity (~87 %) toward photodegradation of organic dyes like Congo Red (CR) and Methylene Blue (MB).Graphical abstractA pyrazolyl-based thiolato single-source precursor for the selective synthesis of isotropic copper-deficient copper(I) sulfide nanocrystals: Synthesis, optical and photocatalytic activity.Gopinath Mondal, Ananyakumari Santra, Pradip Bera, Moumita Acharjya, Sumanta Jana, Dipankar Chattopadhyay, Anup Mondal, Sang Il Seok, Pulakesh Bera.

Population genetic structure and natural selection of Plasmodium falciparum apical membrane antigen-1 in Myanmar isolates.

Science.gov (United States)

Kang, Jung-Mi; Lee, Jinyoung; Moe, Mya; Jun, Hojong; Lê, Hương Giang; Kim, Tae Im; Thái, Thị Lam; Sohn, Woon-Mok; Myint, Moe Kyaw; Lin, Khin; Shin, Ho-Joon; Kim, Tong-Soo; Na, Byoung-Kuk

2018-02-07

Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is one of leading blood stage malaria vaccine candidates. However, genetic variation and antigenic diversity identified in global PfAMA-1 are major hurdles in the development of an effective vaccine based on this antigen. In this study, genetic structure and the effect of natural selection of PfAMA-1 among Myanmar P. falciparum isolates were analysed. Blood samples were collected from 58 Myanmar patients with falciparum malaria. Full-length PfAMA-1 gene was amplified by polymerase chain reaction and cloned into a TA cloning vector. PfAMA-1 sequence of each isolate was sequenced. Polymorphic characteristics and effect of natural selection were analysed with using DNASTAR, MEGA4, and DnaSP programs. Polymorphic nature and natural selection in 459 global PfAMA-1 were also analysed. Thirty-seven different haplotypes of PfAMA-1 were identified in 58 Myanmar P. falciparum isolates. Most amino acid changes identified in Myanmar PfAMA-1 were found in domains I and III. Overall patterns of amino acid changes in Myanmar PfAMA-1 were similar to those in global PfAMA-1. However, frequencies of amino acid changes differed by country. Novel amino acid changes in Myanmar PfAMA-1 were also identified. Evidences for natural selection and recombination event were observed in global PfAMA-1. Among 51 commonly identified amino acid changes in global PfAMA-1 sequences, 43 were found in predicted RBC-binding sites, B-cell epitopes, or IUR regions. Myanmar PfAMA-1 showed similar patterns of nucleotide diversity and amino acid polymorphisms compared to those of global PfAMA-1. Balancing natural selection and intragenic recombination across PfAMA-1 are likely to play major roles in generating genetic diversity in global PfAMA-1. Most common amino acid changes in global PfAMA-1 were located in predicted B-cell epitopes where high levels of nucleotide diversity and balancing natural selection were found. These results highlight the

Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

International Nuclear Information System (INIS)

Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.; Areso, P.; Hauptmann, M.; Frazer, A.

1991-01-01

This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125 I-iodopindolol ( 125 I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125 I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125 I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125 I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125 I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125 I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus

Measurements of isothermal (vapor + liquid) phase equilibrium for {trifluoroiodomethane (R13I1) + 1,1-difluoroethane (R152a)} from T = (258.150 to 283.150) K

International Nuclear Information System (INIS)

Gong, Maoqiong; Cheng, Kuiwei; Dong, Xueqiang; Guo, Hao; Zhao, Yanxing; Wu, Jianfeng

2015-01-01

Highlights: • VLE data for (R13I1 + R152a) system were measured at four temperatures. • Experiments were based on the vapor-recirculation method. • VLE data were correlated using PR−VdWs and PR−HV−NRTL models. • Azeotropic behavior can be found. - Abstract: In this paper, isothermal (vapor + liquid) equilibrium (VLE) values for {trifluoroiodomethane (R13I1) + 1,1-difluoroethane (R152a)} at T = (258.150 to 283.150) K are presented. The experimental apparatus was based on a vapor-recirculation method. The VLE measurements were regressed by the Peng–Robinson equation of state with two models, the Van der Waals mixing rules and the Huron–Vidal mixing rules using the NRTL activity coefficient model. The newly measured VLE values satisfied the thermodynamic consistency test. The results have led to that the two models selected are both suitable for the description of the binary system. Azeotropic behavior can be found for the system measured

21 CFR 73.3112 - C.I. Vat Orange 1.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false C.I. Vat Orange 1. 73.3112 Section 73.3112 Food... COLOR ADDITIVES EXEMPT FROM CERTIFICATION Medical Devices § 73.3112 C.I. Vat Orange 1. (a) Identity. The color additive is C.I. Vat Orange 1, Colour Index No. 59105. (b) Uses and restrictions. (1) The...

40 CFR 1048.410 - How must I select, prepare, and test my in-use engines?

Science.gov (United States)

2010-07-01

... my in-use engines? 1048.410 Section 1048.410 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS CONTROL OF EMISSIONS FROM NEW, LARGE NONROAD SPARK-IGNITION ENGINES Testing In-use Engines § 1048.410 How must I select, prepare, and test my in-use engines? (a) You...

Structural characterization of chemical warfare agent degradation products in decontamination solutions with proton band-selective (1)H-(31)P NMR spectroscopy.

Science.gov (United States)

Koskela, Harri; Hakala, Ullastiina; Vanninen, Paula

2010-06-15

Decontamination solutions, which are usually composed of strong alkaline chemicals, are used for efficient detoxification of chemical warfare agents (CWAs). The analysis of CWA degradation products directly in decontamination solutions is challenging due to the nature of the matrix. Furthermore, occasionally an unforeseen degradation pathway can result in degradation products which could be eluded to in standard analyses. Here, we present the results of the application of proton band-selective (1)H-(31)P NMR spectroscopy, i.e., band-selective 1D (1)H-(31)P heteronuclear single quantum coherence (HSQC) and band-selective 2D (1)H-(31)P HSQC-total correlation spectroscopy (TOCSY), for ester side chain characterization of organophosphorus nerve agent degradation products in decontamination solutions. The viability of the approach is demonstrated with a test mixture of typical degradation products of nerve agents sarin, soman, and VX. The proton band-selective (1)H-(31)P NMR spectroscopy is also applied in characterization of unusual degradation products of VX in GDS 2000 solution.

A Novel Ion - selective Polymeric Membrane Sensor for Determining Thallium(I) With High Selectivity

International Nuclear Information System (INIS)

Kassim, Anuar; Rezayi, Majid; Ahmadzadeh, Saeid; Yusof, Noor Azah; Tee, Tan Wee; Abdullah, Abd Halim; Rounaghi, Gholamhossein; Mohajeri, Masoomeh; Heng, Lee Yook

2011-01-01

Thallium is a toxic metal that introduced into the environment mainly as a waste from the production of zinc, cadmium, and lead and by combustion of coal. Thallium causes gastrointestinal irritation and nerve damage when people are exposed to it for relatively short period of time. For long term, thallium has the potential to cause the following effects: change in blood chemistry, damage to liver, kidney, intestinal and testicular tissue, and hair loss. In this work a membrane was prepared by use of 4'-nitrobenzo -18-crown-6 (4'NB18C6) as an ion carrier, polyvinylchloride (PVC) as a matrix, and diocthylphetalate (DOP) as a plasticizer for making an ion selective electrode for measurement of Tl + cation in solutions. The amount of 4'-nitrobenzo-18C6 and polyvinylchloride were optimized in the preparation of the membrane. The response of the electrode was Nernstian within the concentration range 1.0 x 10 -8 to 1.0 x 10 -1 M. This sensor displays a drift in Nernstian response for this cation with increasing the amount of ionophore and decreasing the amount of polyvinylchloride.The results of potentiometric measurements showed that, this electrode also responses to Cu 2+ Ni 2+ and Pb 2+ cations, but the electrode has a wider dynamic range and a lower detection limit to Tl + cation. The effects of various parameters such as pH, different cations interferences, effect of the amount of ionophore and polyvinylchloride and time on response of the coated ion selective electrode were investigated. Finally the constructed electrode was used in complexometric and precipitation titrations of Tl + cation with EDTA and KBr, respectively. The response of the fabricated electrode at concentration range from 1.0 x 10 -8 to 1.0 x 10 -1 M is linear with a Nernstian slope of 57.27 mV.

A Novel Ion - selective Polymeric Membrane Sensor for Determining Thallium(I) With High Selectivity

Science.gov (United States)

Kassim, Anuar; Rezayi, Majid; Ahmadzadeh, Saeid; Rounaghi, Gholamhossein; Mohajeri, Masoomeh; Azah Yusof, Noor; Tee, Tan Wee; Yook Heng, Lee; Halim Abdullah, Abd

2011-02-01

Thallium is a toxic metal that introduced into the environment mainly as a waste from the production of zinc, cadmium, and lead and by combustion of coal. Thallium causes gastrointestinal irritation and nerve damage when people are exposed to it for relatively short period of time. For long term, thallium has the potential to cause the following effects: change in blood chemistry, damage to liver, kidney, intestinal and testicular tissue, and hair loss. In this work a membrane was prepared by use of 4'-nitrobenzo -18-crown-6 (4'NB18C6) as an ion carrier, polyvinylchloride (PVC) as a matrix, and diocthylphetalate (DOP) as a plasticizer for making an ion selective electrode for measurement of Tl+ cation in solutions. The amount of 4'-nitrobenzo-18C6 and polyvinylchloride were optimized in the preparation of the membrane. The response of the electrode was Nernstian within the concentration range 1.0 × 10-8 to 1.0 × 10-1M. This sensor displays a drift in Nernstian response for this cation with increasing the amount of ionophore and decreasing the amount of polyvinylchloride.The results of potentiometric measurements showed that, this electrode also responses to Cu2+ Ni2+ and Pb2+ cations, but the electrode has a wider dynamic range and a lower detection limit to Tl+ cation. The effects of various parameters such as pH, different cations interferences, effect of the amount of ionophore and polyvinylchloride and time on response of the coated ion selective electrode were investigated. Finally the constructed electrode was used in complexometric and precipitation titrations of Tl+ cation with EDTA and KBr, respectively. The response of the fabricated electrode at concentration range from 1.0 × 10-8 to 1.0 × 10-1M is linear with a Nernstian slope of 57.27 mV.

Population genetic structure and natural selection of apical membrane antigen-1 in Plasmodium vivax Korean isolates.

Science.gov (United States)

Kang, Jung-Mi; Lee, Jinyoung; Cho, Pyo-Yun; Moon, Sung-Ung; Ju, Hye-Lim; Ahn, Seong Kyu; Sohn, Woon-Mok; Lee, Hyeong-Woo; Kim, Tong-Soo; Na, Byoung-Kuk

2015-11-16

Plasmodium vivax apical membrane antigen-1 (PvAMA-1) is a leading candidate antigen for blood stage malaria vaccine. However, antigenic variation is a major obstacle in the development of an effective vaccine based on this antigen. In this study, the genetic structure and the effect of natural selection of PvAMA-1 among Korean P. vivax isolates were analysed. Blood samples were collected from 66 Korean patients with vivax malaria. The entire PvAMA-1 gene was amplified by polymerase chain reaction and cloned into a TA cloning vector. The PvAMA-1 sequence of each isolate was sequenced and the polymorphic characteristics and effect of natural selection were analysed using the DNASTAR, MEGA4, and DnaSP programs. Thirty haplotypes of PvAMA-1, which were further classified into seven different clusters, were identified in the 66 Korean P. vivax isolates. Domain II was highly conserved among the sequences, but substantial nucleotide diversity was observed in domains I and III. The difference between the rates of non-synonymous and synonymous mutations suggested that the gene has evolved under natural selection. No strong evidence indicating balancing or positive selection on PvAMA-1 was identified. Recombination may also play a role in the resulting genetic diversity of PvAMA-1. This study is the first comprehensive analysis of nucleotide diversity across the entire PvAMA-1 gene using a single population sample from Korea. Korean PvAMA-1 had limited genetic diversity compared to PvAMA-1 in global isolates. The overall pattern of genetic polymorphism of Korean PvAMA-1 differed from other global isolates and novel amino acid changes were also identified in Korean PvAMA-1. Evidences for natural selection and recombination event were observed, which is likely to play an important role in generating genetic diversity across the PvAMA-1. These results provide useful information for the understanding the population structure of P. vivax circulating in Korea and have important

Forchlorfenuron disrupts SEPT9_i1 filaments and inhibits HIF-1.

Directory of Open Access Journals (Sweden)

Dikla Vardi-Oknin

Full Text Available Forchlorfenuron (FCF is a synthetic plant cytokinin that has been shown to alter yeast and mammalian septin organization. Septins are a highly conserved family of GTP-binding cytoskeletal proteins. Mammalian septins are involved in diverse cellular processes including tumorigenesis. We have been studying the interaction between septin 9 isoform 1 (SEPT9_i1 and hypoxia inducible factor-1α (HIF-1α, the oxygen regulated subunit of HIF-1. HIF-1 is a key transcription factor in the hypoxic responses pathway, and its activation has been observed in carcinogenesis and numerous cancers. SEPT9_i1/HIF-1α interaction plays an important role in upregulation of HIF-1 transcriptional activity by preventing HIF-1α's ubiquitination and degradation leading to increased tumor growth and angiogenesis. We tested the hypothesis whether FCF affects SEPT9_i1 filamentous structures and consequently HIF-1 pathway in cancer cells. We showed that FCF suppresses tumorigenic properties, including proliferation, migration and transformation, in prostate cancer cells. FCF did not alter SEPT9_i1 steady state protein expression levels but it affected its filamentous structures and subcellular localization. FCF induced degradation of HIF-1α protein in a dose- and time-dependent manner. This inhibition was also shown in other common cancer types tested. Rapid degradation of HIF-1α protein levels was accompanied by respective inhibition in HIF-1α transcriptional activity. Moreover, HIF-1α protein half-life was markedly decreased in the presence of FCF compared with that in the absence of FCF. The FCF-induced degradation of HIF-1α was mediated in a significant part via the proteasome. To the best of our knowledge, this is the first demonstration of specific manipulation of septin filaments by pharmacological means having downstream inhibitory effects on the HIF-1 pathway.

1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D4 Receptor.

Science.gov (United States)

Del Bello, Fabio; Bonifazi, Alessandro; Giorgioni, Gianfabio; Cifani, Carlo; Micioni Di Bonaventura, Maria Vittoria; Petrelli, Riccardo; Piergentili, Alessandro; Fontana, Stefano; Mammoli, Valerio; Yano, Hideaki; Matucci, Rosanna; Vistoli, Giulio; Quaglia, Wilma

2018-04-26

In the present article, the M 1 mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D 4 R selectivity over D 2 R and D 3 R and to behave as a D 4 R antagonist. To better understand the structural features required for the selective interaction with the D 4 R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D 4 R affinity and selectivity not only over the other D 2 -like subtypes, but also over M 1 -M 5 mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating G i protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D 4 R in disorders in which this subtype is involved.

Online dynamical downscaling of temperature and precipitation within the iLOVECLIM model (version 1.1)

Science.gov (United States)

Quiquet, Aurélien; Roche, Didier M.; Dumas, Christophe; Paillard, Didier

2018-02-01

This paper presents the inclusion of an online dynamical downscaling of temperature and precipitation within the model of intermediate complexity iLOVECLIM v1.1. We describe the following methodology to generate temperature and precipitation fields on a 40 km × 40 km Cartesian grid of the Northern Hemisphere from the T21 native atmospheric model grid. Our scheme is not grid specific and conserves energy and moisture in the same way as the original climate model. We show that we are able to generate a high-resolution field which presents a spatial variability in better agreement with the observations compared to the standard model. Although the large-scale model biases are not corrected, for selected model parameters, the downscaling can induce a better overall performance compared to the standard version on both the high-resolution grid and on the native grid. Foreseen applications of this new model feature include the improvement of ice sheet model coupling and high-resolution land surface models.

Geodesy and Mapping (Selected Articles),

Science.gov (United States)

1979-08-16

August 1979 MICROFICHE NR. C-0/O GEODESY AND MAPPING (SELECTED ARTICLES) English pages: 53 Source: Geodezja i Kartograflia, Vol. 27, Nr. 2, 1978, pp. 83...Hausbrandt S., Wyrdwnanie sieci trygonemetryernych z odrzuceniem zalolenia bezbIfdneil pwo- ktdw dowiqzania, Geodezja i Kartografia. T III, z. 1, 1954. [2

HERITABILITY AND RESPONSE TO SELECTION FOR GROWTH IN THE F1 GENERATION OF CRAYFISH Procambarus acanthophorus

Directory of Open Access Journals (Sweden)

Carlos Perez Rostro

2012-11-01

Full Text Available The crayfish Procambarus (A. acanthophorus is a crustacean relevant for regional fisheries in Veracruz, Mexico, with ideal aquaculture characteristics, except for its small size. Thus, a study was conducted with the aim to evaluate the response to selection in the first generation (F1 and heritability (h2 of the crayfish. A group of 2135 organisms with average weight (±S.D. 4.1 ± 1.79 g were captured from the wild (G0, and 10 % (i = 1,755 of the population was selected with the highest body weight by gender: 140 females (5.62 ± 1.97 g and 48 males (6.02 ± 1.9 g, forming the progenitors of the selection line (LS. The control line (LC was formed from a batch obtained at random. Thirty full-sib families were obtained per line (F1, and cultured individually for five months in a recirculation system with mechanical and biological filtration under laboratory conditions and supplied with food twice a day (Camaronina 35 % protein. Monthly heritability (h2 in broad sense was estimated using a full-sib design, based on the components of variance (ANOVA REML method and the growth was compared between lines in the F1. The mean h2's for weight after five months of culture were 0.27±0.11 for LC and 0.34±0.12 for LS, being the LS in F1 9.6 % heavier than the LC, with 84 and 88 % survival at the end of the study. It is possible to implement a breeding program based on selection for species growth.

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

Science.gov (United States)

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

2015-04-09

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

Vienna Fortran - A Language Specification. Version 1.1

Science.gov (United States)

1992-03-01

these include critical sections, events and locks. New instructions for node I/O are provided. In addition, there are a number of intrinsic functions to...form SELECT DCASE (Al,..,,Ar) capl,..., capm END SELECT where * r > 1 and all Ai, 1 < i < r, are array names. The Ai are called selectors. At the time of

Induction of galectin-1 expression by HTLV-I Tax and its impact on HTLV-I infectivity

Directory of Open Access Journals (Sweden)

Sato Sachiko

2008-11-01

Full Text Available Abstract Background Cell-free Human T-cell Leukemia Virus type I (HTLV-I virions are poorly infectious and cell-to-cell contact is often required to achieve infection. Other factors might thus importantly contribute in increasing infection by HTLV-I. Galectin-1 is a galactoside-binding lectin which is secreted by activated T lymphocytes. Several functions have been attributed to this protein including its capacity to increase cell-to-cell adhesion. Based on previous studies, we postulated that this protein could also accentuate HTLV-I infection. Results Herein, we demonstrate that galectin-1 expression and release are higher in HTLV-I-infected T cells in comparison to uninfected T cells. Furthermore, galectin-1 expression was activated in various cell lines expressing the wild type viral Tax protein while this induction was minimal upon expression of NF-κB activation-defective TaxM22. Cotransfection of these Tax expression vectors with galectin-1 promoter-driven luciferase constructs confirmed that Tax upregulated galectin-1 promoter activity. However, a NF-κB-independent mechanism was strongly favoured in this induction of galectin-1 expression as no activation of the promoter was apparent in Jurkat cells treated with known NF-κB activators. Using HTLV-I envelope pseudotyped HIV-1 virions, galectin-1 was shown to increase infectivity. In addition, a co-culture assay with HTLV-I-infected cells also indicated an increase in cell fusion upon addition of galectin-1. This effect was not mediated by factors present in the supernatant of the HTLV-I-infected cells. Conclusion These data suggest that HTLV-I Tax increases galectin-1 expression and that this modulation could play an important role in HTLV-I infection by stabilizing both cell-to-cell and virus-cell interactions.

Type I and type II interferons upregulate functional type I interleukin-1 receptor in a human fibroblast cell line TIG-1.

Science.gov (United States)

Takii, T; Niki, N; Yang, D; Kimura, H; Ito, A; Hayashi, H; Onozaki, K

1995-12-01

The regulation of type I interleukin-1 receptor (IL-1R) expression by type I, interferon (IFN)-alpha A/D, and type II IFN, IFN-gamma, in a human fibroblast cell line TIG-1 was investigated. After 2 h stimulation with human IFN-alpha A/D or IFN-gamma, the levels of type I IL-1R mRNA increased. We previously reported that IL-1 upregulates transcription and cell surface molecules of type I IL-1R in TIG-1 cells through induction of prostaglandin (PG) E2 and cAMP accumulation. However, indomethacin was unable to inhibit the effect of IFNs, indicating that IFNs augment IL-1R expression through a pathway distinct from that of IL-1. The augmentation was also observed in other fibroblast cell lines. Nuclear run-on assays and studies of the stability of mRNA suggested that the increase in IL-1R mRNA was a result of the enhanced transcription of IL-1R gene. Binding studies using 125I-IL-1 alpha revealed that the number of cell surface IL-1R increased with no change in binding affinity by treatment with these IFNs. Pretreatment of the cells with IFNs enhanced IL-1-induced IL-6 production, indicating that IFNs upregulate functional IL-1R. IL-1 and IFNs are produced by the same cell types, as well as by the adjacent different cell types, and are concomitantly present in lesions of immune and inflammatory reactions. These results therefore suggest that IFNs exhibit synergistic effects with IL-1 through upregulation of IL-1R. Augmented production of IL-6 may also contribute to the reactions.

Harmane: an atypical neurotransmitter?

Science.gov (United States)

Abu Ghazaleh, Haya; Lalies, Maggie D; Nutt, David J; Hudson, Alan L

2015-03-17

Harmane is an active component of clonidine displacing substance and a candidate endogenous ligand for imidazoline binding sites. The neurochemistry of tritiated harmane was investigated in the present study examining its uptake and release properties in the rat brain central nervous system (CNS) in vitro. At physiological temperature, [(3)H]harmane was shown to be taken up in rat brain cortex. Further investigations demonstrated that treatment with monoamine uptake blockers (citalopram, nomifensine and nisoxetine) did not alter [(3)H]harmane uptake implicating that the route of [(3)H]harmane transport was distinct from the monoamine uptake systems. Furthermore, imidazoline ligands (rilmenidine, efaroxan, 2-BFI and idazoxan) showed no prominent effect on [(3)H]harmane uptake suggesting the lack of involvement of imidazoline binding sites. Subsequent analyses showed that disruption of the Na(+) gradient using ouabain or choline chloride did not block [(3)H]harmane uptake suggesting a Na(+)-independent transport mechanism. Moreover, higher temperatures (50°C) failed to impede [(3)H]harmane uptake implying a non-physiological transporter. The failure of potassium to evoke the release of preloaded [(3)H]harmane from rat brain cortex indicates that the properties of this putative endogenous ligand for imidazoline binding sites do not resemble that of a conventional neurotransmitter. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

CYP2E1 Rsa I/Pst I polymorphism contributes to oral cancer susceptibility: a meta-analysis.

Science.gov (United States)

Niu, Yuming; Hu, Yuanyuan; Wu, Mingyue; Jiang, Fei; Shen, Ming; Tang, Chunbo; Chen, Ning

2012-01-01

Previous data on association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk were controversial. To investigate the association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk. We performed a meta-analysis to assess the relationship between oral cancer and genotype with English language until June 2010. Twelve published case-control studies of 1259 patients with oral cancer and 2262 controls were acquired. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association in codominant and dominant models. Overall, the pooled ORs indicated a significant association between CYP2E1 Rsa I/Pst I polymorphism and oral cancer risk (for c1/c2 vs. c1/c1: OR=1.30, 95% CI=1.04-1.62, Pheterogeneity=0.57; for (c1/c2+c2/c2) vs. c1/c1: OR=1.32, 95% CI=1.07-1.64, Pheterogeneity=0.57, respectively). In subgroup analysis by race, the same significant risks were found among Asian (for c1/c2 vs. c1/c1: OR=1.41, 95% CI=1.05-1.91, Pheterogeneity=0.92; for (c1/c2+c2/c2) vs. c1/c1: OR=1.43, 95% CI=1.08-1.88, Pheterogeneity=0.97, respectively). In conclusion, this meta-analysis demonstrates that CYP2E1 Rsa I/Pst I c2 allele may be a biomarker for oral cancer, especially among Asian populations.

Reasons for the deviation of I1/I3 and τ1 from the expected lifetime parameters of positronium annihilation in polymers

International Nuclear Information System (INIS)

Dlubek, G.; Eichler, S.; Huebner, Ch.; Nagel, Ch.

1999-01-01

High quality positron lifetime spectra were taken for several amorphous polymers. The spectra were analysed using the routine MELT which assumes continuous lifetime distributions, as well as the discrete-term analysis routine LIFSPECFIT. Disagreements between the analysed lifetime parameters and theoretical expectations, I 1 /I 3 > I p-Ps /I o-Ps =1/3 and τ 1 >τ p-Ps , which are well known, also appear in our results. The disagreements are distinctly larger using a discrete-term routine than when applying MELT (or CONTIN). From the analysis of computer-generated spectra, we found that these disagreements may be well understood by assuming a distribution of e + lifetimes in addition to an o-Ps lifetime distribution, both of which can occur as consequence of size and shape distributions of free-volume holes in amorphous polymers (or of bubbles in molecular liquids). The disagreements appear to be due to the inability of the routines correctly to mirror very broad lifetime distributions. For broad distributions, MELT (and also CONTIN) delivers, as an artefact of the spectrum analysis, a distribution consisting of two narrow subpeaks instead of a single broad one. The lower subpeak of the e + lifetime distribution may mix with the p-Ps lifetime component resulting in artificially large values for τ 1 and I 1 . That is the reason for the unphysical increase of τ 1 and I 1 with decreasing I 3 observed in the analysed parameters of simulated as well as experimental spectra

Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I.

Directory of Open Access Journals (Sweden)

Marc U Baumann

Full Text Available Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

Wild Carrot Differentiation in Europe and Selection at DcAOX1 Gene?

Directory of Open Access Journals (Sweden)

Tânia Nobre

Full Text Available By definition, the domestication process leads to an overall reduction of crop genetic diversity. This lead to the current search of genomic regions in wild crop relatives (CWR, an important task for modern carrot breeding. Nowadays massive sequencing possibilities can allow for discovery of novel genetic resources in wild populations, but this quest could be aided by the use of a surrogate gene (to first identify and prioritize novel wild populations for increased sequencing effort. Alternative oxidase (AOX gene family seems to be linked to all kinds of abiotic and biotic stress reactions in various organisms and thus have the potential to be used in the identification of CWR hotspots of environment-adapted diversity. High variability of DcAOX1 was found in populations of wild carrot sampled across a West-European environmental gradient. Even though no direct relation was found with the analyzed climatic conditions or with physical distance, population differentiation exists and results mainly from the polymorphisms associated with DcAOX1 exon 1 and intron 1. The relatively high number of amino acid changes and the identification of several unusually variable positions (through a likelihood ratio test, suggests that DcAOX1 gene might be under positive selection. However, if positive selection is considered, it only acts on some specific populations (i.e. is in the form of adaptive differences in different population locations given the observed high genetic diversity. We were able to identify two populations with higher levels of differentiation which are promising as hot spots of specific functional diversity.

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

Crystal structures of four green fluorescent protein (GFP) chromophore analogues with different packing interactions could be tuned by appropriate substitutions around the imidazolin-5-one ring are reported here. Compound 1 was crystallized from tetrahydrofuran at room temperature while compounds 2-4 have been ...

Balancing selection and recombination as evolutionary forces caused population genetic variations in golden pheasant MHC class I genes.

Science.gov (United States)

Zeng, Qian-Qian; He, Ke; Sun, Dan-Dan; Ma, Mei-Ying; Ge, Yun-Fa; Fang, Sheng-Guo; Wan, Qiu-Hong

2016-02-18

The major histocompatibility complex (MHC) genes are vital partners in the acquired immune processes of vertebrates. MHC diversity may be directly associated with population resistance to infectious pathogens. Here, we screened for polymorphisms in exons 2 and 3 of the IA1 and IA2 genes in 12 golden pheasant populations across the Chinese mainland to characterize their genetic variation levels, to understand the effects of historical positive selection and recombination in shaping class I diversity, and to investigate the genetic structure of wild golden pheasant populations. Among 339 individual pheasants, we identified 14 IA1 alleles in exon 2 (IA1-E2), 11 IA1-E3 alleles, 27 IA2-E2 alleles, and 28 IA2-E3 alleles. The non-synonymous substitution rate was significantly greater than the synonymous substitution rate at sequences in the IA2 gene encoding putative peptide-binding sites but not in the IA1 gene; we also found more positively selected sites in IA2 than in IA1. Frequent recombination events resulted in at least 9 recombinant IA2 alleles, in accordance with the intermingling pattern of the phylogenetic tree. Although some IA alleles are widely shared among studied populations, large variation occurs in the number of IA alleles across these populations. Allele frequency analysis across 2 IA loci showed low levels of genetic differentiation among populations on small geographic scales; however, significant genetic differentiation was observed between pheasants from the northern and southern regions of the Yangtze River. Both STRUCTURE analysis and F-statistic (F ST ) value comparison classified those populations into 2 major groups: the northern region of the Yangtze River (NYR) and the southern region of the Yangtze River (SYR). More extensive polymorphisms in IA2 than IA1 indicate that IA2 has undergone much stronger positive-selection pressure during evolution. Moreover, the recombination events detected between the genes and the intermingled phylogenetic

Selective electronalysis of peracetic acid in the presence of a large excess of H{sub 2}O{sub 2} at Au(1 1 1)-like gold electrode

Energy Technology Data Exchange (ETDEWEB)

Awad, M.I., E-mail: mawad70@yahoo.com [Department of Chemistry, Faculty of Science, Cairo University (Egypt)

2012-06-12

Highlights: Black-Right-Pointing-Pointer Analysis of peracetic acid in the presence of a large excess of H{sub 2}O{sub 2} is introduced. Black-Right-Pointing-Pointer Au(1 1 1)-like gold electrode serves as an ideal for this purpose. Black-Right-Pointing-Pointer The analysis is characterized by high selectivity and sensitivity. - Abstract: Peracetic acid (PAA) has been selectively electroanalyzed in the presence of a large excess of hydrogen peroxide (H{sub 2}O{sub 2}), about 500 fold that of PAA, using Au (1 1 1)-like gold electrode in acetate buffer solutions of pH 5.4. Au(1 1 1)-like gold electrode was prepared by a controlled reductive desorption of a previously assembled thiol, typically cysteine, monolayer onto the polycrystalline gold (poly-Au) electrode. Cysteine molecules were selectively removed from the Au(1 1 1) facets of the poly-Au electrode, keeping the other two facets (i.e., Au(1 1 0) and Au(1 0 0)) under the protection of the adsorbed cysteine. It has been found that Au(1 1 1)-like gold electrode positively shifts the reduction peak of PAA, while, fortunately, shifts the reduction peak of H{sub 2}O{sub 2} negatively, achieving a large potential separation (around 750 mV) between the two reduction peaks as compared with that (around 450 mV) obtained at the poly-Au electrode. This large potential separation between the two reduction peaks enabled the analysis of PAA in the presence of a large excess of H{sub 2}O{sub 2}. In addition, the positive shift of the reduction peak of PAA gives the present method a high immunity against the interference of the dissolved oxygen.

THE zCOSMOS-SINFONI PROJECT. I. SAMPLE SELECTION AND NATURAL-SEEING OBSERVATIONS

Energy Technology Data Exchange (ETDEWEB)

Mancini, C.; Renzini, A. [INAF-OAPD, Osservatorio Astronomico di Padova, Vicolo Osservatorio 5, I-35122 Padova (Italy); Foerster Schreiber, N. M.; Hicks, E. K. S.; Genzel, R.; Tacconi, L.; Davies, R. [Max-Planck-Institut fuer Extraterrestrische Physik, Giessenbachstrasse, D-85748 Garching (Germany); Cresci, G. [Osservatorio Astrofisico di Arcetri (OAF), INAF-Firenze, Largo E. Fermi 5, I-50125 Firenze (Italy); Peng, Y.; Lilly, S.; Carollo, M.; Oesch, P. [Institute of Astronomy, Department of Physics, Eidgenossische Technische Hochschule, ETH Zurich CH-8093 (Switzerland); Vergani, D.; Pozzetti, L.; Zamorani, G. [INAF-Bologna, Via Ranzani, I-40127 Bologna (Italy); Daddi, E. [CEA-Saclay, DSM/DAPNIA/Service d' Astrophysique, F-91191 Gif-Sur Yvette Cedex (France); Maraston, C. [Institute of Cosmology and Gravitation, University of Portsmouth, Dennis Sciama Building, Burnaby Road, PO1 3HE Portsmouth (United Kingdom); McCracken, H. J. [IAP, 98bis bd Arago, F-75014 Paris (France); Bouche, N. [Department of Physics, University of California, Santa Barbara, CA 93106 (United States); Shapiro, K. [Aerospace Research Laboratories, Northrop Grumman Aerospace Systems, Redondo Beach, CA 90278 (United States); and others

2011-12-10

The zCOSMOS-SINFONI project is aimed at studying the physical and kinematical properties of a sample of massive z {approx} 1.4-2.5 star-forming galaxies, through SINFONI near-infrared integral field spectroscopy (IFS), combined with the multiwavelength information from the zCOSMOS (COSMOS) survey. The project is based on one hour of natural-seeing observations per target, and adaptive optics (AO) follow-up for a major part of the sample, which includes 30 galaxies selected from the zCOSMOS/VIMOS spectroscopic survey. This first paper presents the sample selection, and the global physical characterization of the target galaxies from multicolor photometry, i.e., star formation rate (SFR), stellar mass, age, etc. The H{alpha} integrated properties, such as, flux, velocity dispersion, and size, are derived from the natural-seeing observations, while the follow-up AO observations will be presented in the next paper of this series. Our sample appears to be well representative of star-forming galaxies at z {approx} 2, covering a wide range in mass and SFR. The H{alpha} integrated properties of the 25 H{alpha} detected galaxies are similar to those of other IFS samples at the same redshifts. Good agreement is found among the SFRs derived from H{alpha} luminosity and other diagnostic methods, provided the extinction affecting the H{alpha} luminosity is about twice that affecting the continuum. A preliminary kinematic analysis, based on the maximum observed velocity difference across the source and on the integrated velocity dispersion, indicates that the sample splits nearly 50-50 into rotation-dominated and velocity-dispersion-dominated galaxies, in good agreement with previous surveys.

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

Science.gov (United States)

Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

2017-12-15

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

Introduction of the human proα1(I) collagen gene into proα1(I)-deficient Mov-13 mouse cells leads to formation of functional mouse-human hybrid type I collagen

International Nuclear Information System (INIS)

Schnieke, A.; Dziadek, M.; Bateman, J.; Mascara, T.; Harbers, K.; Gelinas, R.; Jaenisch, R.

1987-01-01

The Mov-13 mouse strain carries a retroviral insertion in the proα1(I) collagen gene that prevents transcription of the gene. Cell lines derived from homozygous embryos do not express type I collagen although normal amounts of proα2 mRNA are synthesized. The authors have introduced genomic clones of either the human or mouse proα1(I) collagen gene into homozygous cell lines to assess whether the human or mouse proα1(I) chains can associate with the endogenous mouse proα2(I) chain to form stable type I collagen. The human gene under control of the simian virus 40 promoter was efficiently transcribed in the transfected cells. Protein analyses revealed that stable heterotrimers consisting of two human α1 chains and one mouse α2 chain were formed and that type I collagen was secreted by the transfected cells at normal rates. However, the electrophoretic migration of both α1(I) and α2(I) chains in the human-mouse hybrid molecules were retarded, compared to the α(I) chains in control mouse cells. Inhibition of the posttranslational hydroxylation of lysine and proline resulted in comigration of human and mouse α1 and α2 chains, suggesting that increased posttranslational modification caused the altered electrophoretic migration in the human-mouse hybrid molecules. Amino acid sequence differences between the mouse and human α chains may interfere with the normal rate of helix formation and increase the degree of posttranslational modifications similar to those observed in patients with lethal perinatal osteogenesis imperfecta. The Mov-13 mouse system should allow the authors to study the effect specific mutations introduced in transfected proα1(I) genes have on the synthesis, assembly, and function of collagen I

Model for how type I restriction enzymes select cleavage sites in DNA

International Nuclear Information System (INIS)

Studier, F.W.; Bandyopadhyay, P.K.

1988-01-01

Under appropriate conditions, digestion of phage T7 DNA by the type I restriction enzyme EcoK produces an orderly progression of discrete DNA fragments. All details of the fragmentation pattern can be explained on the basis of the known properties of type I enzymes, together with two further assumptions: (i) in the ATP-stimulated translocation reaction, the enzyme bound at the recognition sequence translocates DNA toward itself from both directions simultaneously; and (ii) when translocation causes neighboring enzymes to meet, they cut the DNA between them. The kinetics of digestion at 37 degree C indicates that the rate of translocation of DNA from each side of a bound enzyme is about 200 base pairs per second, and the cuts are completed within 15-25 sec of the time neighboring enzymes meet. The resulting DNA fragments each contain a single recognition site with an enzyme (or subunit) remaining bound to it. At high enzyme concentrations, such fragments can bu further degraded, apparently by cooperation between the specifically bound and excess enzymes. This model is consistent with a substantial body of previous work on the nuclease activity of EcoB and EcoK, and it explains in a simple way how cleavage sites are selected

The iSelect 9 K SNP analysis revealed polyploidization induced revolutionary changes and intense human selection causing strong haplotype blocks in wheat.

Science.gov (United States)

Hao, Chenyang; Wang, Yuquan; Chao, Shiaoman; Li, Tian; Liu, Hongxia; Wang, Lanfen; Zhang, Xueyong

2017-01-30

A Chinese wheat mini core collection was genotyped using the wheat 9 K iSelect SNP array. Total 2420 and 2396 polymorphic SNPs were detected on the A and the B genome chromosomes, which formed 878 haplotype blocks. There were more blocks in the B genome, but the average block size was significantly (P polyploidization of wheat (both tetraploidization and hexaploidization) induced revolutionary changes in both the A and the B genomes, with a greater increase of gene diversity compared to their diploid ancestors. Modern breeding has dramatically increased diversity in the gene coding regions, though obvious blocks were formed on most of the chromosomes in both tetraploid and hexaploid wheats. Tag-SNP markers identified in this study can be used for marker assisted selection using haplotype blocks as a wheat breeding strategy. This strategy can also be employed to facilitate genome selection in other self-pollinating crop species.

Reasons for the deviation of I1/I3 and τ1 from the expected lifetime parameters of positronium annihilation in polymers

International Nuclear Information System (INIS)

Dlubek, G.; Eichler, S.; Huebner, C.; Nagel, C.

1999-01-01

High quality positron lifetime spectra were taken for several amorphous polymers. The spectra were analysed using the routine MELT which assumes continuous lifetime distributions, as well as the discrete-term analysis routine LIFSPECFIT. Disagreements between the analysed lifetime parameters and theoretical expectations, I 1 /I 3 I p-Ps /I o-Ps =3D1/3 and τ 1 τ p-Ps , which are well known, also appear in our results. The disagreements are distinctly larger using a discrete-term routine than when applying MELT (or CONTIN). From the analysis of computer-generated spectra, we found that these disagreements may be well understood by assuming a distribution of e + lifetimes in addition to an o-Ps lifetime distribution, both of which can occur as consequence of size and shape distributions of free-volume holes in amorphous polymers (or of bubbles in molecular liquids). The disagreements appear to be due to the inability of the routines correctly to mirror very broad lifetime distributions. For broad distributions, MELT (and also CONTIN) delivers, as an artefact of the spectrum analysis, a distribution consisting of two narrow subpeaks instead of a single broad one. The lower subpeak of the e + lifetime distribution may mix with the p-Ps lifetime component resulting in artificially large values for τ 1 and I 1 . That is the reason for the unphysical increase of τ 1 and I 1 with decreasing I 3 observed in the analysed parameters of simulated as well as experimental spectra. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

A Novel Ion - selective Polymeric Membrane Sensor for Determining Thallium(I) With High Selectivity

Energy Technology Data Exchange (ETDEWEB)

Kassim, Anuar; Rezayi, Majid; Ahmadzadeh, Saeid; Yusof, Noor Azah; Tee, Tan Wee; Abdullah, Abd Halim [Department of Chemistry Faculty of Science, Universiti Putra Malaysia 43400 Serdang, Selangor (Malaysia); Rounaghi, Gholamhossein; Mohajeri, Masoomeh [Department of Chemistry, Factuality of Sciences, Islamic Azad University of Mashhad, Mashhad (Iran, Islamic Republic of); Heng, Lee Yook, E-mail: anuar@science.upm.edu.my [School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor D.E. (Malaysia)

2011-02-15

Thallium is a toxic metal that introduced into the environment mainly as a waste from the production of zinc, cadmium, and lead and by combustion of coal. Thallium causes gastrointestinal irritation and nerve damage when people are exposed to it for relatively short period of time. For long term, thallium has the potential to cause the following effects: change in blood chemistry, damage to liver, kidney, intestinal and testicular tissue, and hair loss. In this work a membrane was prepared by use of 4'-nitrobenzo -18-crown-6 (4'NB18C6) as an ion carrier, polyvinylchloride (PVC) as a matrix, and diocthylphetalate (DOP) as a plasticizer for making an ion selective electrode for measurement of Tl{sup +} cation in solutions. The amount of 4'-nitrobenzo-18C6 and polyvinylchloride were optimized in the preparation of the membrane. The response of the electrode was Nernstian within the concentration range 1.0 x 10{sup -8} to 1.0 x 10{sup -1}M. This sensor displays a drift in Nernstian response for this cation with increasing the amount of ionophore and decreasing the amount of polyvinylchloride.The results of potentiometric measurements showed that, this electrode also responses to Cu{sup 2+} Ni{sup 2+} and Pb{sup 2+} cations, but the electrode has a wider dynamic range and a lower detection limit to Tl{sup +} cation. The effects of various parameters such as pH, different cations interferences, effect of the amount of ionophore and polyvinylchloride and time on response of the coated ion selective electrode were investigated. Finally the constructed electrode was used in complexometric and precipitation titrations of Tl{sup +} cation with EDTA and KBr, respectively. The response of the fabricated electrode at concentration range from 1.0 x 10{sup -8} to 1.0 x 10{sup -1}M is linear with a Nernstian slope of 57.27 mV.

Harmane and harmalan are bioactive components of classical clonidine-displacing substance.

Science.gov (United States)

Parker, Christine A; Anderson, Neil J; Robinson, Emma S J; Price, Rhiannon; Tyacke, Robin J; Husbands, Stephen M; Dillon, Michael P; Eglen, Richard M; Hudson, Alan L; Nutt, David J; Crump, Matthew P; Crosby, John

2004-12-28

Elucidation of the structure of the endogenous ligand(s) for imidazoline binding sites, clonidine-displacing substance (CDS), has been a major goal for many years. Crude CDS from bovine lung was purified by reverse-phase high-pressure liquid chromatography. Electrospray mass spectrometry (ESMS) and nuclear magnetic resonance ((1)H NMR) analysis revealed the presence of L-tryptophan and 1-carboxy-1-methyltetrahydro-beta-carboline in the active CDS extract. Competition radioligand binding studies, however, failed to show displacement of specific [(3)H]clonidine binding to rat brain membranes for either compound. Further purification of the bovine lung extract allowed the isolation of the beta-carbolines harmane and harmalan as confirmed by ESMS, (1)H NMR, and comparison with synthetic standards. Both compounds exhibited a high (nanomolar) affinity for both type 1 and type 2 imidazoline binding sites, and the synthetic standards were shown to coelute with the active classical CDS extracts. We therefore propose that the beta-carbolines harmane and harmalan represent active components of classical CDS. The identification of these compounds will allow us to establish clear physiological roles for CDS.

Desarrollo de un sistema de regeneración en Papa criolla (<i>Solanum phurejai> Juz <i>et> Buck var. Yema de huevo clon 1

Directory of Open Access Journals (Sweden)

Diazgranados Cristina

2007-06-01

Full Text Available

En el presente estudio se obtuvo un 46% de regeneración en explantes sin cocultivo de <i> i>Solanum phurejai> (Juzet <i>et> Buck variedad Yema de huevo clon 1 con la utilización del medio CIP-MS suplementado con reguladores de crecimiento (2 mg· L-1 ZR, 0,02 mg· L^-1 ANA, 0,02 mg· L^-1 AG₃. A fin de mejorar los porcentajes de regeneración se modificó la proporción citoquininas:auxinas del CIP-MS obteniéndose un 55% de formación de callo con concentraciones de 2 mg· L -1 ZR y 0,04 mg· L^-1 ANA. Posteriormente se evaluó el efecto de tres concentraciones de ácido giberélico (0,02 mg· L^-1 , 0,05 mg· L^-1 y 0,1 mg· L^-1 obteniéndose un 87,6% de callogénesis y un 48,6% de regeneración mediante la utilización de un medio que contenía 2 mg· L^-1 ZR, 0,04 mg· L^-1 ANA, 0,02 mg· L^-1 AG₃ en explantes bajo condiciones de cocultivo. Estos resultados fueron corroborados en un segundo ensayo de regeneración bajo condiciones de cocultivo con <i>Agrobacterium tumefaciensi> cepa LBA4404 transformada mediante el vector binario pNOV022, de lo cual se obtuvieron porcentajes de callogénesis y regeneración muy similares. Previamente se reportó un promedio de 4 ± 3,3 regenerantes por callo utilizando entrenudos de <i>S. phurejai> mientras en este estudio se obtuvieron 15,2 ± 3 regenerantes por callo.

Synthesis and evaluation of [125I]I-TSA as a brain nicotinic acetylcholine receptor α7 subtype imaging agent

International Nuclear Information System (INIS)

Ogawa, Mikako; Tatsumi, Ryo; Fujio, Masakazu; Katayama, Jiro; Magata, Yasuhiro

2006-01-01

Introduction: Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) α 7 subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3'-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3'] oxazolidin]-2'-one (Br-TSA), which has a high affinity and selectivity for α 7 nAChRs. Therefore we synthesized (R)-3'-(5-[ 125 I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'- [1',3']oxazolidin]-2'-one ([ 125 I]I-TSA) and evaluated its potential for the in vivo detection of α 7 nAChR in brain. Methods: In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [ 125 I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 μl, i.c.v.) or nonradioactive I-TSA (50 μmol/kg, i.v.). Results: I-TSA exhibited a high affinity and selectivity for the α 7 nAChR (K i for α 7 nAChR=0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus (α 7 nAChR-rich region) and was rather rapid in the cerebellum (α 7 nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus. Conclusion: Despite its high affinity and selectivity, [ 125 I]I-TSA does not appear to be a suitable tracer for in vivo α 7 nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed

Ocean thermal energy conversion power system development-I. Phase I. Preliminary design report. Volume 1. Final report

Energy Technology Data Exchange (ETDEWEB)

1978-12-18

The results of a conceptual and preliminary design study of Ocean Thermal Energy Conversion (OTEC) closed loop ammonia power system modules performed by Lockheed Missiles and Space Company, Inc. (LMSC) are presented. This design study is the second of 3 tasks in Phase I of the Power System Development-I Project. The Task 2 objectives were to develop: 1) conceptual designs for a 40 to 50-MW(e) closed cycle ammonia commercial plant size power module whose heat exchangers are immersed in seawater and whose ancillary equipments are in a shirt sleeve environment; preliminary designs for a modular application power system sized at 10-MW(e) whose design, construction and material selection is analogous to the 50 MW(e) module, except that titanium tubes are to be used in the heat exchangers; and 3) preliminary designs for heat exchanger test articles (evaporator and condenser) representative of the 50-MW(e) heat exchangers using aluminum alloy, suitable for seawater service, for testing on OTEC-1. The reference ocean platform was specified by DOE as a surface vessel with the heat exchanger immersed in seawater to a design depth of 0 to 20 ft measured from the top of the heat exchanger. For the 50-MW(e) module, the OTEC 400-MW(e) Plant Ship, defined in the Platform Configuration and Integration study, was used as the reference platform. System design, performance, and cost are presented. (WHK)

Electrochemical evaluation of under-deposit corrosion and its inhibition using the wire beam electrode method

Energy Technology Data Exchange (ETDEWEB)

Tan Yongjun, E-mail: yj.tan@curtin.edu.a [Western Australian Corrosion Research Group, Department of Chemistry, Curtin University, GPO Box U1987, Perth (Australia); Fwu, Young; Bhardwaj, Kriti [Western Australian Corrosion Research Group, Department of Chemistry, Curtin University, GPO Box U1987, Perth (Australia)

2011-04-15

Research highlights: A new experiment method for evaluating under-deposit corrosion and its inhibitors. Under-deposit corrosion did not occur in a CO{sub 2} saturated pure brine solution. Inhibitor imidazoline addition and O{sub 2} contamination initiated under-deposit corrosion. Inhibitor imidazoline reduced general corrosion but enhanced localised corrosion. - Abstract: A new experimental method has been applied to evaluate under-deposit corrosion and its inhibition by means of an electrochemically integrated multi-electrode array, namely the wire beam electrode (WBE). Maps showing galvanic current and corrosion potential distributions were measured from a WBE surface that was partially covered by sand. Under-deposit corrosion did not occur during the exposure of the WBE to carbon dioxide saturated brine under ambient temperature. The introduction of corrosion inhibitor imidazoline and oxygen into the brine was found to significantly affect the patterns and rates of corrosion, leading to the initiation of under-deposit corrosion over the WBE.

Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

DEFF Research Database (Denmark)

Mehlsen, J; Trap-Jensen, J

1986-01-01

Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

48 CFR 536.602-1 - Selection criteria.

Science.gov (United States)

2010-10-01

... area of the project and knowledge of locality of the project” as one of several selection criteria. (1... services (based on the total contract price) will be accomplished within the geographical boundaries...

Plasminogen activator inhibitor-I-related regulation of procollagen I (α1 and α2) by antitransforming growth factor-β1 treatment during radiation-impaired wound healing

International Nuclear Information System (INIS)

Schultze-Mosgau, Stefan; Kopp, Juergen; Thorwarth, Michael; Roedel, Franz; Melnychenko, Ivan; Grabenbauer, Gerhard G.; Amann, Kerstin; Wehrhan, Falk

2006-01-01

Purpose: Plasminogen activator inhibitor (PAI)-1 mediates transforming growth factor-β 1 (TGF-β 1 )-related signaling by stimulating collagen Type I synthesis in radiation-impaired wound healing. The regulation of α(I)-procollagen is contradictory in fibroblasts of different fibrotic lesions. It is not known whether anti-TGF-β 1 treatment specifically inhibits α(I)-procollagen synthesis. We used an experimental wound healing study to address anti-TGF-β 1 -associated influence on α(I)-procollagen synthesis. Methods and Materials: A free flap was transplanted into the preirradiated (40 Gy) or nonirradiated neck region of Wistar rats: Group 1 (n = 8) surgery alone; Group 2 (n = 14) irradiation and surgery; Group 3 (n = 8) irradiation and surgery and anti-TGF-β 1 treatment. On the 14th postoperative day, skin samples were processed for fibroblast culture, in situ hybridization for TGF-β 1 , immunohistochemistry, and immunoblotting for PAI-1, α 1 /α 2 (I)-procollagen. Results: Anti-TGF-β 1 significantly reduced TGF-β 1 mRNA (p 1 treatment in vivo significantly reduced α 1 (I)-procollagen protein (p 2 (I)-procollagen expression. Conclusion: These results emphasize anti-TGF-β 1 treatment to reduce radiation-induced fibrosis by decreasing α 1 (I)-procollagen synthesis in vivo. α 1 (I)-procollagen and α 2 (I)-procollagen might be differentially regulated by anti-TGF-β 1 treatment. Increased TGF-β signaling in irradiated skin fibroblasts seemed to be reversible, as shown by a reduction in PAI-1 expression after anti-TGF-β 1 treatment

Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Fujii, Yasuyuki, E-mail: y.fujii@po.rd.taisho.co.jp [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)

2012-03-23

Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

Comparative proteomics analysis of proteins expressed in the I-1 and I-2 internodes of strawberry stolons

Directory of Open Access Journals (Sweden)

Lai Wenguo

2011-05-01

Full Text Available Abstract Background Strawberries (Fragaria ananassa reproduce asexually through stolons, which have strong tendencies to form adventitious roots at their second node. Understanding how the development of the proximal (I-1 and distal (I-2 internodes of stolons differ should facilitate nursery cultivation of strawberries. Results Herein, we compared the proteomic profiles of the strawberry stolon I-1 and I-2 internodes. Proteins extracted from the internodes were separated by two-dimensional gel electrophoresis, and 164 I-1 protein spots and 200 I-2 protein spots were examined further. Using mass spectrometry and database searches, 38 I-1 and 52 I-2 proteins were identified and categorized (8 and 10 groups, respectively according to their cellular compartmentalization and functionality. Many of the identified proteins are enzymes necessary for carbohydrate metabolism and photosynthesis. Furthermore, identification of proteins that interact revealed that many of the I-2 proteins form a dynamic network during development. Finally, given our results, we present a mechanistic scheme for adventitious root formation of new clonal plants at the second node. Conclusions Comparative proteomic analysis of I-1 and I-2 proteins revealed that the ubiquitin-proteasome pathway and sugar-hormone pathways might be important during adventitious root formation at the second node of new clonal plants.

[11C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain

International Nuclear Information System (INIS)

Halldin, Christer; Erixon-Lindroth, Nina; Pauli, Stefan; Chou, Yuan-Hwa; Okubo, Yoshiro; Karlsson, Per; Lundkvist, Camilla; Olsson, Hans; Farde, Lars; Guilloteau, Denis; Emond, Patrick

2003-01-01

The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compound as a radioligand for positron emission tomography (PET) examination of DAT in the human brain. The high affinity DAT compound N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (PE2I) was radiolabelled by the O-methylation approach and the binding was characterised by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography. O-methylation of the corresponding free acid precursor with [ 11 C]methyl triflate gave high radiochemical yield (80%) and specific radioactivity (55 GBq/μmol). [ 11 C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equilibrium, which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabelled β-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [ 11 C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, respectively, at peak equilibrium, which appeared at 40-50 min and 20 min, respectively, after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [ 11 C]PE2I was 15-20% at 40 min after injection. The present characterisation of binding in monkey and man suggests that [ 11 C]PE2I is a suitable PET radioligand for quantitative regional examination of DAT in man. (orig.)

Tema 1: Programmering af robotenheder i grundskolen

Directory of Open Access Journals (Sweden)

Stine Ejsing-Duun

2016-01-01

Full Text Available I denne artikel undersøger vi potentialerne for at lære matematik gennem programmering af robotter. Vi foreslår en model med tre indbyrdes afhængige læringspotentialer, som programmering fordrer. Det omfatter elevens evne til at; (1 tænke i algoritmer, (2 producere viden og artefakter gennem brug af matematik og (3 foretage abstraktion og indkapsling. Programmering er blevet en del af grundskolens læringsmål i flere lande. I Danmark er programmering et læringsmål i forenklede fælles mål for Fysik/Kemi og desuden en del af den nationale undervisningsvejledning for matematik. En analyse af potentialerne i at anvende programmering i forbindelse med disse fag er derfor væsentlig. I denne artikel fokuserer vi på samspillet mellem matematik og programmering gennem litteraturstudier og analyse af empiriske situationer fra undervisning i programmering af LEGO Mindstorms. Teoretisk anvendes den instrumentelle tilgang til teknologi i matematikundervisning. Analysen viser en række måder, hvorpå didaktisk opmærksomhed på epistemisk forhandling kan understøtte læring af matematik gennem programmering.

26 CFR 301.6323(i)-1 - Special rules.

Science.gov (United States)

2010-04-01

... organization to communicate information unless such communication is part of his regular duties or unless he... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Special rules. 301.6323(i)-1 Section 301.6323(i)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) PROCEDURE AND...

Fracture Mechanics Evaluation of B-1 Materials. Volume I. Text

Science.gov (United States)

1976-10-01

4V Microstructures 2-37 P.4-1 TIG Welding Setup 2-60 2.4-2 Macrographs Showing Transverse Cross- 2-61 Sections of Typical Weld Joints 2.4-3 Diffusion...concavity. k. PAW welding parameters were: Keyhole Mode (First Pass) 1fWelding-Amperage - 185 Pilot Arc Amperage - P5 1/5" Diameter Tungsten -P% Thoria...of tooling employed. 2. •𔃼󈧿 r a • 4 .fA A A ~ . - 4N. I 141Eb,~..0 1171 :41ýI t4, 1. r "I j, O~ vN;I ___4 A Ad2 Figuire 2.4-1i TIG Welding , Setup

Geodesy and Cartography (Selected Articles),

Science.gov (United States)

1979-08-10

C-OO/b73 GEODESY AND CARTOGRAPHY (SELECTED ARTICLES) English pages: 40 Source: GeodezJa i Kartografia, Vol. 27, Nr. 1, 1978, PP. 3-27 Country of...1976. 14) kledzixski, J., Zibek, Z., Czarnecki, K., Rogowski, J.B., Problems in Using Satellite Surveys in an Astronomical-Geodesic Network, Geodezja i...Based on Observations of Low-Low Satellites Using Collocation Methods, Geodezja i Kartografia, Vol. XXVI, No. 4, 1977. [-7. Krynski, J., Schwarz, K.P

Further analysis of the inhibition by agmatine on the cardiac sympathetic outflow: Role of the α2-adrenoceptor subtypes.

Science.gov (United States)

Cobos-Puc, Luis; Aguayo-Morales, Hilda; Ventura-Sobrevilla, Janeth; Luque-Contreras, Diana; Chin-Chan, Miguel

2017-06-15

This study has investigated the role of the α 2 -adrenoceptor subtypes involved in the inhibition of the cardiac sympathetic outflow induced by intravenous (i.v) infusions of agmatine. Therefore, we analysed the effect of an i.v. bolus injections of the selective antagonists BRL 44408 (300μg/kg; α 2A ), imiloxan (3000μg/kg; α 2B ), and JP-1302 (300μg/kg; α 2C ) given separately, and their combinations: BRL 44408 plus Imiloxan, JP 1302 plus imiloxan, BRL 44408 plus JP-1302, BRL 44408 plus imiloxan plus JP-1302 on the cardiac sympatho-inhibition of agmatine. Also, the effect of the combination BRL 44408 plus JP-1302 plus AGN 192403 (3000μg/kg; I 1 antagonist) was evaluated. In this way, i.v. infusions of 1000μg/kg min of agmatine, but not 300, inhibited the tachycardic response induced by electrical stimulation. Furthermore, the antagonists used or their combinations had no effect on the electrically-induced tachycardic response. On the other hand, the inhibitory response of agmatine was: (1) partially antagonized by BRL 44408 or JP-1302 given separately, a similar response was observed when we administered their combination with imiloxan, but not by imiloxan alone, (2) antagonized in greater magnitude by the combination BRL 44408 plus JP-1302 or the combination BRL 44408 plus imiloxan plus JP-1302, and (3) abolished by the combination BRL 44408 plus JP-1302 plus AGN 192403. Taken together, these results demonstrate that the α 2A - and α 2C -adrenoceptor subtypes and I 1 -imidazoline receptors are involved in the inhibition of the cardiac sympathetic outflow induced by agmatine. Copyright © 2017 Elsevier B.V. All rights reserved.

Transformation of bisdithiocarbamate fungicides and the chemical nature of their residues in plants

International Nuclear Information System (INIS)

Vonk, J.W.

1975-01-01

Studies on the fate of 1,2- 14 C-disodium ethylenebisdithiocarbamate (nabam) applied to roots and leaves of cucumber plants under laboratory conditions have revealed that ethylenethiourea (ETU) and dihydro-3 H-imidazodithiazole (DIDT) were major initial breakdown products. On applying nabam to roots, residues in the plants consisted mainly of ETU, which was rapidly metabolized to 2-imidazoline and ethyleneurea. Moreover, a considerable amount of unidentified, mostly polar material was found. After 19 days, 87% of the total radioactivity taken up could be recovered. Of this only 22% could be identified. Two weeks after applying nabam to leaves, about 89% of the applied activity could be recovered. ETU, DIDT, a small amount of 2-imidazoline, and unknown polar material were present in or on the treated leaf. Only 0.3% had moved into the untreated parts. (author)

Variable selection in near-infrared spectroscopy: Benchmarking of feature selection methods on biodiesel data

International Nuclear Information System (INIS)

Balabin, Roman M.; Smirnov, Sergey V.

2011-01-01

During the past several years, near-infrared (near-IR/NIR) spectroscopy has increasingly been adopted as an analytical tool in various fields from petroleum to biomedical sectors. The NIR spectrum (above 4000 cm -1 ) of a sample is typically measured by modern instruments at a few hundred of wavelengths. Recently, considerable effort has been directed towards developing procedures to identify variables (wavelengths) that contribute useful information. Variable selection (VS) or feature selection, also called frequency selection or wavelength selection, is a critical step in data analysis for vibrational spectroscopy (infrared, Raman, or NIRS). In this paper, we compare the performance of 16 different feature selection methods for the prediction of properties of biodiesel fuel, including density, viscosity, methanol content, and water concentration. The feature selection algorithms tested include stepwise multiple linear regression (MLR-step), interval partial least squares regression (iPLS), backward iPLS (BiPLS), forward iPLS (FiPLS), moving window partial least squares regression (MWPLS), (modified) changeable size moving window partial least squares (CSMWPLS/MCSMWPLSR), searching combination moving window partial least squares (SCMWPLS), successive projections algorithm (SPA), uninformative variable elimination (UVE, including UVE-SPA), simulated annealing (SA), back-propagation artificial neural networks (BP-ANN), Kohonen artificial neural network (K-ANN), and genetic algorithms (GAs, including GA-iPLS). Two linear techniques for calibration model building, namely multiple linear regression (MLR) and partial least squares regression/projection to latent structures (PLS/PLSR), are used for the evaluation of biofuel properties. A comparison with a non-linear calibration model, artificial neural networks (ANN-MLP), is also provided. Discussion of gasoline, ethanol-gasoline (bioethanol), and diesel fuel data is presented. The results of other spectroscopic

Online dynamical downscaling of temperature and precipitation within the iLOVECLIM model (version 1.1

Directory of Open Access Journals (Sweden)

A. Quiquet

2018-02-01

Full Text Available This paper presents the inclusion of an online dynamical downscaling of temperature and precipitation within the model of intermediate complexity iLOVECLIM v1.1. We describe the following methodology to generate temperature and precipitation fields on a 40 km  ×  40 km Cartesian grid of the Northern Hemisphere from the T21 native atmospheric model grid. Our scheme is not grid specific and conserves energy and moisture in the same way as the original climate model. We show that we are able to generate a high-resolution field which presents a spatial variability in better agreement with the observations compared to the standard model. Although the large-scale model biases are not corrected, for selected model parameters, the downscaling can induce a better overall performance compared to the standard version on both the high-resolution grid and on the native grid. Foreseen applications of this new model feature include the improvement of ice sheet model coupling and high-resolution land surface models.

Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

DEFF Research Database (Denmark)

Madsen, U; Bräuner-Osborne, H; Frydenvang, Karla Andrea

2001-01-01

Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (i......GluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown...... to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments...

Selectivity switch for nitrogen functionalization of styrene on Au(1 1 1)

Science.gov (United States)

Deng, Xingyi; Friend, Cynthia M.

2008-03-01

Functionalization of styrene to form N-containing hydrocarbons, e.g. 2-phenylaziridine, benzonitrile, and benzyl nitrile, is achieved by reaction with adsorbed NH a and N a on Au(1 1 1). Electron-induced decomposition of condensed NH 3 was used to produce NH a, N a and H a on Au(1 1 1) at 110 K. The selectivity of the reactions is strongly dependent on the relative concentrations of the surface species. The addition of NH to styrene results in the production of 2-phenylaziridine, whereas adsorbed N and H atoms lead to the formation of nitriles benzonitrile and benzyl nitrile and, respectively, ethylbenzene. This work clearly establishes the utility of Au for promoting functionalization of olefins with nitrogen.

B1 gradient coherence selection using a tapered stripline.

Science.gov (United States)

van Meerten, S G J; Tijssen, K C H; van Bentum, P J M; Kentgens, A P M

2018-01-01

Pulsed-field gradients are common in modern liquid state NMR pulse sequences. They are often used instead of phase cycles for the selection of coherence pathways, thereby decreasing the time required for the NMR experiment. Soft off-resonance pulses with a B 1 gradient result in a spatial encoding similar to that created by pulsed-field (B 0 ) gradients. In this manuscript we show that pulse sequences with pulsed-field gradients can easily be converted to one which uses off-resonance B 1 field gradient (OFFBEAT) pulses. The advantage of B 1 gradient pulses for coherence selection is that the chemical shift evolution during the pulses is (partially) suppressed. Therefore no refocusing echos are required to correct for evolution during the gradient pulses. A tapered stripline is shown to be a convenient tool for creating a well-defined gradient in the B 1 field strength. B 1 gradient coherence selection using a tapered stripline is a simple and cheap alternative to B 0 pulsed-field gradients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Modeling HIV-1 drug resistance as episodic directional selection.

Science.gov (United States)

Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L; Scheffler, Konrad

2012-01-01

The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

Modeling HIV-1 drug resistance as episodic directional selection.

Directory of Open Access Journals (Sweden)

Ben Murrell

Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

A recyclable Au(I) catalyst for selective homocoupling of arylboronic acids: significant enhancement of nano-surface binding for stability and catalytic activity.

Science.gov (United States)

Zhang, Xin; Zhao, Haitao; Wang, Jianhui

2010-08-01

Au nanoparticles stabilized by polystyrene-co-polymethacrylic acid microspheres (PS-co-PMAA) were prepared and characterized via X-ray diffraction (XRD), and transmission electron microscope (TEM). The Au nanoparticles supported on the microspheres showed highly selective catalytic activity for homo-coupling reactions of arylboronic acids in a system of aryl-halides and arylboronic acids. X-ray photoelectron spectroscopy (XPS) spectra of the catalyst shows large amounts of Au(I) complexes band to the surface of the Au nanoparticles, which contributes to the selective homocoupling of the arylboronic acids. More importantly, this supported Au complex is a highly recyclable catalyst. The supported Au catalyst can be recycled and reused at least 6 times for a phenylboronic acid reactant, whereas the parent complex shows very low catalytic activity for this compound. The high catalytic activity of this material is attributed to: (1) the high surface to volume ratio which leads to more active sites being exposed to reactants; (2) the strong surface binding of the Au nanoparticle to the Au(I) complexes, which enhances both the stability and the catalytic activity of these complexes.

Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

Energy Technology Data Exchange (ETDEWEB)

Medina, Jesus R.; Becker, Christopher J.; Blackledge, Charles W.; Duquenne, Celine; Feng, Yanhong; Grant, Seth W.; Heerding, Dirk; Li, William H.; Miller, William H.; Romeril, Stuart P.; Scherzer, Daryl; Shu, Arthur; Bobko, Mark A.; Chadderton, Antony R.; Dumble, Melissa; Gardiner, Christine M.; Gilbert, Seth; Liu, Qi; Rabindran, Sridhar K.; Sudakin, Valery; Xiang, Hong; Brady, Pat G.; Campobasso, Nino; Ward, Paris; Axten, Jeffrey M. (GSKPA)

2014-10-02

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

Three Cyanide-Bridged One-Dimensional Single Chain Co"I"I"I-Mn"I"I Complexes: Rational Design, Synthesis, Crystal Structures and Magnetic Properties

International Nuclear Information System (INIS)

Zhang, Daopeng; Zhao, Zengdian; Wang, Ping; Chen, Xia

2012-01-01

Two pyridinecarboxamide dicyanidecobalt(III) building blocks and two mononuclear seven-coordinated macrocycle manganese(II) compounds have been rationally selected to assemble cyanide-bridged heterobimetallic complexes, resulting in three cyanide-bridged Co"I"I"I-Mn"I"I complexes. Single X-ray diffraction analysis show that these complexes {[Mn(L"1)][Co(bpb)]}ClO_4·CH_3OH·0.5H_2O (1), {[Mn(L"2)][Co(bpb)]}ClO_4·0.5CH_3OH (2) and {[Mn(L"1)][Cobpmb]}ClO_4·H_2O (3) (L"1 = 3,6-diazaoctane-1,8-diamine, L"2 = 3,6-dioxaoctano-1,8- diamine: bpb"2"- = 1,2-bis(pyridine-2-carboxamido)benzenate, bpmb"2"- = 1,2-bis(pyridine-2-carboxamido)-4- methyl-benzenate) all present predictable one-dimensional single chain structures. The molecular structures of these one-dimensional complexes consists of alternating units of [Mn(L)]"2"+ (L = L"1 or L"2) and [Co(L')(CN)_2]"- (L' = bpb"2"-, or bpmb"2"-), forming a cyanide-bridged cationic polymeric chain with free ClO_4"- as the balance anion. The coordination geometry of manganese(II) ion in the three one-dimensional complexes is a slightly distorted pentagonal-bipyrimidal with two cyanide nitrogen atoms at the trans positions and N_5 or N_3O_2 coordinating mode at the equatorial plane from ligand L"1 or L"2. Investigation over magnetic properties of these complexes reveals that the very weak magnetic coupling between neighboring Mn(II) ions connected by the diamagnetic dicyanidecobalt(III) building block. A best-fit to the magnetic susceptibility of complex 1 leads to the magnetic coupling constants J = .0.084(3) cm"-"1

Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator Ponesimod.

Science.gov (United States)

Lott, Dominik; Lehr, Thorsten; Dingemanse, Jasper; Krause, Andreas

2017-09-15

Ponesimod is a selective sphingosine-1-phosphate-1 (S1P 1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative uptitration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod. A direct-effect I max model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from nine clinical studies enabled characterization of interindividual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses vs. gradual uptitration with respect to the occurrence of bradycardia. The results indicate a better safety profile when using gradual uptitration. The model allows studying dosing regimens not clinically tested in silico. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Arbejdspladsvurdering i små virksomheder med 1-4 ansatte

DEFF Research Database (Denmark)

Hasle, Peter; Esben, Dalskinn

En analyse af mulighederne for at gennemføre arbejdspladsvurdering i mikrovirksomheder med 1-4 ansatte.......En analyse af mulighederne for at gennemføre arbejdspladsvurdering i mikrovirksomheder med 1-4 ansatte....

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

Science.gov (United States)

Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M.; Daley, George Q.; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D.

2012-01-01

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma1 receptor ligand for positron emission tomography

International Nuclear Information System (INIS)

Kawamura, Kazunori; Tsukada, Hideo; Shiba, Kazuhiro; Tsuji, Chieko; Harada, Norihiro; Kimura, Yuichi; Ishiwata, Kiichi

2007-01-01

The [ 18 F]fluoromethyl analog of the sigma 1 selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([ 18 F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma 1 receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma 1 receptor ( K i for sigma 1 receptor, 6.4 nM; K i for sigma 2 receptor, 250 nM) that was compatible with the affinity of SA4503 ( K i for sigma 1 receptor, 4.4 nM; K i for sigma 2 receptor, 242 nM). [ 18 F]FM-SA4503 was synthesized by 18 F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9-16.6% at the end of bombardment with a specific activity of 37.8-283 TBq/mmol at the end of synthesis. In mice, the uptake of [ 18 F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [ 18 F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22-32% and 11-25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [ 18 F]FM-SA4503 showed specific binding to sigma 1 receptors in mice and monkeys; therefore, [ 18 F]FM-SA4503 has the potential for mapping sigma 1 receptors in the brain

Study of some properties of 's' neutron resonance parameters for target nuclei I = 1/2 and I = 3/2 in function of spin value J = I + 1/2 in the energy range 1 {yields} 5000 eV; Etude de quelques proprietes des parametres de resonances des neutrons ''s'' pour des noyaux cibles I = 1/2 et I = 3/2 en fonction de la valeur du spin J = I + 1/2 dans le domaine d'energie 1 eV {yields} 5000 eV

Energy Technology Data Exchange (ETDEWEB)

Julien, J [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires

1967-05-15

Different kinds of experiments and analysis methods allowing to achieve neutron resonances parameters in the low energy range (1 eV {yields} 5000 eV) are described. A great deal of effort to improve experimental conditions and data processing in order to know the spin value J = I {+-} 1/2 has been spent. The time of flight method was used. A few target nuclei I = 3/2 and 1 = 1/2 have been studied. For I = 3/2 (Ga, As, 3r, Au) we find S{sub o} J = 2 {approx_equal} 2 S{sub o} J = 1 and S{sub o} J = 1 {approx_equal} S{sub o} J = 0 for I = 1/2 (Tm, Pt) but {sup 77}Se. Fluctuations of the total radiative width {gamma}{sub {gamma}} depend on the spin value I = I {+-} 1/2 when E1 transition, are enhanced for one of the both spin states. The magnitude of these fluctuations can be explained of the strength of E1 transitions (E{sub {gamma}} {approx} 7 MeV) is supposed to be proportional to E{sup 5}{sub {gamma}} instead of E{sup 3}{sub {gamma}}. The distribution of levels spacings against spin value J are considered and are compared to theoretical predictions. (author) [French] On decrit les differentes methodes d'analyse permettant d'obtenir les parametres des resonances de neutron dans le domaine d'energie 1 eV {yields} 5000 eV. Un effort particulier a ete fait pour connaitre la valeur du spin J = I {+-} 1/2. Les types d'experience et les analyses des donnees, developpes et ameliores pour determiner J sont decrits. Les resultats obtenus ont permis l'etude de differentes proprietes en fonction du spin J. On trouve: S{sub o} J 2 {approx_equal} 2 S{sub o} J = 1 pour les noyaux I = 3/2 etudies (Ga, As, Br, Au) et S{sub o} J = 1 {approx_equal} S{sub o} J = 0 Pour le Tm et {sup 195}Pt de spin I = 1/2. On constate que les largeurs radiatives totales {gamma}{sub {gamma}} fluctuent si des transitions E1 aux premiers etats excites sont favorisees. Ces fluctuations peuvent etre expliquees si on suppose que les intensites de ces transitions sont proportionnelles a E{sup 5}{sub {gamma

[{sup 11}C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain

Energy Technology Data Exchange (ETDEWEB)

Halldin, Christer; Erixon-Lindroth, Nina; Pauli, Stefan; Chou, Yuan-Hwa; Okubo, Yoshiro; Karlsson, Per; Lundkvist, Camilla; Olsson, Hans; Farde, Lars [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, 17176, Stockholm (Sweden); Guilloteau, Denis; Emond, Patrick [INSERM U316 Universite Francois Rabelais, Tours (France)

2003-09-01

The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compound as a radioligand for positron emission tomography (PET) examination of DAT in the human brain. The high affinity DAT compound N-(3-iodoprop-2E-enyl)-2{beta}-carbomethoxy-3{beta}-(4-methylphenyl)nortropane (PE2I) was radiolabelled by the O-methylation approach and the binding was characterised by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography. O-methylation of the corresponding free acid precursor with [{sup 11}C]methyl triflate gave high radiochemical yield (80%) and specific radioactivity (55 GBq/{mu}mol). [{sup 11}C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equilibrium, which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabelled {beta}-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [{sup 11}C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, respectively, at peak equilibrium, which appeared at 40-50 min and 20 min, respectively, after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [{sup 11}C]PE2I was 15-20% at 40 min after injection. The present characterisation of binding in monkey and man suggests that [{sup 11}C]PE2I is a suitable PET radioligand for quantitative regional examination of DAT in man. (orig.)

Co-receptor choice by V alpha14i NKT cells is driven by Th-POK expression rather than avoidance of CD8-mediated negative selection.

Science.gov (United States)

Engel, Isaac; Hammond, Kirsten; Sullivan, Barbara A; He, Xi; Taniuchi, Ichiro; Kappes, Dietmar; Kronenberg, Mitchell

2010-05-10

Mouse natural killer T (NKT) cells with an invariant V alpha14-J alpha18 rearrangement (V alpha14 invariant [V alpha14i] NKT cells) are either CD4(+)CD8(-) or CD4(-)CD8(-). Because transgenic mice with forced CD8 expression in all T cells exhibited a profound NKT cell deficit, the absence of CD8 has been attributed to negative selection. We now present evidence that CD8 does not serve as a coreceptor for CD1d recognition and that the defect in development in CD8 transgene homozygous mice is the result of a reduction in secondary T cell receptor alpha rearrangements. Thymocytes from mice hemizygous for the CD8 transgene have a less severe rearrangement defect and have functional CD8(+) V alpha14i NKT cells. Furthermore, we demonstrate that the transcription factor Th, Poxviruses and Zinc finger, and Krüppel family (Th-POK) is expressed by V alpha14i NKT cells throughout their differentiation and is necessary both to silence CD8 expression and for the functional maturity of V alpha14i NKT cells. We therefore suggest that Th-POK expression is required for the normal development of V alpha14i NKT cells and that the absence of CD8 expression by these cells is a by-product of such expression, as opposed to the result of negative selection of CD8-expressing V alpha14i NKT cells.

Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

DEFF Research Database (Denmark)

Vatten, Lars J; Nilsen, Tom I L; Juul, Anders

2008-01-01

OBJECTIVE: To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia. METHODS: Nested case-control study within a cohort of 29 948 pregnant women. Cases were women, who later...... developed preeclampsia, and controls were randomly selected women, who did not develop preeclampsia. IGF-I and IGFBP-1 were measured with ELISA in maternal blood samples that were collected in the first and second trimesters. We assessed associations of IGF-I and IGFBP-1 concentrations with later...... development of preterm (before the 37th week of gestation) and term preeclampsia. RESULTS: An increase in IGF-I from the first to second trimester was associated with higher risk of preterm preeclampsia; the odds ratio (OR) for the highest compared with lowest quartile of increase was 4.9 (95% confidence...

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

OpenAIRE

Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nocicep...

[A Phase 1 study of beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP)].

Science.gov (United States)

Torizuka, K; Yonekura, Y; Nishimura, T; Tamaki, N; Uehara, T; Ikekubo, K; Hino, M

1991-07-01

Phase 1 study of beta-methyl-p-(123I)-iodophenylpentadecanoic acid (123I-BMIPP), a new radiopharmaceutical developed for the evaluation of myocardial fatty acid metabolism, was performed in six normal volunteers to evaluate its biodistribution and safety. After intravenous injection of 111 MBq of 123I-BMIPP, the agent accumulated to the myocardium rapidly (5.4 +/- 0.6% at 1.5 hr after injection) and was washed-out slowly (5.1 +/- 0.4% at 3.0hr). 123I-BMIPP demonstrated no significant accumulation to any specific organs other than myocardium, liver and muscle. Myocardium was clearly visualized in the planar and SPECT images obtained 30 min and 3 hrs after injection. The absorption doses from 123I-BMIPP estimated by MIRD method were lower than those from 201Tl in all organs. Neither adverse reactions nor abnormal clinical laboratory findings were found in the safety evaluation. These results suggest 123I-BMIPP is a promising agent for evaluating myocardial fatty acid metabolism.

Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series.

Science.gov (United States)

Rudolph, Joachim; Aliagas, Ignacio; Crawford, James J; Mathieu, Simon; Lee, Wendy; Chao, Qi; Dong, Ping; Rouge, Lionel; Wang, Weiru; Heise, Christopher; Murray, Lesley J; La, Hank; Liu, Yanzhou; Manning, Gerard; Diederich, François; Hoeflich, Klaus P

2015-06-11

To increase kinase selectivity in an aminopyrazole-based PAK1 inhibitor series, analogues were designed to interact with the PAK1 deep-front pocket pre-DFG residue Thr-406, a residue that is hydrophobic in most kinases. This goal was achieved by installing lactam head groups to the aminopyrazole hinge binding moiety. The corresponding analogues represent the most kinase selective ATP-competitive Group I PAK inhibitors described to date. Hydrogen bonding with the Thr-406 side chain was demonstrated by X-ray crystallography, and inhibitory activities, particularly against kinases with hydrophobic pre-DFG residues, were mitigated. Leveraging hydrogen bonding side chain interactions with polar pre-DFG residues is unprecedented, and similar strategies should be applicable to other appropriate kinases.

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

Science.gov (United States)

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

2015-05-01

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

The ATLAS3D project - I. A volume-limited sample of 260 nearby early-type galaxies: science goals and selection criteria

Science.gov (United States)

Cappellari, Michele; Emsellem, Eric; Krajnović, Davor; McDermid, Richard M.; Scott, Nicholas; Verdoes Kleijn, G. A.; Young, Lisa M.; Alatalo, Katherine; Bacon, R.; Blitz, Leo; Bois, Maxime; Bournaud, Frédéric; Bureau, M.; Davies, Roger L.; Davis, Timothy A.; de Zeeuw, P. T.; Duc, Pierre-Alain; Khochfar, Sadegh; Kuntschner, Harald; Lablanche, Pierre-Yves; Morganti, Raffaella; Naab, Thorsten; Oosterloo, Tom; Sarzi, Marc; Serra, Paolo; Weijmans, Anne-Marie

2011-05-01

The ATLAS3D project is a multiwavelength survey combined with a theoretical modelling effort. The observations span from the radio to the millimetre and optical, and provide multicolour imaging, two-dimensional kinematics of the atomic (H I), molecular (CO) and ionized gas (Hβ, [O III] and [N I]), together with the kinematics and population of the stars (Hβ, Fe5015 and Mg b), for a carefully selected, volume-limited (1.16 × 105 Mpc3) sample of 260 early-type (elliptical E and lenticular S0) galaxies (ETGs). The models include semi-analytic, N-body binary mergers and cosmological simulations of galaxy formation. Here we present the science goals for the project and introduce the galaxy sample and the selection criteria. The sample consists of nearby (D 15°) morphologically selected ETGs extracted from a parent sample of 871 galaxies (8 per cent E, 22 per cent S0 and 70 per cent spirals) brighter than MK statistically representative of the nearby galaxy population. We present the size-luminosity relation for the spirals and ETGs and show that the ETGs in the ATLAS3D sample define a tight red sequence in a colour-magnitude diagram, with few objects in the transition from the blue cloud. We describe the strategy of the SAURON integral field observations and the extraction of the stellar kinematics with the pPXF method. We find typical 1σ errors of ΔV≈ 6 km s-1, Δσ≈ 7 km s-1, Δh3≈Δh4≈ 0.03 in the mean velocity, the velocity dispersion and Gauss-Hermite (GH) moments for galaxies with effective dispersion σe≳ 120 km s-1. For galaxies with lower σe (≈40 per cent of the sample) the GH moments are gradually penalized by pPXF towards zero to suppress the noise produced by the spectral undersampling and only V and σ can be measured. We give an overview of the characteristics of the other main data sets already available for our sample and of the ongoing modelling projects.

Selective mGAT2 (BGT-1) GABA Uptake Inhibitor

DEFF Research Database (Denmark)

Vogensen, Stine Byskov; Jørgensen, Lars; Madsen, Karsten Kirkegaard

2013-01-01

β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1−4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compou...... 17b displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors....

Fitness Advantage of mcr-1–Bearing IncI2 and IncX4 Plasmids in Vitro

Directory of Open Access Journals (Sweden)

Renjie Wu

2018-02-01

Full Text Available The objective of this study was to assess the impact of diverse plasmids bearing colistin resistance gene mcr-1 on host fitness. Forty-seven commensal E. coli isolates recovered from the pig farm where mcr-1 was first identified were screened for mcr-1. mcr-1-bearing plasmids were characterized by sequencing. The fitness impact of mcr-1-bearing plasmids was evaluated by in vitro competition assays. Twenty-seven (57.5% E. coli isolates were positive for mcr-1. The mcr-1 genes were mainly located on plasmids belonging to IncI2 (n = 5, IncX4 (n = 11, IncHI2/ST3 (n = 8, IncFII (n = 2, and IncY (n = 2. InHI2 plasmids also carried other resistance genes (floR, blaCTX−M, and fosA3 and were only detected in isolates from nursery pigs. Sequences of the representative mcr-1–bearing plasmids were almost identical to those of the corresponding plasmid types reported previously. An increase in the fitness of IncI2- and IncX4-carrying strains was observed, while the presence of IncHI2, IncFII and IncY plasmids showed a fitness cost although an insignificant fitness increase was initially observed in IncFII or IncY plasmids-containing strains. Acquisition of IncI2-type plasmid was more beneficial for host E. coli DH5α than either IncHI2 or IncX4 plasmid, while transformants with IncHI2-type plasmid presented a competitive disadvantage against IncI2 or IncX4 plasmid containing strains. In conclusion, IncI2, IncX4, and IncHI2 were the major plasmid types driving the dissemination of mcr-1 in this farm. Increased fitness or co-selection by other antimicrobials might contribute to the further dissemination of the three epidemic mcr-1–positive plasmids (IncI2, IncX4, and IncHI2 in this farm and worldwide.

iFER: facial expression recognition using automatically selected geometric eye and eyebrow features

Science.gov (United States)

Oztel, Ismail; Yolcu, Gozde; Oz, Cemil; Kazan, Serap; Bunyak, Filiz

2018-03-01

Facial expressions have an important role in interpersonal communications and estimation of emotional states or intentions. Automatic recognition of facial expressions has led to many practical applications and became one of the important topics in computer vision. We present a facial expression recognition system that relies on geometry-based features extracted from eye and eyebrow regions of the face. The proposed system detects keypoints on frontal face images and forms a feature set using geometric relationships among groups of detected keypoints. Obtained feature set is refined and reduced using the sequential forward selection (SFS) algorithm and fed to a support vector machine classifier to recognize five facial expression classes. The proposed system, iFER (eye-eyebrow only facial expression recognition), is robust to lower face occlusions that may be caused by beards, mustaches, scarves, etc. and lower face motion during speech production. Preliminary experiments on benchmark datasets produced promising results outperforming previous facial expression recognition studies using partial face features, and comparable results to studies using whole face information, only slightly lower by ˜ 2.5 % compared to the best whole face facial recognition system while using only ˜ 1 / 3 of the facial region.

A Study of Quasar Selection in the Supernova Fields of the Dark Energy Survey

International Nuclear Information System (INIS)

Tie, S. S.; Martini, P.; Mudd, D.; Ostrovski, F.; Reed, S. L.

2017-01-01

In this paper, we present a study of quasar selection using the supernova fields of the Dark Energy Survey (DES). We used a quasar catalog from an overlapping portion of the SDSS Stripe 82 region to quantify the completeness and efficiency of selection methods involving color, probabilistic modeling, variability, and combinations of color/probabilistic modeling with variability. In all cases, we considered only objects that appear as point sources in the DES images. We examine color selection methods based on the Wide-field Infrared Survey Explorer (WISE) mid-IR W1-W2 color, a mixture of WISE and DES colors (g - i and i-W1), and a mixture of Vista Hemisphere Survey and DES colors (g - i and i - K). For probabilistic quasar selection, we used XDQSO, an algorithm that employs an empirical multi-wavelength flux model of quasars to assign quasar probabilities. Our variability selection uses the multi-band χ"2-probability that sources are constant in the DES Year 1 griz-band light curves. The completeness and efficiency are calculated relative to an underlying sample of point sources that are detected in the required selection bands and pass our data quality and photometric error cuts. We conduct our analyses at two magnitude limits, i 85% for both i-band magnitude limits and efficiencies of >80% to the bright limit and >60% to the faint limit; however, the giW1 and giW1+variability methods give the highest quasar surface densities. The XDQSOz method and combinations of W1W2/giW1/XDQSOz with variability are among the better selection methods when both high completeness and high efficiency are desired. We also present the OzDES Quasar Catalog of 1263 spectroscopically confirmed quasars from three years of OzDES observation in the 30 deg"2 of the DES supernova fields. Finally, the catalog includes quasars with redshifts up to z ~ 4 and brighter than i = 22 mag, although the catalog is not complete up to this magnitude limit.

Overexpression of peroxiredoxin I and thioredoxin1 in human breast carcinoma

Directory of Open Access Journals (Sweden)

Kim Il-Han

2009-06-01

Full Text Available Abstract Background Peroxiredoxins (Prxs are a novel group of peroxidases containing high antioxidant efficiency. The mammalian Prx family has six distinct members (Prx I-VI in various subcellular locations, including peroxisomes and mitochondria, places where oxidative stress is most evident. The function of Prx I in particular has been implicated in regulating cell proliferation, differentiation, and apoptosis. Since thioredoxin1 (Trx1 as an electron donor is functionally associated with Prx I, we investigated levels of expression of both Prx I and Trx1. Methods We investigated levels of expression of both Prx I and Trx1 in breast cancer by real-time polymerase chain reaction (RT-PCR and Western blot. Results Levels of messenger RNA (mRNA for both Prx I and Trx1 in normal human breast tissue were very low compared to other major human tissues, whereas their levels in breast cancer exceeded that in other solid cancers (colon, kidney, liver, lung, ovary, prostate, and thyroid. Among members of the Prx family (Prx I-VI and Trx family (Trx1, Trx2, Prx I and Trx1 were preferentially induced in breast cancer. Moreover, the expression of each was associated with progress of breast cancer and correlated with each other. Western blot analysis of different and paired breast tissues revealed consistent and preferential expression of Prx I and Trx1 protein in breast cancer tissue. Conclusion Prx I and Trx1 are overexpressed in human breast carcinoma and the expression levels are associated with tumor grade. The striking induction of Prx I and Trx1 in breast cancer may enable their use as breast cancer markers.

The design strategy of selective PTP1B inhibitors over TCPTP.

Science.gov (United States)

Li, XiangQian; Wang, LiJun; Shi, DaYong

2016-08-15

Protein tyrosine phosphatase 1B (PTP1B) has already been well studied as a highly validated therapeutic target for diabetes and obesity. However, the lack of selectivity limited further studies and clinical applications of PTP1B inhibitors, especially over T-cell protein tyrosine phosphatase (TCPTP). In this review, we enumerate the published specific inhibitors of PTP1B, discuss the structure-activity relationships by analysis of their X-ray structures or docking results, and summarize the characteristic of selectivity related residues and groups. Furthermore, the design strategy of selective PTP1B inhibitors over TCPTP is also proposed. We hope our work could provide an effective way to gain specific PTP1B inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

A pioneer experience in Malaysia on In-house Radio-labelling of "1"3"1I-rituximab in the treatment of Non-Hodgkin's Lymphoma and a case report of high dose "1"3"1I-rituximab-BEAM conditioning autologous transplant

International Nuclear Information System (INIS)

Kuan, Jew Win; Law, Chiong Soon; Wong, Xiang Qi; Ko, Ching Tiong; Awang, Zool Hilmi; Chew, Lee Ping; Chang, Kian Meng

2016-01-01

Radioimmunotherapy is an established treatment modality in Non-Hodgkin's lymphoma. The only two commercially available radioimmunotherapies – "9"0Y-ibritumomab tiuxetan is expensive and "1"3"1I-tositumomab has been discontinued from commercial production. In resource limited environment, self-labelling "1"3"1I-rituximab might be the only viable practical option. We reported our pioneer experience in Malaysia on self-labelling "1"3"1I-rituximab, substituting autologous haematopoietic stem cell transplantation (HSCT) and a patient, the first reported case, received high dose "1"3"1I-rituximab (6000 MBq/163 mCi) combined with BEAM conditioning for autologous HSCT. - Highlights: • Usual dose: Day 0 (dosimetry) – 5 mCi, Day 7 (therapeutic) 0.75 Gy to whole body. • High dose: 6000 MBq (163 mCi) on Day − 18, BEAM conditioning starts on Day − 8. • Self-labelled "1"3"1I-rituximab is a viable treatment in resource limited environment. • "1"3"1I-rituximab may substitute autologous transplant. • High dose "1"3"1I-rituximab-BEAM is a feasible conditioning regime.

It Takes Three: Selection, Influence, and De-Selection Processes of Depression in Adolescent Friendship Networks

Science.gov (United States)

Van Zalk, Maarten Herman Walter; Kerr, Margaret; Branje, Susan J. T.; Stattin, Hakan; Meeus, Wim H. J.

2010-01-01

The authors of this study tested a selection-influence-de-selection model of depression. This model explains friendship influence processes (i.e., friends' depressive symptoms increase adolescents' depressive symptoms) while controlling for two processes: friendship selection (i.e., selection of friends with similar levels of depressive symptoms)…

A Study of the Radioprotective Activity of the Imidazole Nucleus and Some of Its Derivatives; Etude de l'activite radioprotectrice du noyau imidazole et de quelquesuns de ses derives

Energy Technology Data Exchange (ETDEWEB)

Rinaldi, R; Bernard, Y [Commissariat a l' Energie Atomique. Centre d' Etudes Nucleaires, 38 - Grenoble (France)

1962-07-01

A study was made of the radioprotective properties of 8 compounds derived from imidazole. The effectiveness of the compounds was tested in mice exposed to a lethal dose of x radiation. Results showed that imidazole afforded protection to about 85% of the animals. Little protection was afforded by imidazoline and thione-imidazoline compounds in spite of the existence of a free sulfhydryl group in these compounds. (authors) [French] Cette etude a ete consacree a la determination des proprietes radioprotectrices eventuelles de huit composes derives de l'imidazole. Ces substances ont ete, soit synthetisees, soit obtenues dans le commerce. Leur efficacite a ete mise en evidence par le pourcentage de survie obtenu chez des souris soumises a une dose mortelle de rayons X. Les resultats ont fait apparaitre: - l'activite remarquable de l'imidazole qui protege environ 85 pour cent des animaux; - la protection faible ou nulle obtenue avec les imidazolinones et les thione-imidazolines, malgre la presence dans la molecule de ces dernieres d'un groupement sulfhydrile libre. (auteurs)

CR4056, a new analgesic I2 ligand, is highly effective against bortezomib-induced painful neuropathy in rats

Directory of Open Access Journals (Sweden)

Meregalli C

2012-06-01

Full Text Available Cristina Meregalli,1 Cecilia Ceresa,1 Annalisa Canta,1 Valentina Alda Carozzi,1 Alessia Chiorazzi,1 Barbara Sala,1 Norberto Oggioni,1 Marco Lanza,2 Ornella Letar,i2 Flora Ferrari,2 Federica Avezza,1 Paola Marmiroli,1 GianFranco Caselli,2 Guido Cavaletti11Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, 2Pharmacology and Toxicology Department, Rottapharm | Madaus Research Center, Monza, ItalyAbstract: Although bortezomib (BTZ is the frontline treatment for multiple myeloma, its clinical use is limited by the occurrence of painful peripheral neuropathy, whose treatment is still an unmet clinical need. Previous studies have shown chronic BTZ administration (0.20 mg/kg intravenously three times a week for 8 weeks to female Wistar rats induced a peripheral neuropathy similar to that observed in humans. In this animal model of BTZ-induced neurotoxicity, the present authors evaluated the efficacy of CR4056, a novel I2 ligand endowed with a remarkable efficacy in several animal pain models. CR4056 was administered in a wide range of doses (0.6–60 mg/kg by gavage every day for 2–3 weeks in comparison with buprenorphine (Bupre (28.8 µg/kg subcutaneously every day for 2 weeks and gabapentin (Gaba (100 mg/kg by gavage every day for 3 weeks. Chronic administration of BTZ reduced nerve conduction velocity and induced allodynia. CR4056, Bupre, or Gaba did not affect the impaired nerve conduction velocity. Conversely, CR4056 dose-dependently reversed BTZ-induced allodynia (minimum effective dose 0.6 mg/kg. The optimal dose found, 6 mg/kg, provided a constant pain relief throughout the treatment period and without rebound after suspension, being effective when coadministered with BTZ, starting before or after allodynia was established, or when administered alone after BTZ cessation. A certain degree of tolerance was seen after 7 days of administration, but only at the highest doses (20 and 60 mg/kg. Bupre was effective

Quantum state-to-state dynamics for the quenching process of Br(2P1/2) + H2(v(i) = 0, 1, j(i) = 0).

Science.gov (United States)

Xie, Changjian; Jiang, Bin; Xie, Daiqian; Sun, Zhigang

2012-03-21

Quantum state-to-state dynamics for the quenching process Br((2)P(1/2)) + H(2)(v(i) = 0, 1, j(i) = 0) → Br((2)P(3/2)) + H(2)(v(f), j(f)) has been studied based on two-state model on the recent coupled potential energy surfaces. It was found that the quenching probabilities have some oscillatory structures due to the interference of reflected flux in the Br((2)P(1/2)) + H(2) and Br((2)P(3/2)) + H(2) channels by repulsive potential in the near-resonant electronic-to-vibrational energy transfer process. The final vibrational state resolved integral cross sections were found to be dominated by the quenching process Br((2)P(1/2)) + H(2)(v) → Br((2)P(3/2)) + H(2)(v+1) and the nonadiabatic reaction probabilities for Br((2)P(1/2)) + H(2)(v = 0, 1, j(i) = 0) are quite small, which are consistent with previous theoretical and experimental results. Our calculated total quenching rate constant for Br((2)P(1/2)) + H(2)(v(i) = 0, j(i) = 0) at room temperature is in good agreement with the available experimental data. © 2012 American Institute of Physics

Selection and Characterization of Palmitic Acid Responsive Patients with an OXPHOS Complex I Defect

Directory of Open Access Journals (Sweden)

Tom E. J. Theunissen

2017-10-01

a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.

Synthesis of [[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaze pine 3-carboxylate, a potential SPECT imaging agent for diazepam-intensive (DI) benzodiazepine receptors

Energy Technology Data Exchange (ETDEWEB)

He, Xiaoshu; Matecka, Dorota; Gu, Ziqiang; Rice, K C; Costa, B.R. de [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Lee, K S [National Inst. of Mental Health, Washington, DC (United States); Wong, Garry; Skolnick, Phil [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States). Lab. of Neuroscience

1994-01-01

[[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine 3-carboxylate ([[sup 123]I]3), a high affinity and selective radioligand for the diazepam insensitive (DI) benzodiazepine receptor was synthesized in 2 steps from tert-butyl 8-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaz epine 3-carboxylate. (Author).

RELAP5-3D Developmental Assessment: Comparison of Versions 4.2.1i and 4.1.3i

Energy Technology Data Exchange (ETDEWEB)

Bayless, Paul D. [Idaho National Lab. (INL), Idaho Falls, ID (United States)

2014-06-01

Figures have been generated comparing the parameters used in the developmental assessment of the RELAP5-3D code using versions 4.2.1i and 4.1.3i. The figures, which are the same as those used in Volume III of the RELAP5-3D code manual, compare calculations using the semi-implicit solution scheme with available experiment data. These figures provide a quick, visual indication of how the code predictions changed between these two code versions and can be used to identify cases in which the assessment judgment may need to be changed in Volume III of the code manual. Changes to the assessment judgments made after reviewing all of the assessment cases are also provided.

Crystal structure of human cyclin-dependent kinase-2 complex with MK2 inhibitor TEI-I01800: insight into the selectivity

Energy Technology Data Exchange (ETDEWEB)

Fujino, Aiko; Fukushima, Kei; Kubota, Takaharu; Kosugi, Tomomi; Takimoto-Kamimura, Midori, E-mail: m.kamimura@teijin.co.jp [Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512 (Japan)

2013-11-01

The Gly-rich loop of cyclin-dependent kinase 2 (CDK2) bound to TEI-I01800 as an MK2 specific inhibitor forms a β-sheet which is a common structure in CDK2–ligand complexes. Here, the reason why TEI-I01800 does not become a strong inhibitor against CDK2 based on the conformation of TEI-I01800 is presented. Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2) is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the MK2–TEI-I01800 complex has been reported; its Gly-rich loop was found to form an α-helix, not a β-sheet as has been observed for other Ser/Thr kinases. TEI-I01800 is 177-fold selective against MK2 compared with CDK2; in order to understand the inhibitory mechanism of TEI-I01800, the cyclin-dependent kinase 2 (CDK2) complex structure with TEI-I01800 was determined at 2.0 Å resolution. Interestingly, the Gly-rich loop of CDK2 formed a β-sheet that was different from that of MK2. In MK2, TEI-I01800 changed the secondary structure of the Gly-rich loop from a β-sheet to an α-helix by collision between Leu70 and a p-ethoxyphenyl group at the 7-position and bound to MK2. However, for CDK2, TEI-I01800 bound to CDK2 without this structural change and lost the interaction with the substituent at the 7-position. In summary, the results of this study suggest that the reason for the selectivity of TEI-I01800 is the favourable conformation of TEI-I01800 itself, making it suitable for binding to the α-form MK2.

Selective oxidation of i-butene and i-butene to methacrolein and methacrylic acid over Keggin-type polyoxometalate and MoVTeNbOx catalysts. A comparative catalytic and in situ-spectroscopic study

Energy Technology Data Exchange (ETDEWEB)

Bentrup, U.; Brueckner, A.; Kant, M.; Kolf, S.; Dingerdissen, U. [Institut fuer Angewandte Chemie Berlin-Adlershof e.V. (Germany); Jansen, S.; Maschmeyer, D.; Sieger, H.; Zanthoff, H.W. [Degussa AG, Marl (Germany)

2005-07-01

An alternative to overcome the drawbacks connected with POM catalysts may be the development of suitable mixed metal oxide catalysts. MoVTeNbO{sub x} materials could be promising candidates since they revaled remarkable performance in the selective oxidation of propane to acrylic acid. However, up to now their behaviour in the selective oxidation of i-butane has rarely been studied. The investigations presented in this paper are focused on the interaction of feed components (i-butane / i-butene, O{sub 2}, H{sub 2}O) with Keggin-type polyoxometalate and MoVTeNbO{sub x} catalysts. FTIR spectroscopy was used to identify adsorbed intermediates and products while the novel simultaneous operando-EPR/UV-vis/Raman/GC technique revealed to be an excellent tool to follow the behaviour of V and Mo sites. In relation to the results of catalytic tests, structure-reactivity relationships are derived. (orig.)

Synthesis and evaluation of fluorine-18-labeled SA4503 as a selective sigma{sub 1} receptor ligand for positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Kawamura, Kazunori [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan) and Center for Integrated Human Brain Science, Brain Research Institute, University of Niigata, Niigata, Niigata 951-8585 (Japan)]. E-mail: kawamurak@bri.niigata-u.ac.jp; Tsukada, Hideo [Central Research Laboratory, Hamamatsu Photonics, K.K., Hamamatsu, Shizuoka 434-8601 (Japan); Shiba, Kazuhiro [Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa 920-8640 (Japan); Tsuji, Chieko [NARD Institute, Ltd., Amagasaki, Hyogo 660-0805 (Japan); Harada, Norihiro [Central Research Laboratory, Hamamatsu Photonics, K.K., Hamamatsu, Shizuoka 434-8601 (Japan); Kimura, Yuichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan); Ishiwata, Kiichi [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0022 (Japan)

2007-07-15

The [{sup 18}F]fluoromethyl analog of the sigma{sub 1} selective ligand 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) ([{sup 18}F]FM-SA4503) was prepared and its potential evaluated for the in vivo measurement of sigma{sub 1} receptors with positron emission tomography (PET). FM-SA4503 had selective affinity for the sigma{sub 1} receptor ( K {sub i} for sigma{sub 1} receptor, 6.4 nM; K {sub i} for sigma{sub 2} receptor, 250 nM) that was compatible with the affinity of SA4503 ( K {sub i} for sigma{sub 1} receptor, 4.4 nM; K {sub i} for sigma{sub 2} receptor, 242 nM). [{sup 18}F]FM-SA4503 was synthesized by {sup 18}F-fluoromethylation of O-demethyl SA4503 in the radiochemical yield of 2.9-16.6% at the end of bombardment with a specific activity of 37.8-283 TBq/mmol at the end of synthesis. In mice, the uptake of [{sup 18}F]FM-SA4503 in the brain was gradually increased for 30 min after injection, and then decreased. In the blocking study, brain uptake was significantly decreased by co-injection of haloperidol to 32% of control, and FM-SA4503 to 52% of control. In PET study of the monkey brain, high uptake was found in the cerebral cortex, thalamus and striatum. The radioactivity level of [{sup 18}F]FM-SA4503 in the brain regions gradually increased over a period of 120 min after injection, followed by a stable plateau phase until 180 min after injection. In pretreatment with haloperidol measurement of the monkey brain, the radioactivity level was 22-32% and 11-25% of the baseline at 60 and 180 min, respectively, after injection, suggesting high receptor-specific binding. [{sup 18}F]FM-SA4503 showed specific binding to sigma{sub 1} receptors in mice and monkeys; therefore, [{sup 18}F]FM-SA4503 has the potential for mapping sigma{sub 1} receptors in the brain.

Synthesis and evaluation of [{sup 125}I]I-TSA as a brain nicotinic acetylcholine receptor {alpha}{sub 7} subtype imaging agent

Energy Technology Data Exchange (ETDEWEB)

Ogawa, Mikako [Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192 (Japan); Tatsumi, Ryo [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Fujio, Masakazu [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Katayama, Jiro [Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, Yokohama 227-0033 (Japan); Magata, Yasuhiro [Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu Medical University, Hamamatsu 431-3192 (Japan)]. E-mail: magata@hama-med.ac.jp

2006-04-15

Introduction: Some in vitro investigations have suggested that the nicotinic acetylcholine receptor (nAChR) {alpha}{sub 7} subtype is implicated in Alzheimer's disease, schizophrenia and others. Recently, we developed (R)-3'-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'-[1',3'] oxazolidin]-2'-one (Br-TSA), which has a high affinity and selectivity for {alpha}{sub 7} nAChRs. Therefore we synthesized (R)-3'-(5-[{sup 125}I]iodothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5'- [1',3']oxazolidin]-2'-one ([{sup 125}I]I-TSA) and evaluated its potential for the in vivo detection of {alpha}{sub 7} nAChR in brain. Methods: In vitro binding affinity of I-TSA was measured in rat brain homogenates. Radioiodination was accomplished by a Br-I exchange reaction. Biodistribution studies were undertaken in mice by tail vein injection of [{sup 125}I]I-TSA. In vivo receptor blocking studies were carried out by treating mice with methyllycaconitine (MLA; 5 nmol/5 {mu}l, i.c.v.) or nonradioactive I-TSA (50 {mu}mol/kg, i.v.). Results: I-TSA exhibited a high affinity and selectivity for the {alpha}{sub 7} nAChR (K {sub i} for {alpha}{sub 7} nAChR=0.54 nM). Initial uptake in the brain was high (4.42 %dose/g at 5 min), and the clearance of radioactivity was relatively slow in the hippocampus ({alpha}{sub 7} nAChR-rich region) and was rather rapid in the cerebellum ({alpha}{sub 7} nAChR poor region). The hippocampus to cerebellum uptake ratio was 0.9 at 5 min postinjection, but it was increased to 1.8 at 60 min postinjection. Although the effect was not statistically significant, administration of I-TSA and MLA decreased the accumulation of radioactivity in hippocampus. Conclusion: Despite its high affinity and selectivity, [{sup 125}I]I-TSA does not appear to be a suitable tracer for in vivo {alpha}{sub 7} nAChR receptor imaging studies due to its high nonspecific binding. Further structural optimization is needed.

Selection and characterization of single stranded DNA aptamers recognizing fumonisin B1

International Nuclear Information System (INIS)

Chen, Xiujuan; Huang, Yukun; Duan, Nuo; Wu, Shijia; Xia, Yu; Ma, Xiaoyuan; Ding, Zhansheng; Wang, Zhouping; Zhu, Changqing; Jiang, Yuan

2014-01-01

We present an improved method for the selection of single-stranded DNA aptamers that can recognize fumonisin B 1 (FB 1 ). FB 1 is a carcinogenic mycotoxin mainly found in corn and corn-based food products worldwide, posing a global threat to feed and food safety. Selection was based on the mag-SELEX (magnetic bead systematic evolution of ligands by exponential enrichment) technology modified by adopting free analogs of targets rather than immobilized targets for counter selections. Firstly, aptamer candidates for FB 1 were selected from an 80 nt random DNA library after 13 rounds of selection. Next, binding assays were performed for affinity evaluation, and circular dichroism spectroscopy was used to investigate their conformation. A high-affinity aptamer designated as F10 (with a dissociation constant of 62 ± 5 nM) was identified and tested for its specificity by competitive binding assays. The results demonstrate that this improved mag-SELEX technology facilitates aptamer screening because it avoids the tedious immobilization of counter-selection molecules on magnetic beads. The aptamers obtained by this technique open new possibilities for the detection of FB 1 via aptasensors. (author)

Procedure for the Selection and Validation of a Calibration Model I-Description and Application.

Science.gov (United States)

Desharnais, Brigitte; Camirand-Lemyre, Félix; Mireault, Pascal; Skinner, Cameron D

2017-05-01

Calibration model selection is required for all quantitative methods in toxicology and more broadly in bioanalysis. This typically involves selecting the equation order (quadratic or linear) and weighting factor correctly modelizing the data. A mis-selection of the calibration model will generate lower quality control (QC) accuracy, with an error up to 154%. Unfortunately, simple tools to perform this selection and tests to validate the resulting model are lacking. We present a stepwise, analyst-independent scheme for selection and validation of calibration models. The success rate of this scheme is on average 40% higher than a traditional "fit and check the QCs accuracy" method of selecting the calibration model. Moreover, the process was completely automated through a script (available in Supplemental Data 3) running in RStudio (free, open-source software). The need for weighting was assessed through an F-test using the variances of the upper limit of quantification and lower limit of quantification replicate measurements. When weighting was required, the choice between 1/x and 1/x2 was determined by calculating which option generated the smallest spread of weighted normalized variances. Finally, model order was selected through a partial F-test. The chosen calibration model was validated through Cramer-von Mises or Kolmogorov-Smirnov normality testing of the standardized residuals. Performance of the different tests was assessed using 50 simulated data sets per possible calibration model (e.g., linear-no weight, quadratic-no weight, linear-1/x, etc.). This first of two papers describes the tests, procedures and outcomes of the developed procedure using real LC-MS-MS results for the quantification of cocaine and naltrexone. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Plk1 is essential for proper chromosome segregation during meiosis I/meiosis II transition in pig oocytes.

Science.gov (United States)

Zhang, Zixiao; Chen, Changchao; Ma, Liying; Yu, Qiuchen; Li, Shuai; Abbasi, Benazir; Yang, Jiayi; Rui, Rong; Ju, Shiqiang

2017-08-29

Polo-like kinase 1 (Plk1), as a characteristic regulator in meiosis, organizes multiple biological events of cell division. Although Plk1 has been implicated in various functions in somatic cell mitotic processes, considerably less is known regarding its function during the transition from metaphase I (MI) to metaphase II (MII) stage in oocyte meiotic progression. In this study, the possible role of Plk1 during the MI-to-MII stage transition in pig oocytes was addressed. Initially, the spatiotemporal expression and subcellular localization pattern of Plk1 were revealed in pig oocytes from MI to MII stage using indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses. Moreover, a highly selective Plk1 inhibitor, GSK461364, was used to determine the potential role of Plk1 during this MI-to-MII transition progression. Upon expression, Plk1 exhibited a specific dynamic intracellular localization, and co-localization of Plk1 with α-tubulin was revealed in the meiotic spindle of pig oocyte during the transition from MI to MII stage. GSK461364 treatment significantly blocked the first polar body (pbI) emission in a dose-dependent manner and resulted in a failure of meiotic maturation, with a larger percentage of the GSK461364-treated oocytes arresting in the anaphase-telophase I (ATI) stage. Further subcellular structure examination results showed that inhibition of Plk1 with GSK461364 had no visible effect on spindle assembly but caused a significantly higher proportion of the treated oocytes to have obvious defects in homologous chromosome segregation at ATI stage. Thus, these results indicate that Plk1 plays an essential role during the meiosis I/meiosis II transition in porcine oocytes, and the regulation is associated with Plk1's effects on homologous chromosome segregation in the ATI stage.

Main: 1W0I [RPSD[Archive

Lifescience Database Archive (English)

Full Text Available Synonym: 3-Ketoacyl-Acyl Carrier Protein Synthase, Mitochondrial Beta-Ketoacyl-Acyl Carrier Protein Synthase; Chai...VIVLEEYEHAKRRGAKIYAELCGYGMSGDAHHITQPPEDGKGAVLAMTRALRQSGLCPNQIDYVNAHATSTPIGDAVEARAI...KTVFSEHATSGTLAFSSTKGATGHLLGAAGAVEAIFSILAIHHGVAPMTLNVKNPDPIFDKRFMPLTTSKKMLVRTAMSNSFGFGGTNASLLFASI arabi_1W0I.jpg ...

26 CFR 1.904(i)-1 - Limitation on use of deconsolidation to avoid foreign tax credit limitations.

Science.gov (United States)

2010-04-01

... foreign tax credit limitations. 1.904(i)-1 Section 1.904(i)-1 Internal Revenue INTERNAL REVENUE SERVICE... United States § 1.904(i)-1 Limitation on use of deconsolidation to avoid foreign tax credit limitations... applying the foreign tax credit provisions of section 59(a), sections 901 through 908, and section 960, the...

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

Science.gov (United States)

Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

A complex selection signature at the human AVPR1B gene

Directory of Open Access Journals (Sweden)

Cagliani Rachele

2009-06-01

Full Text Available Abstract Background The vasopressin receptor type 1b (AVPR1B is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Results Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg in this region has been subjected to directional selection. Conclusion Although the underlying selective pressure(s remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

A complex selection signature at the human AVPR1B gene.

Science.gov (United States)

Cagliani, Rachele; Fumagalli, Matteo; Pozzoli, Uberto; Riva, Stefania; Cereda, Matteo; Comi, Giacomo P; Pattini, Linda; Bresolin, Nereo; Sironi, Manuela

2009-06-01

The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg) in this region has been subjected to directional selection. Although the underlying selective pressure(s) remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

HIF-1α and GLUT-1 Expression in Atypical Endometrial Hyperplasia, Type I and II Endometrial Carcinoma: A Potential Role in Pathogenesis

Science.gov (United States)

Abdou, Asmaa Gaber; Wahed, Moshira Mohammed Abdel; Kassem, Hend Abdou

2016-01-01

Introduction Hypoxia-Inducible Factor 1α (HIF-1α) is one of the major adaptive responses to hypoxia, regulating the activity of glucose transporter -1 (GLUT-1), responsible for glucose uptake. Aim To evaluate the immunohistochemical expression of both HIF-1α and GLUT-1 in type I and II endometrial carcinoma and their correlation with the available clinicopathologic variables in each type. Materials and Methods A retrospective study was conducted on archival blocks diagnosed from pathology department between April 2010 and August 2014 included 9 cases of atypical hyperplasia and 67 cases of endometrial carcinoma. Evaluation of both HIF-1α and GLUT-1 expression using standard immunohistochemical techniques performed on cut sections from selected paraffin embedded blocks. Statistical Analysis Descriptive analysis of the variables and statistical significances were calculated by non-parametric chi-square test using the Statistical Package for the Social Sciences version 12.0 (SPSS). Results HIF-1α was expressed in epithelial (88.9%, 52.2%, 61.2% and 50%) and stromal (33.3%, 74.6%. 71.4% and 83.3%) components of hyperplasia, total cases of EC, type I and II EC, respectively. GLUT-1 was expressed in the epithelial component of 88.9%, 98.5%, 98% and 100% of hyperplasia, total EC cases, type I and II EC, respectively. The necrosis related pattern of epithelial HIF-1α expression was in favour of type II (p=0.018) and grade III (p=0.038). HIF-1α H-score was associated with high apoptosis in both type I and total cases of EC (p=0.04). GLUT-1 H-score was negatively correlated with apoptotic count (p=0.04) and associated with high grade (p=0.003) and advanced stage in total EC (p=0.004). GLUT-1 H-score was correlated with the pattern of HIF-1α staining in all cases of EC (p= 0.04). Conclusion The role of HIF-1α in epithelial cells may differ from that of stromal cells in EC; however they augment the expression of each other supporting the crosstalk between them. The

Selective inhibition of CTCF binding by iAs directs TET-mediated reprogramming of 5-hydroxymethylation patterns in iAs-transformed cells

Science.gov (United States)

Rea, Matthew; Gripshover, Tyler; Fondufe-Mittendorf, Yvonne

2017-01-01

Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To gain an understanding into how iAs might impact TET expression, we found that iAs inhibits the binding of CTCF at the proximal, weak CTCF binding sites of the TET1 and TET2 gene promoters and enhances CTCF binding at the stronger distal binding site. Further analyses suggest that this distal site acts as an enhancer, thus high CTCF occupancy at the enhancer region of TET1 and TET2 possibly drives their high expression in iAs-transformed cells. These results have major implications in understanding the impact of differential CTCF binding, genome architecture and its consequences in iAs-mediated pathogenesis. PMID:29175454

Trypanocidal 1,3-arylene diketone bis(guanylhydrazone)s. Structure-activity relationships among substituted and heterocyclic analogues.

Science.gov (United States)

Ulrich, P; Cerami, A

1984-01-01

Based on the antitrypanosomal activity of 1,3-diacetylbenzene bis(guanylhydrazone) (4) and 2,6-diacetylpyridine bis(guanylhydrazone) (17), a number of substituted and heterocyclic 1,3-arylene diketone bis(guanylhydrazone)s were prepared and tested against Trypanosoma brucei infections in mice. A wide range of ED50 values was observed among 5-substituted derivatives of 4. The 5-amino analogue 5 and 5-acetamido analogue 6 were about twice as active as 4. 1,3,5-Triacetylbenzene tris(guanylhydrazone) (12) was about 9 times as active as 4 and was approximately one-half as active as the currently used trypanocide diminazene aceturate in this test system. Other 5-derivatives had activity equivalent to or less than that of the parent compound 4. Three new heterocyclic analogues were all less active than 2,6-diacetylpyridine derivative 17 and benzene derivative 4. Ring substitution ortho to the guanylhydrazone side chains was invariably detrimental to activity. Side-chain homologues 1,3-dipentanoylbenzene bis(guanylhydrazone) and 1,3-diacetylbenzene bis(2-imidazolin-2-ylhydrazone) were essentially inactive.

Superoxide dismutase 1 is positively selected to minimize protein aggregation in great apes

DEFF Research Database (Denmark)

Dasmeh, Pouria; Kepp, Kasper Planeta

2017-01-01

Positive (adaptive) selection has recently been implied in human superoxide dismutase 1 (SOD1), a highly abundant antioxidant protein with energy signaling and antiaging functions, one of very few examples of direct selection on a human protein product (exon); the molecular drivers...... and SOD1 aggregates and triggered by aging. Our study thus marks an example of direct selection for a particular chemical phenotype (high net charge and stability) in a single human protein with possible implications for the evolution of aging....... of this selection are unknown. We mapped 30 extant SOD1 sequences to the recently established mammalian species tree and inferred ancestors, key substitutions, and signatures of selection during the protein's evolution. We detected elevated substitution rates leading to great apes (Hominidae) at ~1 per 2 million...

Induced desensitization of the insulinotropic effects of antidiabetic drugs, BTS 67 582 and tolbutamide.

Science.gov (United States)

McClenaghan, N H; Ball, A J; Flatt, P R

2000-05-01

Acute and chronic mechanisms of action of novel insulinotropic antidiabetic drug, BTS 67 582 (1, 1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate), were examined in the stable cultured BRIN-BD11 cell line. BTS 67 582 (100 - 400 microM) stimulated a concentration-dependent increase (PBTS 67 582 in culture time-dependently decreased subsequent responsiveness to acute challenge with 200 microM BTS 67 582 or 200 microM tolbutamide at 12 - 18 h (PBTS 67 582 and tolbutamide. Culture with 100 microM BTS 67 582 or 100 microM tolbutamide did not affect basal insulin secretion, cellular insulin content, or cell viability and exerted no influence on the secretory responsiveness to 200 microM of the imidazoline, efaroxan. While 18 h BTS 67 582 culture did not affect the insulin-releasing actions (PBTS 67 582 shares a common signalling pathway to sulphonylurea but not imidazoline drugs. Desensitization of drug action may provide an important approach to dissect sites of action of novel and established insulinotropic antidiabetic agents.

Selection of radioresistant tumor cells and presence of ALDH1 activity in vitro

International Nuclear Information System (INIS)

Mihatsch, Julia; Toulany, Mahmoud; Bareiss, Petra M.; Grimm, Sabrina; Lengerke, Claudia; Kehlbach, Rainer; Rodemann, H. Peter

2011-01-01

Background: Tumor resistance to radiotherapy has been hypothesized to be mediated by a tumor subpopulation, called cancer stem cells (CSCs). Based on the proposed function of CSCs in radioresistance, we explored the cancer stem cell properties of cells selected for radioresistance phenotype. Materials and methods: A549 and SK-BR-3 cells were radioselected with four single doses of 4 or 3 Gy in intervals of 10-12 days and used for colony formation assay and γ-H2AX foci formation assay. Expression of putative stem cell markers, i.e. Sox2, Oct4, ALDH1, and CD133 were analyzed using Western blotting. A549 and SK-BR-3 cells sorted based on their ALDH1 activity were analyzed in clonogenic survival assays. Results: Radioselected A549 and SK-BR-3 cells (A549-R, SK-BR-3-R) showed increased radioresistance and A549-R cells presented enhanced repair of DNA-double strand breaks. PI3K inhibition significantly reduced radioresistance of A549-R cells. Cell line specific differences in the expression of the putative CSC markers Sox2 and Oct4 were observed when parental and radioselected cells were compared but could not be directly correlated to the radioresistant phenotype. However, enzyme activity of the putative stem cell marker ALDH1 showed a correlation to radioresistance. Conclusions: Subpopulations of pooled radioresistant colonies, selected by various radiation exposures were analyzed for the presence of putative stem cell markers. Although the pattern of Sox2, Oct4, and CD133 expression was not generally associated with radioresistance, presence of ALDH1 seems to be indicative for subpopulations with increased radioresistance.