Chiral separation of G-type chemical warfare nerve agents via analytical supercritical fluid chromatography.

PubMed

Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

2014-12-01

Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(-) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(-) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc.

Analysis of chemical warfare agents in food products by atmospheric pressure ionization-high field asymmetric waveform ion mobility spectrometry-mass spectrometry.

PubMed

Kolakowski, Beata M; D'Agostino, Paul A; Chenier, Claude; Mester, Zoltán

2007-11-01

Flow injection high field asymmetric waveform ion mobility spectrometry (FAIMS)-mass spectrometry (MS) methodology was developed for the detection and identification of chemical warfare (CW) agents in spiked food products. The CW agents, soman (GD), sarin (GB), tabun (GA), cyclohexyl sarin (GF), and four hydrolysis products, ethylphosphonic acid (EPA), methylphosphonic acid (MPA), pinacolyl methylphosphonic acid (Pin MPA), and isopropyl methylphosphonic acid (IMPA) were separated and detected by positive ion and negative ion atmospheric pressure ionization-FAIMS-MS. Under optimized conditions, the compensation voltages were 7.2 V for GD, 8.0 V for GA, 7.2 V for GF, 7.6 V for GB, 18.2 V for EPA, 25.9 V for MPA, -1.9 V for PinMPA, and +6.8 V for IMPA. Sample preparation was kept to a minimum, resulting in analysis times of 3 min or less per sample. The developed methodology was evaluated by spiking bottled water, canola oil, cornmeal, and honey samples at low microgram per gram (or microg/mL) levels with the CW agents or CW agent hydrolysis products. The detection limits observed for the CW agents in the spiked food samples ranged from 3 to 15 ng/mL in bottled water, 1-33 ng/mL in canola oil, 1-34 ng/g in cornmeal, and 13-18 ng/g in honey. Detection limits were much higher for the CW agent hydrolysis products, with only MPA being detected in spiked honey samples.

Mass Spectrometry to Identify New Biomarkers of Nerve Agent Exposure

DTIC Science & Technology

2010-04-01

target for oganophosphorus agent (OP) binding to enzymes is the active site serine in the consensus sequence GlyXSerXGly of acetylcholinesterase. By...human plasma. Task 6. Use a second method, for example enzyme activity assays or immunoprecipitation, to confirm the identity of soman-labeled proteins...spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin: a potential

Screening of nerve agent degradation products by MALDI-TOFMS.

PubMed

Shu, You-Ren; Su, An-Kai; Liu, Ju-Tsung; Lin, Cheng-Huang

2006-07-01

A novel method for the rapid screening of degradation products derived from nerve agents by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is described. Five standard products were selected as model compounds, including isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA), isobutyl methylphosphonic acid (i-BuMPA), and cyclohexyl methylphosphonic acid (CHMPA), which are degradation products of Sarin (GB), Soman (GD), VX, Russian VX (RVX), and GF, respectively. For comparison, CHCA (alpha-cyano-4-hydroxycinnamic acid) and DCCA (7-(diethylamino)coumarin-3-carboxylic acid) were used as the MALDI-matrix when the third harmonic generation (355 nm) of a Nd:YAG laser and a hydrogen Raman laser (multifrequency laser) were used, respectively. The method permitted the five nerve agent degradation products to be screened rapidly and successfully, suggesting that it has the potential for use as a routine monitoring tool.

Metal-Organic Framework Modified Glass Substrate for Analysis of Highly Volatile Chemical Warfare Agents by Paper Spray Mass Spectrometry.

PubMed

Dhummakupt, Elizabeth S; Carmany, Daniel O; Mach, Phillip M; Tovar, Trenton M; Ploskonka, Ann M; Demond, Paul S; DeCoste, Jared B; Glaros, Trevor

2018-03-07

Paper spray mass spectrometry has been shown to successfully analyze chemical warfare agent (CWA) simulants. However, due to the volatility differences between the simulants and real G-series (i.e., sarin, soman) CWAs, analysis from an untreated paper substrate proved difficult. To extend the analytical lifetime of these G-agents, metal-organic frameworks (MOFs) were successfully integrated onto the paper spray substrates to increase adsorption and desorption. In this study, several MOFs and nanoparticles were tested to extend the analytical lifetimes of sarin, soman, and cyclosarin on paper spray substrates. It was found that the addition of either UiO-66 or HKUST-1 to the paper substrate increased the analytical lifetime of the G-agents from less than 5 min detectability to at least 50 min.

Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hemmert, Andrew C.; Otto, Tamara C.; Wierdl, Monika

Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex withmore » the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P{sub R} enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P{sub S} isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P{sub S} isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.« less

Measurement of breakthrough volumes of volatile chemical warfare agents on a poly(2,6-diphenylphenylene oxide)-based adsorbent and application to thermal desorption-gas chromatography/mass spectrometric analysis.

PubMed

Kanamori-Kataoka, Mieko; Seto, Yasuo

2015-09-04

To establish adequate on-site solvent trapping of volatile chemical warfare agents (CWAs) from air samples, we measured the breakthrough volumes of CWAs on three adsorbent resins by an elution technique using direct electron ionization mass spectrometry. The trapping characteristics of Tenax(®) TA were better than those of Tenax(®) GR and Carboxen(®) 1016. The latter two adsorbents showed non-reproducible breakthrough behavior and low VX recovery. The specific breakthrough values were more than 44 (sarin) L/g Tenax(®) TA resin at 20°C. Logarithmic values of specific breakthrough volume for four nerve agents (sarin, soman, tabun, and VX) showed a nearly linear correlation with the reciprocals of their boiling points, but the data point of sulfur mustard deviated from this linear curve. Next, we developed a method to determine volatile CWAs in ambient air by thermal desorption-gas chromatography (TD-GC/MS). CWA solutions that were spiked into the Tenax TA(®) adsorbent tubes were analyzed by a two-stage TD-GC/MS using a Tenax(®) TA-packed cold trap tube. Linear calibration curves for CWAs retained in the resin tubes were obtained in the range between 0.2pL and 100pL for sarin, soman, tabun, cyclohexylsarin, and sulfur mustard; and between 2pL and 100pL for VX and Russian VX. We also examined the stability of CWAs in Tenax(®) TA tubes purged with either dry or 50% relative humidity air under storage conditions at room temperature or 4°C. More than 80% sarin, soman, tabun, cyclohexylsarin, and sulfur mustard were recovered from the tubes within 2 weeks. In contrast, the recoveries of VX and Russian VX drastically reduced with storage time at room temperature, resulting in a drop to 10-30% after 2 weeks. Moreover, we examined the trapping efficiency of Tenax TA(®) adsorbent tubes for vaporized CWA samples (100mL) prepared in a 500mL gas sampling cylinder. In the concentration range of 0.2-2.5mg/m(3), >50% of sarin, soman, tabun, cyclohexylsarin, and HD were recovered, whereas <1% of VX and Russian VX were recovered in the same concentration range. The results indicate that CWA vapors, with the exception of VX and Russian VX, can be measured by an on-site collection procedure using the Tenax(®) TA resin tubes, followed by a subsequent TD-GC/MS analysis. Copyright © 2015 Elsevier B.V. All rights reserved.

Chiral Separation of G-type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

PubMed Central

Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

2014-01-01

Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(–) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(–) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. Chirality 26:817–824, 2014. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc. PMID:25298066

Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

PubMed

Smith, C D; Lee, R B; Moran, A V; Sipos, M L

2016-01-01

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period. Published by Elsevier Inc.

Selective chromo-fluorogenic detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) with a unique probe based on a boron dipyrromethene (BODIPY) dye.

PubMed

Barba-Bon, Andrea; Costero, Ana M; Gil, Salvador; Martínez-Máñez, Ramón; Sancenón, Félix

2014-11-21

A novel colorimetric probe (P4) for the selective differential detection of DFP (a Sarin and Soman mimic) and DCNP (a Tabun mimic) was prepared. Probe P4 contains three reactive sites; i.e. (i) a nucleophilic phenol group able to undergo phosphorylation with nerve gases, (ii) a carbonyl group as a reactive site for cyanide; and (iii) a triisopropylsilyl (TIPS) protecting group that is known to react with fluoride. The reaction of P4 with DCNP in acetonitrile resulted in both the phosphorylation of the phenoxy group and the release of cyanide, which was able to react with the carbonyl group of P4 to produce a colour modulation from pink to orange. In contrast, phosphorylation of P4 with DFP in acetonitrile released fluoride that hydrolysed the TIPS group in P4 to yield a colour change from pink to blue. Probe P4 was able to discriminate between DFP and DCNP with remarkable sensitivity; limits of detection of 0.36 and 0.40 ppm for DCNP and DFP, respectively, were calculated. Besides, no interference from other organophosphorous derivatives or with presence of acid was observed. The sensing behaviour of P4 was also retained when incorporated into silica gel plates or onto polyethylene oxide membranes, which allowed the development of simple test strips for the colorimetric detection of DCNP and DFP in the vapour phase. P4 is the first probe capable of colorimetrically differentiating between a Tabun mimic (DCNP) and a Sarin and Soman mimic (DFP).

Monitoring of Diisopropyl Fluorophosphate Hydrolysis by Fluoride-Selective Polymeric Films Using Absorbance Spectroscopy

PubMed Central

Ramanathan, Madhumati; Wang, Lin; Wild, James R.; Meyeroff, Mark E.; Simonian, Aleksandr L.

2012-01-01

In this study, a novel system for the detection and quantification of organofluorophosphonates (OFP) has been developed by using an optical sensing polymeric membrane to detect the fluoride ions produced upon OFP hydrolysis. Diisopropyl fluorophosphate (DFP), a structural analogue of Type G Chemical Warfare Agents such as Sarin (GB) and Soman (GD), is used as the surrogate target analyte. An optical sensing fluoride-ion-selective polymeric film was formulated from plasticized PVC containing aluminum(III) octaethylporphyrin and ETH 7075 chromoionophore (Al[OEP]-ETH 7075). Selected formulations were used to detect the fluoride ions produced by the catalytic hydrolysis of DFP by the enzyme organophosphate hydrolase (OPH, EC 3.1.8.1). The changes in absorbance that corresponded to the deprotonated state of chromoionophore within the film results from simultaneous co-extraction of fluoride and protons as DFP hydrolysis takes place in the solution phase in contact with the film. The developed sensing system demonstrates excellent sensitivity for concentrations as low as 0.1 µM DFP. PMID:20441875

Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition.

PubMed

Fawcett, William P; Aracava, Yasco; Adler, Michael; Pereira, Edna F R; Albuquerque, Edson X

2009-02-01

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

Expression of Membrane-Bound Human AminopeptidaseP as a Soluble Enzyme and an Investigation into Its Efficacy Towards Offering Protection Against the Toxicity of Chemical Warfare Nerve Agents

DTIC Science & Technology

2016-09-01

survival rate of guinea pigs from GF toxicity [31]. The overall catalytic efficiency of II-G1 reported by Worek against GF was 8.4 × 107 M-1 min-1 and...al., Protection against soman or VX poisoning by human butyrylcholinesterase in guinea pigs and cynomolgus monkeys. Chem Biol Interact, 2005. 157...97-102. 30. Valiyaveettil, M., et al., Protective efficacy of catalytic bioscavenger, paraoxonase 1 against sarin and soman exposure in guinea pigs

Dissociation of sarin on a cement analogue surface: Effects of humidity and confined geometry

DOE PAGES

O’Brien, Christopher J.; Greathouse, Jeffery A.; Tenney, Craig M.

2016-11-22

Here, first-principles molecular dynamics simulations were used to investigate the dissociation of sarin (GB) on the calcium silicate hydrate (CSH) mineral tobermorite (TBM), a surrogate for cement. CSH minerals (including TBM) and amorphous materials of similar composition are the major components of Portland cement, the binding agent of concrete. Metadynamics simulations were used to investigate the effect of the TBM surface and confinement in a microscale pore on the mechanism and free energy of dissociation of GB. Our results indicate that both the adsorption site and the humidity of the local environment significantly affect the sarin dissociation energy. In particular,more » sarin dissociation in a low-water environment occurs via a dealkylation mechanism, which is consistent with previous experimental studies.« less

The sources, fate, and toxicity of chemical warfare agent degradation products.

PubMed Central

Munro, N B; Talmage, S S; Griffin, G D; Waters, L C; Watson, A P; King, J F; Hauschild, V

1999-01-01

We include in this review an assessment of the formation, environmental fate, and mammalian and ecotoxicity of CW agent degradation products relevant to environmental and occupational health. These parent CW agents include several vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD), and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and Lewisite; four nerve agents (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)); and the blood agent cyanogen chloride. The degradation processes considered here include hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly address decontamination but not combustion processes. Because CW agents are generally not considered very persistent, certain degradation products of significant persistence, even those that are not particularly toxic, may indicate previous CW agent presence or that degradation has occurred. Of those products for which there are data on both environmental fate and toxicity, only a few are both environmentally persistent and highly toxic. Major degradation products estimated to be of significant persistence (weeks to years) include thiodiglycol for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl phosphonic acid, and possibly S-(2-diisopropylaminoethyl) methylphosphonothioic acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a closely related contaminant of GB, diisopropyl methylphosphonate, are also persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess high mammalian toxicity. Unlike other CW agents, sulfur mustard agents (e.g., HD) are somewhat persistent; therefore, sites or conditions involving potential HD contamination should include an evaluation of both the agent and thiodiglycol. Images Figure 1 Figure 3 Figure 5 PMID:10585900

beta-Aminoalcohols as Potential Reactivators of Aged Sarin-/Soman-Inhibited Acetylcholinesterase

DTIC Science & Technology

2017-02-08

This approach includes high - quality quantum mechanical/molecular mechanical calcula- tions, providing reliable reactivation steps and energetics...I. V. Khavrutskii Department of Defense Biotechnology High Performance Computing Software Applications Institute Telemedicine and Advanced...b] Dr. A. Wallqvist Department of Defense Biotechnology High Performance Computing Software Applications Institute Telemedicine and Advanced

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{submore » R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.« less

Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry.

PubMed

Li, He; Schopfer, Lawrence M; Nachon, Florian; Froment, Marie-Thérèse; Masson, Patrick; Lockridge, Oksana

2007-11-01

Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase (AChE) by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N, or S and Y can be methyl, OR, or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a nonreactivatable enzyme. Aging mechanisms have been studied primarily using AChE. However, some recent studies have indicated that organophosphate-inhibited butyrylcholinesterase (BChE) may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to study the aging mechanism of human BChE inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate (DFP), isomalathion, soman, sarin, cyclohexyl sarin, VX, and VR. Inhibited BChE was aged in the presence of H2O18 to allow incorporation of (18)O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate conjugates were identified through peptide mass mapping. Our results showed no aging of VX- and VR-treated BChE at 25 degrees C, pH 7.0. However, BChE inhibited by dichlorvos, echothiophate, DFP, soman, sarin, and cyclohexyl sarin aged exclusively through O-C bond cleavage, i.e., the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage.

Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes.

PubMed

Samanta, Uttamkumar; Kirby, Stephen D; Srinivasan, Prabhavathi; Cerasoli, Douglas M; Bahnson, Brian J

2009-08-15

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

An Acetylcholinesterase-Based Chronoamperometric Biosensor for Fast and Reliable Assay of Nerve Agents

PubMed Central

Pohanka, Miroslav; Adam, Vojtech; Kizek, Rene

2013-01-01

The enzyme acetylcholinesterase (AChE) is an important part of cholinergic nervous system, where it stops neurotransmission by hydrolysis of the neurotransmitter acetylcholine. It is sensitive to inhibition by organophosphate and carbamate insecticides, some Alzheimer disease drugs, secondary metabolites such as aflatoxins and nerve agents used in chemical warfare. When immobilized on a sensor (physico-chemical transducer), it can be used for assay of these inhibitors. In the experiments described herein, an AChE- based electrochemical biosensor using screen printed electrode systems was prepared. The biosensor was used for assay of nerve agents such as sarin, soman, tabun and VX. The limits of detection achieved in a measuring protocol lasting ten minutes were 7.41 × 10−12 mol/L for sarin, 6.31 × 10−12 mol/L for soman, 6.17 × 10−11 mol/L for tabun, and 2.19 × 10−11 mol/L for VX, respectively. The assay was reliable, with minor interferences caused by the organic solvents ethanol, methanol, isopropanol and acetonitrile. Isopropanol was chosen as suitable medium for processing lipophilic samples. PMID:23999806

Efficacy of the Tertiary Oxime Monoisonitrosoacetone (MINA) Against Lethal Sarin Intoxication in the Guinea Pig

DTIC Science & Technology

2007-10-01

Sarin 5a. CONTRACT NUMBER Intoxication in the Guinea Pig 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Koplovitz, I and...efficacy of MINA as a treatment for lethal sarin (GB) intoxication in guinea pigs . Male animals were challenged subcutaneously (s.c.) with 2 LD50s...oximes that are readily able to enter the brain. 15. SUBJECT TERMS oximes, brain, sarin, reactivation, nerve agents, guinea pigs 16. SECURITY

Quantitation of five organophosphorus nerve agent metabolites in serum using hydrophilic interaction liquid chromatography and tandem mass spectrometry

PubMed Central

Hamelin, Elizabeth I.; Schulze, Nicholas D.; Shaner, Rebecca L.; Coleman, Rebecca M.; Lawrence, Richard J.; Crow, Brian S.; Jakubowski, E. M.; Johnson, Rudolph C.

2015-01-01

Although nerve agent use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. Exposure can be detected through the analysis of the hydrolysis products in urine as well as blood. An analytical method to detect exposure to five nerve agents, including VX, VR (Russian VX), GB (sarin), GD (soman) and GF (cyclosarin), through the analysis of the hydrolysis products, which are the primary metabolites, in serum has been developed and characterized. This method uses solid phase extraction coupled with high performance liquid chromatography for separation and isotopic dilution tandem mass spectrometry for detection. An uncommon buffer of ammonium fluoride was used to enhance ionization and improve sensitivity when coupled with hydrophilic interaction liquid chromatography resulting in detection limits from 0.3–0.5 ng/mL. The assessment of two quality control samples demonstrated high accuracy (101–105%) and high precision (5–8%) for the detection of these five nerve agent hydrolysis products in serum. PMID:24633507

Study of efficacy of reactivator HI 6 in reactivation of immobilized acetylcholinesterase, inhibited by organophosphorus chemical warfare agents of the "G" series.

PubMed

Hoskovcová, Monika; Halámek, Emil; Kobliha, Zbynĕk

2009-01-01

Reactivation with bis quaternary aldoxime HI-6, chemical formula 1-(2-hydroxyamino-methylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride of immobilized enzyme acetylcholinesterase inhibited by nerve agent type "G" was studied. This aldoxime is effective in reactivation of sarin-inhibited acetylcholinesterase. Substantially lower reactivation potency was observed with cyclosarin-inhibited enzyme and almost no effect was found for that acetylcholinesterase is the enzyme complex. HI 6 is completely ineffective towards the soman-inhibited enzyme: After a 2-minute inhibition of the enzyme with soman no ability to define reactivator the inhibited enzymes and complexes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Talbot, B.G.; Lennox, W.J.

A pretreatment for organophosphorus (OP) anticholinesterase (e. g. , soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts MG/KG, IM tested were akineton 0.25, aprophen 8, trihexyphenidyl 2, atropine 16, azaprophen 51, BENACTYZINE 1.25, cogentin 4, dextromethorphan 7.5, ethopropazine 12, kemadrin 11, MEMANTINE 5, promethazine 5, scopolamine 0.081 AND CONTROL 2. PRGs were given 30 min before soman (60 ug/kg, sc; 2 LD50S) or other OP agents. Animals were then observed and graded for signs ofmore » intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs. Pretreatment, physostigmine, anticholinesterases, soman (GD).« less

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

PubMed Central

Abou-Donia, Mohamed B.; Siracuse, Briana; Gupta, Natasha; Sokol, Ashly Sobel

2017-01-01

Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as “cholinergic crisis” (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam. PMID:27705071

Catalytic soman scavenging by Y337A/F338A acetylcholinesterase mutant assisted with novel site-directed aldoximes

PubMed Central

Kovarik, Zrinka; Hrvat, Nikolina Maček; Katalinić, Maja; Sit, Rakesh K.; Paradyse, Alexander; Žunec, Suzana; Musilek, Kamil; Fokin, Valery V.; Taylor, Palmer; Radić, Zoran

2016-01-01

Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin and paraoxon inhibition. We here demonstrate that ex vivo, in whole human blood, 1 μM soman was detoxified within 30 minutes when supplemented with 0.5 μM Y337A/F338A AChE and 100 μM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of forty-two pyridinium aldoximes, and five imidazole 2-aldoxime N-propyl pyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2–3 –fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack. PMID:25835984

Supralethal poisoning by any of the classical nerve agents is effectively counteracted by procyclidine regimens in rats.

PubMed

Myhrer, Trond; Mariussen, Espen; Enger, Siri; Aas, Pål

2015-09-01

A treatment regimen consisting of HI-6, levetiracetam, and procyclidine (termed the triple regimen) has previously been shown to work as a universal therapy against soman poisoning in rats, since it has capacities to function as both prophylactic and therapeutic measure. The purpose of the present study was to examine whether the triple regimen may have antidotal efficacy against intoxication by other classical nerve agents than soman. The treatment was given 1 and 5 min after exposure to a supralethal dose of nerve agents, and the results showed that the triple regimen successfully prevented or terminated seizures and preserved the lives of rats exposed to 5×LD50 of soman, sarin, cyclosarin, or VX, but solely 3×LD50 of tabun was managed by this regimen. To meet the particular antidotal requirements of tabun, the triple regimen was reinforced with obidoxime and was made to a quadruple regimen that effectively treated rats intoxicated by 5×LD50 of tabun. The rats recovered very well and the majority gained pre-exposure body weight within 7 days. Neuropathology was seen in all groups regardless of whether the rats seized or not. The most extensive damage was produced by sarin and cyclosarin. Differentiation between the nerve agents' potency to cause lesions was probably seen because the efficacious treatments ensured survival of supralethal poisoning. A combination of 2 oximes and 2 anticonvulsants may be a prerequisite to counteract effectively high levels of poisoning by any classical nerve agent. Copyright © 2015 Elsevier Inc. All rights reserved.

Fluorescent discrimination between traces of chemical warfare agents and their mimics.

PubMed

Díaz de Greñu, Borja; Moreno, Daniel; Torroba, Tomás; Berg, Alexander; Gunnars, Johan; Nilsson, Tobias; Nyman, Rasmus; Persson, Milton; Pettersson, Johannes; Eklind, Ida; Wästerby, Pär

2014-03-19

An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.

An in vitro and in vivo evaluation of the efficacy of recombinant human liver prolidase as a catalytic bioscavenger of chemical warfare nerve agents.

PubMed

Rezk, Peter E; Zdenka, Pierre; Sabnekar, Praveena; Kajih, Takwen; Mata, David G; Wrobel, Chester; Cerasoli, Douglas M; Chilukuri, Nageswararao

2015-01-01

In this study, we determined the ability of recombinant human liver prolidase to hydrolyze nerve agents in vitro and its ability to afford protection in vivo in mice. Using adenovirus containing the human liver prolidase gene, the enzyme was over expressed by 200- to 300-fold in mouse liver and purified to homogeneity by affinity and gel filtration chromatography. The purified enzyme hydrolyzed sarin, cyclosarin and soman with varying rates of hydrolysis. The most efficient hydrolysis was with sarin, followed by soman and by cyclosarin {apparent kcat/Km [(1.9 ± 0.3), (1.7 ± 0.2), and (0.45 ± 0.04)] × 10(5 )M(-1 )min(-1), respectively}; VX and tabun were not hydrolyzed by the recombinant enzyme. The enzyme hydrolyzed P (+) isomers faster than the P (-) isomers. The ability of recombinant human liver prolidase to afford 24 hour survival against a cumulative dose of 2 × LD50 of each nerve agent was investigated in mice. Compared to mice injected with a control virus, mice injected with the prolidase expressing virus contained (29 ± 7)-fold higher levels of the enzyme in their blood on day 5. Challenging these mice with two consecutive 1 × LD50 doses of sarin, cyclosarin, and soman resulted in the death of all animals within 5 to 8 min from nerve agent toxicity. In contrast, mice injected with the adenovirus expressing mouse butyrylcholinesterase, an enzyme which is known to afford protection in vivo, survived multiple 1 × LD50 challenges of these nerve agents and displayed no signs of toxicity. These results suggest that, while prolidase can hydrolyze certain G-type nerve agents in vitro, the enzyme does not offer 24 hour protection against a cumulative dose of 2 × LD50 of G-agents in mice in vivo.

Evaluation of Chemical Warfare Agent Wipe Sampling ...

EPA Pesticide Factsheets

Report This investigation tested specific (CWAs), including sarin (GB), soman (GD), cyclosarin (GF), sulfur mustard (HD), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) on the non-ideal (e.g., porous and permeable) surfaces of drywall, vinyl tile, wood, laminate, and coated glass. Pesticides (diazinon and malathion) were used so that a comparison is possible with existing literature data (1). Experiments included testing with coupons having surface areas of 10 cm2 and 100 cm2. The 10-cm2 coupons were of a size that could easily be extracted in a 2 oz jar (to provide comparative data for CWA recoveries generated by direct extraction) and the 100-cm2 coupons better represented the area of a surface that might typically be sampled by wipe extraction. In addition, CWA, at a normalized surface concentration of 0.1 µg per cm2 surface area, were spiked on coupons of the tested surfaces. Wipes were wetted with either dichloromethane (DCM) or isopropanol (IPA) before sampling for CWA. Experimental parameters include multiple wipe types, porous/permeable surfaces, coupon surface area, solvent used to wet the wipe (i.e., wetting solvent), and the utility of VX-d14 as an extracted internal standard.

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes.

DTIC Science & Technology

1999-10-01

nerve gas intoxication, as well as of insecticide poisoning. Such structures can yield direct information concerning the functional groups and steric...Glyll7His mutant (48). Recent solution of the 3D structures of conjugates of the nerve agents , sarin, soman, DFP and VX with 7cAChE (49, 50) has revealed... pesticides and chemical warfare agents is a topic of considerable environmental and toxicological importance. Hence, a substantial research effort is being

Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure

DTIC Science & Technology

2016-05-09

Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure Amanda S. Appel,† John H. McDonough,‡ Joseph D...feasible. In this study, hair was evaluated as a long-term repository of nerve agent hydrolysis products. Pinacolyl methylphosphonic acid (PMPA...hydrolysis product of soman) and isopropyl methylphosphonic acid (IMPA; hydrolysis product of sarin) were extracted from hair samples with N,N

Evaluating the Anti-Seizure Efficacy of Novel Adenosine Treatment Regimens in a Soman Rat Model

DTIC Science & Technology

2015-06-01

activity following DPCPX treatment. However, 9 of the 12 rats proceeded to develop seizures and entered status epilepticus (Figure 4). This reaction was...onset. However, stopping status epilepticus once it develops is much more difficult than preventing its onset. The mechanism for terminating seizure...sarin. J Pharmacol Exp Ther 304(3): 1307- 1313. Compton, J. R. (2004). Adenosine Receptor Agonist Pd 81,723 Protects Against Seizure/ Status

Extraction Methodological Contributions Toward Ultra-Performance Liquid ChromatographyTime-of-Flight Mass Spectrometry: Quantification of Free GB from Various Food Matrices

DTIC Science & Technology

2016-02-01

SPECTROMETRY: QUANTIFICATION OF FREE GB FROM VARIOUS FOOD MATRICES ECBC-TR-1351 Sue Y. Bae Mark D. Winemiller RESEARCH AND TECHNOLOGY DIRECTORATE...Flight Mass Spectrometry: Quantification of Free GB from Various Food Matrices 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER...methylphosphonofluoridate (sarin, GB) in various food matrices. The development of a solid-phase extraction method using a normal-phase silica gel column for

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes.

PubMed

RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-04-04

Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2×LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents.

Low Dose Sarin Leads To Murine Cardiac Dysfunction

DTIC Science & Technology

2010-03-01

work directly supported a grant held by Wright State University, grant # GW060050, from the United States Army Medical Research Acquisition Activity ...GB), acts as an irreversible AChE inhibitor. Sarin reacts with the serine hydroxyl residue in the active site of AChE to form a phosphate or...United States Air Force has become increasingly engaged with terrorist groups and other elusive enemies. As these activities increase, the potential for

Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

DTIC Science & Technology

2008-03-01

throughout history where nerve agents have been used on human populations, such as the subway bombing in Tokyo and Matsumoto, Japan. Data can be...kidney, fat, diaphragm, arterial blood, venous blood, bronchial passages, and the skin. The remaining tissues will be lumped together as either slowly...were then further developed as a weapon, whose primary effect is on the central nervous system. These agents are tabun, sarin, soman, and VX. They

Neuroprotective Mechanisms Activated in Non-seizing Rats Exposed to Sarin

DTIC Science & Technology

2015-06-04

after kainic acid-induced seizures. Brain Res. 1424, 1–8. Johnson, E.A., Kan, R.K., 2010. The acute phase response and soman-induced status epilepticus ...2011. Comparison of status epilepticus models induced by pilocarpine and nerve agents – a systematic review of the underlying aetiology and adopted...2007) Nqo2 Loss of Nqo1 and Nqo2 leads to altered intracellular redox status , decreased expression and activation of NF-κB, and altered

Efficacy of liquid and foam decontamination technologies for chemical warfare agents on indoor surfaces.

PubMed

Love, Adam H; Bailey, Christopher G; Hanna, M Leslie; Hok, Saphon; Vu, Alex K; Reutter, Dennis J; Raber, Ellen

2011-11-30

Bench-scale testing was used to evaluate the efficacy of four decontamination formulations on typical indoor surfaces following exposure to the liquid chemical warfare agents sarin (GB), soman (GD), sulfur mustard (HD), and VX. Residual surface contamination on coupons was periodically measured for up to 24h after applying one of four selected decontamination technologies [0.5% bleach solution with trisodium phosphate, Allen Vanguard Surface Decontamination Foam (SDF™), U.S. military Decon Green™, and Modec Inc. and EnviroFoam Technologies Sandia Decontamination Foam (DF-200)]. All decontamination technologies tested, except for the bleach solution, performed well on nonporous and nonpermeable glass and stainless-steel surfaces. However, chemical agent residual contamination typically remained on porous and permeable surfaces, especially for the more persistent agents, HD and VX. Solvent-based Decon Green™ performed better than aqueous-based bleach or foams on polymeric surfaces, possibly because the solvent is able to penetrate the polymer matrix. Bleach and foams out-performed Decon Green for penetrating the highly polar concrete surface. Results suggest that the different characteristics needed for an ideal and universal decontamination technology may be incompatible in a single formulation and a strategy for decontaminating a complex facility will require a range of technologies. Copyright © 2011 Elsevier B.V. All rights reserved.

Pretreatment with human serum butyrylcholinesterase alone prevents cardiac abnormalities, seizures, and death in Göttingen minipigs exposed to sarin vapor.

PubMed

Saxena, Ashima; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Hastings, Nicholas B; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

2011-12-15

Human serum butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a prophylactic countermeasure against organophosphorus nerve agents. This study was designed to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to a lethal dose of sarin (GB) vapor. Male Göttingen minipigs were subjected to: air exposure, GB vapor exposure, or pretreatment with Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection 24 h prior to exposure to 4.1 mg/m(3) of GB vapor for 60 min. Electrocardiograms (ECG), electroencephalograms (EEG), and pupil size were recorded throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB present. Untreated animals exposed to GB vapor exhibited cardiac abnormalities and generalized seizures, ultimately succumbing to respiratory failure. Pretreatment with 3.0 or 6.5 mg/kg of Hu BChE delayed blood gas and acid-base disturbances and the onset of cardiac and neural toxic signs, but failed to increase survivability. Pretreatment with 7.5 mg/kg of Hu BChE, however, completely prevented toxic signs, with blood chemistry and ECG and EEG parameters indistinguishable from control during and after GB exposure. GB bound in plasma was 200-fold higher than plasma from pigs that did not receive Hu BChE, suggesting that Hu BChE scavenged GB in blood and prevented it from reaching other tissues. Thus, prophylaxis with Hu BChE alone not only increased survivability, but also prevented cardiac abnormalities and neural toxicity in minipigs exposed to a lethal dose of GB vapor. Published by Elsevier Inc.

Chemical Warfare Agent Surface Adsorption: Hydrogen Bonding of Sarin and Soman to Amorphous Silica

DTIC Science & Technology

2014-03-17

Prior to experiments, the gas manifold and dosing lines were heated, under vacuum, to 100 °C to minimize water contamination. A stainless steel ...23 L UHV chamber constructed out of 316L stainless steel with all ports equipped with con-flat flanges (Kurt J. Lesker Company). The chamber is...dosed as a neat vapor using a multivalved stainless steel high-vacuum manifold. The entire path of the manifold was evacuated and heated to 100 °C

Effects of low-level sarin and cyclosarin exposure on hippocampal subfields in Gulf War Veterans.

PubMed

Chao, Linda L; Kriger, Stephen; Buckley, Shannon; Ng, Peter; Mueller, Susanne G

2014-09-01

More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Gulf War (GW). We previously reported reduced hippocampal volume in GW veterans with suspected GB/GF exposure relative to matched, unexposed GW veterans estimated from 1.5T magnetic resonance images (MRI). Here we investigate, in a different cohort of GW veterans, whether low-level GB/GF exposure is associated with structural alterations in specific hippocampal subfields, estimated from 4T MRI. The Automatic Segmentation of Hippocampal Subfields (ASHS) technique was used to quantify CA1, CA2, CA3 and dentate gyrus (DG), and subiculum (SUB) subfields volumes from high-resolution T2-weighted images acquired on a 4T MR scanner in 56 GW veterans with suspected GB/GF exposure and 56 "matched" unexposed GW veterans (mean age 49±7 years). GB/GF exposed veterans had smaller CA2 (p=0.003) and CA3/DG (p=0.01) subfield volumes compared to matched, unexposed GW veterans. There were no group difference in total hippocampal volume, quantified with FreeSurfer, and no dose-response relationship between estimated levels of GB/GF exposure and total hippocampal or subfield volume. These findings extend our previous report of structural alterations in the hippocampi of GW veterans with suspected GB/GF exposure to volume changes in the CA2, CA3, and DG hippocampal subfields in a different cohort of GW veterans with suspected GB/GF exposure. Published by Elsevier B.V.

CG-MS/MS Analyses of Biological Samples in Support of Developmental Toxic Effects on Whole-Body Exposure of Rats to GB

DTIC Science & Technology

2015-03-01

Sensitivity to Organophosphorous Anticholinesterase Compounds. Prog. Neurobiol. 1987, 28, 97–129. Shih, T-M.; Penetar, D.M.; McDonough, J.H. Jr.; Romano...J.A.; King, J.M. Age- related Differences in Soman Toxicity and in Blood and Brain Regional Cholinesterase Activity . Brain Res. Bull. 1990, 24...Organophosphates. Toxicol. Appl. Pharmacol. 2004, 198, 132–151. Sterri, S.H.; Berge, G.; Fonnum, F. Esterase Activities and Soman Toxicity in

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun†,‡

PubMed Central

Fleming, Christopher D.; Edwards, Carol C.; Kirby, Stephen D.; Maxwell, Donald M.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

2008-01-01

The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 Å resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 104-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure. PMID:17407327

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

PubMed Central

2014-01-01

Background Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Results Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Conclusion Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents. PMID:24708580

GC-MS/MS Analyses of Biological Samples in Support of Developmental Toxic Effects on Subcutaneous Exposure of Rats to GB

DTIC Science & Technology

2015-11-01

cholinergic symptoms after the release of GB in the Tokyo subway system (Ohbu et al., 1997). In fact, infants and small children may be at greater...Matsui, R.; Sakurai, K.; Hinohara, S. Sarin Poisoning on Tokyo Subway . South. Med. J. 1997, 90, 587–593. Russell, R.W.; Overstreet, D.H. Mechanisms

Indoor sorption of surrogates for sarin and related nerve agents.

PubMed

Singer, Brett C; Hodgson, Alfred T; Destaillats, Hugo; Hotchi, Toshifumi; Revzan, Kenneth L; Sextro, Richard G

2005-05-01

Sorption rate parameters were determined for three organophosphorus (OP) compounds [dimethyl methylphosphonate (DMMP), diethyl ethylphosphonate (DEEP), and triethyl phosphate (TEP)] as surrogates for the G-type nerve agents sarin (GB), soman (GD), and tabun (GA). OP surrogates were injected and vaporized with additional volatile organic compounds into a 50 m3 chamber finished with painted wallboard. Experiments were conducted at two furnishing levels: (i) chamber containing only hard surfaces including a desk, a bookcase, tables, and chairs and (ii) with the addition of plush materials including carpet with cushion, draperies, and upholstered furniture. Each furnishing level was studied with aged and new painted wallboard. Gas-phase concentrations were measured during sealed chamber adsorb and desorb phases and then fit to three mathematical variations of a previously proposed sorption model having a surface sink and allowing for an embedded sink. A four-parameter model allowing unequal transport rates between surface and embedded sinks provided excellent fits for all conditions. To evaluate the potential effect of sorption, this model was incorporated into an indoor air quality simulation model to predict indoor concentrations of a G-type agent and a nonsorbing agent for hypothetical outdoor releases with shelter-in-place (SIP) response. Sorption was simulated using a range of parameters obtained experimentally. Simulations considered outdoor Gaussian plumes of 1- and 5-h duration and infiltration rates of 0.1, 0.3, and 0.9 h(-1). Indoor toxic loads (TL) for a 10-h SIP were calculated as integral C2 dt for a G-type agent. For the 5-h plume, sheltering reduced TLs for the nonsorbing agent to approximately 10-65% of outdoor levels. Analogous TLs for a G-type agent were 2-31% or 0.3-12% of outdoor levels assuming slow or moderate sorption. The relative effect of sorption was more pronounced for the longer plume and higher infiltration rates.

Selective Surface Acoustic Wave-Based Organophosphorus Sensor Employing a Host-Guest Self-Assembly Monolayer of β-Cyclodextrin Derivative

PubMed Central

Pan, Yong; Mu, Ning; Shao, Shengyu; Yang, Liu; Wang, Wen; Xie, Xiao; He, Shitang

2015-01-01

Self-assembly and molecular imprinting technologies are very attractive technologies for the development of artificial recognition systems and provide chemical recognition based on need and not happenstance. In this paper, we employed a β-cyclodextrin derivative surface acoustic wave (SAW) chemical sensor for detecting the chemical warfare agents (CWAs) sarin (O-Isoprophyl methylphosphonofluoridate, GB). Using sarin acid (isoprophyl hydrogen methylphosphonate) as an imprinting template, mono[6-deoxy-6-[(mercaptodecamethylene)thio

Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans

PubMed Central

Chao, Linda L.; Rothlind, Johannes C.; Cardenas, Valerie A.; Meyerhoff, Dieter J.; Weiner, Michael W.

2010-01-01

Background Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Methods Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002–2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. Results GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p≤0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. Conclusions These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. PMID:20580739

Prophylaxis with human serum butyrylcholinesterase protects Göttingen minipigs exposed to a lethal high-dose of sarin vapor.

PubMed

Saxena, Ashima; Hastings, Nicholas B; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

2015-08-05

Serum-derived human butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a potential prophylactic nerve agent countermeasure. Previously, we reported the prophylactic efficacy of Hu BChE in Göttingen minipigs against a whole-body exposure to 4.1mg/m(3) of sarin (GB) vapor, which produced lethality over 60min. Since the toxicity of nerve agent is concentration-dependent, in the present study, we investigated the toxic effects of an almost 3-fold higher rate of GB vapor exposure and the ability of Hu BChE to protect minipigs against this exposure. Male minipigs were subjected to: (1) air exposure; (2) GB vapor exposure; or (3) pretreatment with 7.5mg/kg of Hu BChE by i.m. injection, 24h prior to whole-body exposure to 11.4mg/m(3) of GB vapor for 10min. Electrocardiogram, electroencephalogram, and pupil size were monitored throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB bound to red blood cells and plasma. A novel finding was that saline-treated animals exposed to GB vapor did not develop any seizures, but manifested a variety of cardiac and whole blood toxic signs and rapidly died due to respiratory failure. Strikingly, pre-treatment with 7.5mg/kg of Hu BChE not only prevented lethality, but also avoided all cardiac toxic signs manifested in the non-treated cohort. Thus, Hu BChE alone can serve as an effective prophylactic countermeasure versus a lethal high-dose exposure to GB vapor. Published by Elsevier Ireland Ltd.

Efficacy of human serum butyrylcholinesterase against sarin vapor.

PubMed

Saxena, Ashima; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Hastings, Nicholas B; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

2008-09-25

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a pretreatment drug for organophosphate (OP) poisoning in humans. It was shown to protect mice, rats, guinea pigs, and monkeys against multiple LD(50) challenges of OP nerve agents by i.v. or s.c. bolus injections. Since inhalation is the most likely route of exposure to OP nerve agents on the battlefield or in public places, the aim of this study was to evaluate the efficacy of Hu BChE against whole-body inhalation exposure to sarin (GB) vapor. Male Göttingen minipigs were subjected to one of the following treatments: (1) air exposure; (2) GB vapor exposure; (3) pretreatment with 3 mg/kg of Hu BChE followed by GB vapor exposure; (4) pretreatment with 6.5 mg/kg of Hu BChE followed by GB vapor exposure; (5) pretreatment with 7.5 mg/kg of Hu BChE followed by GB vapor exposure. Hu BChE was administered by i.m. injection, 24h prior to whole-body exposure to GB vapor at a concentration of 4.1 mg/m(3) for 60 min, a dose lethal to 99% of untreated exposed pigs (LCt99). EEG, ECG, and pupil size were monitored throughout exposure, and blood drawn from a surgically implanted jugular catheter before and throughout the exposure period, was analyzed for acetylcholinesterase (AChE) and BChE activities, and the amount of GB present in plasma. All animals exposed to GB vapor alone or pretreated with 3 or 6.5 mg/kg of Hu BChE, died following exposure to GB vapor. All five animals pretreated with 7.5 mg/kg of Hu BChE survived the GB exposure. The amount of GB bound in plasma was 200-fold higher compared to that from plasma of pigs that did not receive Hu BChE, suggesting that Hu BChE was effective in scavenging GB in blood. Additionally, pretreatment with 7.5 mg/kg of Hu BChE prevented cardiac abnormalities and seizure activity observed in untreated animals and those treated with lower doses of Hu BChE.

Department of Defense Chemical and Biological Defense Program. Volume I: Annual Report to Congress

DTIC Science & Technology

2002-04-01

The M21 RSCAAL is an automatic scanning, passive infrared sensor that detects nerve ( GA , GB, and GD) and blister (H and L) agent vapor clouds based on...Point Detection GA - tabun, a nerve agent System GAO - General Accounting Office IPE - Individual Protective Equipment GAS - Group A Streptococcus...IPR - In-Process Review GB - sarin , a nerve agent IPT - Integrated Product Team GC - gas chromatography IR&D - Independent Research & Development GD

Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans.

PubMed

Chao, Linda L; Rothlind, Johannes C; Cardenas, Valerie A; Meyerhoff, Dieter J; Weiner, Michael W

2010-09-01

Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002 and 2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p< or =0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. Copyright © 2010 Elsevier Inc. All rights reserved.

In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate.

PubMed

O'Donnell, John C; McDonough, John H; Shih, Tsung-Ming

2011-12-01

Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.

Stable adducts of nerve agents sarin, soman and cyclosarin with TRIS, TES and related buffer compounds--characterization by LC-ESI-MS/MS and NMR and implications for analytical chemistry.

PubMed

Gäb, Jürgen; John, Harald; Melzer, Marco; Blum, Marc-Michael

2010-05-15

Buffering compounds like TRIS are frequently used in chemical, biochemical and biomedical applications to control pH in solution. One of the prerequisites of a buffer compound, in addition to sufficient buffering capacity and pH stability over time, is its non-reactivity with other constituents of the solution. This is especially important in the field of analytical chemistry where analytes are to be determined quantitatively. Investigating the enzymatic hydrolysis of G-type nerve agents sarin, soman and cyclosarin in buffered solution we have identified stable buffer adducts of TRIS, TES and other buffer compounds with the nerve agents. We identified the molecular structure of these adducts as phosphonic diesters using 1D (1)H-(31)P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates with TRIS and TES are fast enough to compete with spontaneous hydrolysis in aqueous solution and to yield substantial amounts (up to 20-40%) of buffer adduct over the course of several hours. A reaction mechanism is proposed in which the amino function of the buffer serves as an intramolecular proton acceptor rendering the buffer hydroxyl groups nucleophilic enough for attack on the phosphorus atom of the agents. Results show that similar buffer adducts are formed with a range of hydroxyl and amino function containing buffers including TES, BES, TRIS, BIS-TRIS, BIS-TRIS propane, Tricine, Bicine, HEPES and triethanol amine. It is recommended to use alternative buffers like MOPS, MES and CHES when working with G-type nerve agents especially at higher concentrations and over prolonged times. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging.

PubMed

Nachon, Florian; Asojo, Oluwatoyin A; Borgstahl, Gloria E O; Masson, Patrick; Lockridge, Oksana

2005-02-01

Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.

Phosphotriesterase variants with high methylphosphonatase activity and strong negative trade-off against phosphotriesters.

PubMed

Briseño-Roa, Luis; Timperley, Christopher M; Griffiths, Andrew D; Fersht, Alan R

2011-01-01

The most lethal organophosphorus nerve agents (NA), like sarin, soman, agent-VX and Russian-VX, share a methylphosphonate moiety. Pseudomonas diminuta phosphotriesterase (PTE) catalyses the hydrolysis of methylphosphonate NA analogues with a catalytic efficiency orders of magnitude lower than that towards the pesticide paraoxon. With a view to obtaining PTE variants that more readily accept methylphosphonate NA, ~75,000 PTE variants of the substrate-binding residues Gly-60, Ile-106, Leu-303 and Ser-308 were screened with fluorogenic analogues of the NA Russian-VX and cyclosarin. Seven new PTE variants were isolated, purified and their k(cat)/K(M) determined against five phosphotriesters and five methylphosphonate analogues of sarin, cyclosarin, soman, agent-VX and Russian-VX. The novel PTE variants exhibited as much as a 10-fold increase in activity towards the methylphosphonate compounds--many reaching a k(cat)/K(M) of 10⁶ M⁻¹ s⁻¹--and as much as a 29,000-fold decrease in their phosphotriesterase activity. The mutations found in two of the variants, SS0.5 (G60V/I106L/S308G) and SS4.5 (G60V/I106A/S308G), were modelled into a high-resolution structure of PTE-wild type and docked with analogues of cyclosarin and Russian-VX using Autodock 4.2. The kinetic data and docking simulations suggest that the increase in activity towards the methylphosphonates and the loss of function against the phosphotriesters were due to an alteration of the shape and hydrophobicity of the binding pocket that hinders the productive binding of non-chiral racemic phosphotriesters, yet allows the binding of the highly asymmetric methylphosphonates.

Protection against soman-induced neuropathology and respiratory failure: a comparison of the efficacy of diazepam and avizafone in guinea pig.

PubMed

Taysse, L; Daulon, S; Delamanche, S; Bellier, B; Breton, P

2006-08-01

The purpose of this study was to compare the efficacy of diazepam and the pro-diazepam avizafone in preventing the severity of soman-induced pathology in guinea pig. Survival, respiration and seizures of experimental animals were investigated with on-line monitoring of respiratory and EEG parameters. Guinea pigs were pretreated with pyridostigmine (0.1mg/kg i.m.) and 30 min later challenged with 1 or 2 LD50 soman. One minute after intoxication they were treated with atropine (3 or 33.8 mg/kg), pralidoxime chloride (32 mg/kg) and either diazepam (2 mg/kg), avizafone (3.5 mg/kg) or saline solution. The highest dose of atropine (33.8 mg/kg) gave a protective effect in groups treated without anticonvulsants by reducing the severity of clinical signs and death within 24 h but also by decreasing seizure occurrence and brain injuries. When injected at the similar molar dose of 7 micromoles/kg, the protection of anticonvulsants against soman neurotoxicity was higher with the atropine/pralidoxime/avizafone combination than with atropine/pralidoxime/diazepam. Indeed, when atropine was used at the lowest dose, avizafone was found to prevent early mortality and seizures occurrence with better efficacy than diazepam. On the other hand, when added to the therapy, the both anticonvulsants did not prevent the moderate EEG depression (reduction of amplitude by 30-52%) observed under 2 LD50 soman. Moreover, the number of animals suffering from respiratory distress (defined as a decrease of minute ventilation of more than 20% from the baseline value) was enhanced when diazepam or avizafone were used in the therapy. This effect was dependent on the atropine dose and the nature of the anticonvulsant. The beneficial effects of the different therapeutics tested were assessed and compared to the previous data obtained with the same therapies against sarin and from the pharmacokinetics properties of the atropine/diazepam mixture.

Vesicants and nerve agents in chemical warfare. Decontamination and treatment strategies for a changed world.

PubMed

Devereaux, Asha; Amundson, Dennis E; Parrish, J S; Lazarus, Angeline A

2002-10-01

Vesicants and nerve agents have been used in chemical warfare for ages. They remain a threat in today's altered political climate because they are relatively simple to produce, transport, and deploy. Vesicants, such as mustard and lewisite, can affect the skin, eyes, respiratory system, and gastrointestinal system. They leave affected persons at risk for long-term effects. Nerve agents, such as tabun, sarin, soman, and VX, hyperstimulate the muscarinic and nicotinic receptors of the nervous system. Physicians need to familiarize themselves with the clinical findings of such exposures and the decontamination and treatment strategies necessary to minimize injuries and deaths.

Effects of low-level sarin and cyclosarin exposure and Gulf War Illness on brain structure and function: a study at 4T.

PubMed

Chao, Linda L; Abadjian, Linda; Hlavin, Jennifer; Meyerhoff, Deiter J; Weiner, Michael W

2011-12-01

More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Persian Gulf War (GW). We previously found reduced total gray matter (GM) volume in 40 GW veterans with suspected GB/GF exposure relative to 40 matched, unexposed GW veterans on a 1.5T MR scanner. In this study, we reexamine the relationship between GB/GF exposure and volumetric measurements of gross neuroanatomical structures in a different cohort of GW veterans on a 4T MR scanner. Neuropsychological and magnetic resonance imaging (MRI) data from a cross sectional study on Gulf War Illness performed between 2005 and 2010 were used in this study. 4T MRI data were analyzed using automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Binary comparisons of 64 GB/GF exposed veterans and 64 'matched', unexposed veterans revealed reduced GM (p=0.03) and WM (p=0.03) volumes in the exposed veterans. Behaviorally, exposed veterans committed more errors of omission (p=0.02) and tended to have slower responses (p=0.05) than unexposed veterans on the Continuous Performance Test (CPT), a measure sustained and selective attention. Regression analyses confirmed that GB/GF exposure status predicted GM (β=-0.11, p=0.02) and WM (β=-0.14, p=0.03) volumes, and number of CPT omission errors (β=0.22, p=0.02) over and above potentially confounding demographic, clinical, and psychosocial variables. There was no dose-response relationship between estimated levels of GB/GF exposure and brain volume. However, we did find an effect of Gulf War Illness/Chronic Multisymptom Illness on both GM and WM volume in the GB/GF exposed veterans. These findings confirm previous reports by our group and others of central nervous system pathology in GW veterans with suspected exposure to low levels of GB/GF two decades after the exposure. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans.

PubMed

Chao, Linda L; Zhang, Yu; Buckley, Shannon

2015-05-01

We previously found evidence of reduced gray and white matter volume in Gulf War (GW) veterans with predicted low-level exposure to sarin (GB) and cyclosarin (GF). Because loss of white matter tissue integrity has been linked to both gray and white matter atrophy, the current study sought to test the hypothesis that GW veterans with predicted GB/GF exposure have evidence of disrupted white matter microstructural integrity. Measures of fractional anisotropy and directional (i.e., axial and radial) diffusivity were assessed from the 4T diffusion tensor images (DTI) of 59 GW veterans with predicted GB/GF exposure and 59 "matched" unexposed GW veterans (mean age: 48 ± 7 years). The DTI data were analyzed using regions of interest (ROI) analyses that accounted for age, sex, total brain gray and white matter volume, trauma exposure, posttraumatic stress disorder, current major depression, and chronic multisymptom illness status. There were no significant group differences in fractional anisotropy or radial diffusivity. However, there was increased axial diffusivity in GW veterans with predicted GB/GF exposure compared to matched, unexposed veterans throughout the brain, including the temporal stem, corona radiata, superior and inferior (hippocampal) cingulum, inferior and superior fronto-occipital fasciculus, internal and external capsule, and superficial cortical white matter blades. Post hoc analysis revealed significant correlations between higher fractional anisotropy and lower radial diffusivity with better neurobehavioral performance in unexposed GW veterans. In contrast, only increased axial diffusivity in posterior limb of the internal capsule was associated with better psychomotor function in GW veterans with predicted GB/GF exposure. The finding that increased axial diffusivity in a region of the brain that contains descending corticospinal fibers was associated with better psychomotor function and the lack of significant neurobehavioral deficits in veterans with predicted GB/GF exposure hint at the possibility that the widespread increases in axial diffusivity that we observed in GW veterans with predicted GB/GF exposure relative to unexposed controls may reflect white matter reorganization after brain injury (i.e., exposure to GB/GF). Published by Elsevier B.V.

Protection by butyrylcholinesterase against organophosphorus poisoning in nonhuman primates. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Broomfield, C.A.; Maxwell, D.M.; Solana, R.P.

1991-12-31

Butyrylcholinesterase (BuChE) was examined as an in vivo exogenous scavenger for highly toxic organophosphorus (OP) poisons. Protection studies with equine BuChE were carried out in rhesus monkeys trained to perform a Serial Probe Recognition task. The pharmacokinetics of equine BuChE administered i.v. in rhesus monkeys revealed an elimination T1/2 of -620 hr. Animals given 503 nmol of BuChE i.v. and then challenged with 220 to 260 nmol of soman (two LD50; a lethal dose in untreated animals) all survived with no clinical signs of OP poisoning. Serial Probe Recognition performance was depressed after enzyme administration and at 1 hr postsoman.more » However, all monkeys performed the task at base-line levels at 8 hr after soman and throughout the remainder of the experimental period. Two different monkeys each were given two doses of sarin, 183 nmol/ dose (one LD50) after 460 nmol of BuChE. No signs were observed. A third group of monkeys given 253 or 340 nmol (three and four LD50, respectively) of soman after 460 nmol of BuChE required 1 mg/kg of atropine i.v. 1 0 min postsoman, but recovered completely within 24 hr. Our results indicate that BuChE has the required properties to function as a biological scavenger to protect against the pharmacological and behavioral toxicity of OP poisons. Exogenous scavenger, butyrylcholinesterase, nerve agent.« less

Fate of chemical warfare agents and toxic industrial chemicals in landfills.

PubMed

Bartelt-Hunt, Shannon L; Barlaz, Morton A; Knappe, Detlef R U; Kjeldsen, Peter

2006-07-01

One component of preparedness for a chemical attack is planning for the disposal of contaminated debris. To assess the feasibility of contaminated debris disposal in municipal solid waste (MSW) landfills, the fate of selected chemical warfare agents (CWAs) and toxic industrial chemicals (TICs) in MSW landfills was predicted with a mathematical model. Five blister agents [sulfur mustard (HD), nitrogen mustard (HN-2), lewisite (L), ethyldichloroarsine (ED), and phosgene oxime (CX)], eight nerve agents [tabun (GA), sarin (GB), soman (GD), GE, GF, VX, VG, and VM], one riot-control agent [CS], and two TICs [furan and carbon disulfide] were studied. The effects of both infiltration (climate) and contaminant biodegradability on fate predictions were assessed. Model results showed that hydrolysis and gas-phase advection were the principal fate pathways for CWAs and TICs, respectively. Apart from CX and the TICs, none of the investigated compounds was predicted to persist in a landfill for more than 5 years. Climate had little impact on CWA/TIC fate, and biodegradability was only important for compounds with long hydrolysis half-lives. Monte Carlo simulations were performed to assess the influence of uncertainty in model input parameters on CWA/TIC fate predictions. Correlation analyses showed that uncertainty in hydrolysis rate constants was the primary contributor to variance of CWA fate predictions, while uncertainty in the Henry's Law constant and landfill gas-production rate accounted for most of the variance of TIC fate predictions. CWA hydrolysates were more persistent than the parent CWAs, but limited information is available on abiotic or biotic transformation rates for these chemicals.

Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

DTIC Science & Technology

2015-03-01

Analysis of seizure activity and dendritic spine density following exposure to sarin during puberty Methods Female rats were surgically implanted...effects were observed in rats exposed to GB on PND 7 or 21. This study shows that nerve agent exposure during puberty results in severe and life

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

Low-Level Sarin (GB) Vapor Exposure in the Gottingen Minipig: Effect of Exposure Concentration and Duration on Pupil Size

DTIC Science & Technology

2006-09-01

Macary, G. Comparative Study of the Opthalmological Observations in the Yucatan Micropig and the Gottingen Minipig. Scand. J Lab. Anim. Sci. 1998, 25...2002, 28(8), pp 1433-1438. 25. Yoss, R.E.; Moyer, N.J.; Hollenhorst, R.W. Hippus and Other Spontaneous Rhythmic Pupillary Waves. American J. Opthalmology

Identification of chemical warfare agents from vapor samples using a field-portable capillary gas chromatography/membrane-interfaced electron ionization quadrupole mass spectrometry instrument with Tri-Bed concentrator.

PubMed

Nagashima, Hisayuki; Kondo, Tomohide; Nagoya, Tomoki; Ikeda, Toru; Kurimata, Naoko; Unoke, Shohei; Seto, Yasuo

2015-08-07

A field-portable gas chromatograph-mass spectrometer (Hapsite ER system) was evaluated for the detection of chemical warfare agents (CWAs) in the vapor phase. The system consisted of Tri-Bed concentrator gas sampler (trapping time: 3s(-1)min), a nonpolar low thermal-mass capillary gas chromatography column capable of raising temperatures up to 200°C, a hydrophobic membrane-interfaced electron ionization quadrupole mass spectrometer evacuated by a non-evaporative getter pump for data acquisition, and a personal computer for data analysis. Sample vapors containing as little as 22μg sarin (GB), 100μg soman (GD), 210μg tabun (GA), 55μg cyclohexylsarin (GF), 4.8μg sulfur mustard, 390μg nitrogen mustard 1, 140μg of nitrogen mustard 2, 130μg nitrogen mustard 3, 120μg of 2-chloroacetophenone and 990μg of chloropicrin per cubic meter could be confirmed after Tri-Bed micro-concentration (for 1min) and automated AMDIS search within 12min. Using manual deconvolution by background subtraction of neighboring regions on the extracted ion chromatograms, the above-mentioned CWAs could be confirmed at lower concentration levels. The memory effects were also examined and we found that blister agents showed significantly more carry-over than nerve agents. Gasoline vapor was found to interfere with the detection of GB and GD, raising the concentration limits for confirmation in the presence of gasoline by both AMDIS search and manual deconvolution; however, GA and GF were not subject to interference by gasoline. Lewisite 1, and o-chlorobenzylidene malononitrile could also be confirmed by gas chromatography, but it was hard to quantify them. Vapors of phosgene, chlorine, and cyanogen chloride could be confirmed by direct mass spectrometric detection at concentration levels higher than 2, 140, and 10mg/m(3) respectively, by bypassing the micro-concentration trap and gas chromatographic separation. Copyright © 2015 Elsevier B.V. All rights reserved.

Design and development of a personal alarm monitor for use by first responders

NASA Astrophysics Data System (ADS)

Ehntholt, Daniel J.; Louie, Alan S.; Marenchic, Ingrid G.; Forni, Ronald J.

2004-03-01

This paper describes the design and development of a small, portable alarm device that can be used by first responders to an emergency event to warn of the presence of low levels of a toxic nerve gas. The device consists of a rigid reusable portion and a consumable packet that is sensitive to the presence of acetylcholinesterase inhibitors such as the nerve gases Sarin or Soman. The sensitivity level of the alarm is set to be at initial physiological response at the meiosis level, orders of magnitude below lethal concentrations. The AChE enzyme used is specific for nerve-type toxins. A color development reaction is used to demonstrate continued activity of the enzyme over its twelve-hour operational cycle.

Optical constants of neat liquid-chemical warfare agents and related materials measured by infrared spectroscopic ellipsometry

NASA Astrophysics Data System (ADS)

Yang, C. S.-C.; Williams, B. R.; Hulet, M. S.; Tiwald, T. E.; Miles, R. W., Jr.; Samuels, A. C.

2011-05-01

We studied various liquids using a vertical attenuated total reflection (ATR) liquid sampling assembly in conjunction with Infrared Variable Angle Spectroscopic Ellipsometry (IR-VASE), to determine the infrared optical constants of several bulk liquids related to chemical warfare. The index of refraction, n, and the extinction coefficient, k, of isopropyl methylphosphonofluoridate (Sarin or GB), isopropyl alcohol (IPA) (a precursor of GB), and dimethyl methylphosphonate (DMMP)-a commonly employed simulant for GB, measured by our vertical ATR IR-VASE setup are closely matched to those found in other studies. We also report the optical constants of cyclohexyl methylphosphonofluoridate (GF), 2-(diisopropylamino)ethyl methylphosphonothioate (VX), bis-(2-chloroethyl) sulfide (HD), and 2-chlorovinyl dichloroarsine (L, Lewisite). The ATR IR-VASE technique affords an accurate measurement of the optical constants of these hazardous compounds.

A Comprehensive Evaluation of the Efficacy of Leading Oxime Therapies in Guinea Pigs Exposed to Organophosphorus Chemical Warfare Agents or Pesticides

PubMed Central

Wilhelm, Christina M.; Snider, Thomas H.; Babin, Michael C.; Jett, David A.; Platoff, Gennady E.; Yeung, David T.

2014-01-01

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. PMID:25448441

Toxicity studies on agents Gb and Gd (Phase 2): Delayed neuropathy study of soman in SPF white leghorn chickens. Final technical report, July 1985-August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bucci, T.J.; Parker, R.M.; Gosnell, P.A.

1992-05-01

A dose rangefinding study, a delayed neuropathy study, and a neurotoxic esterase study, were performed in White Leghorn chickens using the organophosphate ester Soman. The hens used for the Rangefinding study were dosed once orally with 500, 250, 100, 50, 25, or 0 microns g/Kg GD, on Day 1. They were pretreated and protected daily through Day 7 with atropine. Surviving hens were euthanized with sodium pentobarbital on Day 21. The maximum tolerated dose (MTD) to be used in the Delayed Neuropathy Study was chosen based upon the rangefinding data. Fifty hens were assigned to a Single Dose Delayed Neuropathymore » study. Groups of ten hens were given 14.2 (MTD), 7.1 (MTD/2), 3.5 (MTD/4), 0 (negative control) microns/Kg GD or 51 0 mg/Kg tri-ortho-cresyl phosphate (TOCP) (positive control). Rangefinding study. They were evaluated for signs of neurologic toxicity/ataxia. Necropsy examination was performed on all animals. Sections of cerebellum, medulla, spinal cord (cervical, thoracic, and lumbar), both sciatic nerves and their tibial branch were examined microscopically.... Delayed neuropathy; Agents; Soman; Chickens.« less

Emergency management of chemical weapons injuries.

PubMed

Anderson, Peter D

2012-02-01

The potential for chemical weapons to be used in terrorism is a real possibility. Classes of chemical weapons include nerve agents, vesicants (blister agents), choking agents, incapacitating agents, riot control agents, blood agents, and toxic industrial chemicals. The nerve agents work by blocking the actions of acetylcholinesterase leading to a cholinergic syndrome. Nerve agents include sarin, tabun, VX, cyclosarin, and soman. The vesicants include sulfur mustard and lewisite. The vesicants produce blisters and also damage the upper airways. Choking agents include phosgene and chlorine gas. Choking agents cause pulmonary edema. Incapacitating agents include fentanyl and its derivatives and adamsite. Riot control agents include Mace and pepper spray. Blood agents include cyanide. The mechanism of toxicity for cyanide is blocking oxidative phosphorylation. Toxic industrial chemicals include agents such as formaldehyde, hydrofluoric acid, and ammonia.

Neurosciences and research on chemical weapons of mass destruction in Nazi Germany.

PubMed

Schmaltz, Florian

2006-09-01

As a side-product of industrial research, new chemical nerve agents (Tabun, Sarin, Soman) superior to those available to the Allied Forces were discovered in Nazi Germany. These agents were never used by Germany, even though they were produced at a large scale. This article explores the toxicological and physiological research into the mechanisms of action of these novel nerve agents, and the emergence of military research objectives in neurophysiological and neurotoxicological research. Recently declassified Allied military intelligence files document secret nerve agent research, leading to intensified research on anticholinesterase agents in the peripheral and the central nervous system. The article discusses the involvement of IG Farben scientists, educational, medical and military institutions, and of Nobel Prize laureate Richard Kuhn, director of the Kaiser Wilhelm Institute for Medical Research.

Central Acetylcholinesterase Reactivation by Oximes Improves Survival and Terminates Seizures Following Nerve Agent Intoxication

DTIC Science & Technology

2009-01-01

activity ; GB = sarin; im = intramuscular; ip = intraperitoneal; LD50 = median lethal dose 50%; MINA = monoisonitrosoacetone; MMB-4 = methoxime; OP...inhibited acetylcholinesterase (AChE) activity . We have studied the capability of the tertiary oximes monoisonitrosoacetone (MINA) and diacetylmonoxime...of 20, 26, 35, 46 and 60 mg/kg, there were 0, 9, 17, 60, and 75%, respectively, of animals never exhibited EEG seizure activity with 43, 64, 75, 90

Fluoride Ion Regeneration of Cyclosarin (Gf) from Minipig Tissue and Fluids Following Whole Body GF Vapor Exposure

DTIC Science & Technology

2006-11-01

Quantitation of organophosphorus nerve agent metabolites in human urine using isotope dilution gas chromatography- tandem mass spectrometry. J. Anal...Recent developments to improve nerve agent biomarker techniques include methods for measuring fluoride regenerated Sarin (GB) in blood and tissue...Our efforts extend the fluoride ion regeneration method to be able to determine cyclosarin (GF) in red blood cells, plasma, and tissue of minipig

2014 Review on the Extension of the AMedP-8(C) Methodology to New Agents, Materials, and Conditions

DTIC Science & Technology

2015-08-01

chemical agents, five biological agents, seven radioisotopes , nuclear fallout, or prompt nuclear effects.1 Each year since 2009, OTSG has sponsored IDA...evaluated four agents: anthrax, botulinum toxin, sarin (GB), and distilled mustard (HD), first using the default parameters and methods in HPAC and...the IDA team then made incremental changes to the default casualty parameters and methods to control for all known data and methodological

Hand-held analyser based on microchip electrophoresis with contactless conductivity detection for measurement of chemical warfare agent degradation products

NASA Astrophysics Data System (ADS)

Duran, Karolina-Petkovic; Zhu, Yonggang; Chen, Chuanpin; Swallow, Anthony; Stewart, Robert; Hoobin, Pam; Leech, Patrick; Ovenden, Simon

2008-12-01

This paper reports on the development of a hand-held device for on-site detection of organophosphonate nerve agent degradation products. This field-deployable analyzer relies on efficient microchip electrophoresis separation of alkyl methylphosphonic acids and their sensitive contactless conductivity detection. Miniaturized, low-powered design is coupled with promising analytical performance for separating the breakdown products of chemical warfare agents such as Soman, Sarin and VX . The detector has a detection limit of about 10 μg/mL and has a good linear response in the range 10-300 μg/mL concentration range. Applicability to environmental samples is demonstrated .The new hand-held analyzer offers great promise for converting conventional ion chromatography or capillary electrophoresis sophisticated systems into a portable forensic laboratory for faster, simpler and more reliable on-site screening.

Fluorescent Chemosensors for Toxic Organophosphorus Pesticides: A Review

PubMed Central

Obare, Sherine O.; De, Chandrima; Guo, Wen; Haywood, Tajay L.; Samuels, Tova A.; Adams, Clara P.; Masika, Noah O.; Murray, Desmond H.; Anderson, Ginger A.; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction. PMID:22163587

Fluorescent chemosensors for toxic organophosphorus pesticides: a review.

PubMed

Obare, Sherine O; De, Chandrima; Guo, Wen; Haywood, Tajay L; Samuels, Tova A; Adams, Clara P; Masika, Noah O; Murray, Desmond H; Anderson, Ginger A; Campbell, Keith; Fletcher, Kenneth

2010-01-01

Many organophosphorus (OP) based compounds are highly toxic and powerful inhibitors of cholinesterases that generate serious environmental and human health concerns. Organothiophosphates with a thiophosphoryl (P=S) functional group constitute a broad class of these widely used pesticides. They are related to the more reactive phosphoryl (P=O) organophosphates, which include very lethal nerve agents and chemical warfare agents, such as, VX, Soman and Sarin. Unfortunately, widespread and frequent commercial use of OP-based compounds in agricultural lands has resulted in their presence as residues in crops, livestock, and poultry products and also led to their migration into aquifers. Thus, the design of new sensors with improved analyte selectivity and sensitivity is of paramount importance in this area. Herein, we review recent advances in the development of fluorescent chemosensors for toxic OP pesticides and related compounds. We also discuss challenges and progress towards the design of future chemosensors with dual modes for signal transduction.

Determination of trace amounts of chemical warfare agent degradation products in decontamination solutions with NMR spectroscopy.

PubMed

Koskela, Harri; Rapinoja, Marja-Leena; Kuitunen, Marja-Leena; Vanninen, Paula

2007-12-01

Decontamination solutions are used for an efficient detoxification of chemical warfare agents (CWAs). As these solutions can be composed of strong alkaline chemicals with hydrolyzing and oxidizing properties, the analysis of CWA degradation products in trace levels from these solutions imposes a challenge for any analytical technique. Here, we present results of application of nuclear magnetic resonance spectroscopy for analysis of trace amounts of CWA degradation products in several untreated decontamination solutions. Degradation products of the nerve agents sarin, soman, and VX were selectively monitored with substantially reduced interference of background signals by 1D 1H-31P heteronuclear single quantum coherence (HSQC) spectrometry. The detection limit of the chemicals was at the low part-per-million level (2-10 microg/mL) in all studied solutions. In addition, the concentration of the degradation products was obtained with sufficient confidence with external standards.

Neurosteroids for the potential protection of humans against organophosphate toxicity.

PubMed

Reddy, Doodipala Samba

2016-08-01

This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA A receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA A receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure. © 2016 New York Academy of Sciences.

Differences between male and female rhesus monkey erythrocyte acetylcholinesterase and plasma cholinesterase activity before and after exposure to sarin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woodard, C.L.; Calamaio, C.A.; Kaminskis, A.

The female rhesus monkey has a menstrual cycle like the human. Additionally, several differences in enzyme levels between males and females and in the female during the menstrual cycle are present. Therefore we quantitated plasma cholinesterase (ChE/BuChE) and erythrocyte (RBC) acetylcholinesterase (AChE) activity before and after exposure to sarin (GB)(1 5 ug/kg, iv; a 0.75 LD50), in male and female rhesus (Macaca mulatta) monkeys. Twenty-eight-day preexposure baseline plasma ChE and RBC AChE values for six male and six female rhesus monkeys were compared for intra-animal, within sex and between sex differences. After these baseline values were obtained, the organophosphorus (OP)more » compound/Isopropyl methylphosphono-fluoridate (GB) was administered to atropinized monkeys to determine if there was a significant in vivo difference between the sexes in their response to this intoxication in regard to the rate of BuChE /AChE inhibition, pyridine-2-aldoxime methyl chloride (2-PAM) reactivation of the phosphonylated BuChE and the rate of aging of the phosphonylated:BuChE/AChE. In the pre-exposure portion of the protocol; the intra-animal and intra-group BuChE/AChE variations were found to be minimal; but there were significant differences between the male and female monkeys in both plasma BuChE and RBC AChE levels; although probably clinically insignificant in respect to an OP intoxication. No significant cyclic fluctuations were seen during the 28-day study in either sex.« less

Therapy against organophosphate poisoning: The importance of anticholinergic drugs with antiglutamatergic properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weissman, Ben Avi; Raveh, Lily

2008-10-15

Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of amore » stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.« less

Membrane Inlet Mass Spectrometry for Homeland Security and Forensic Applications

NASA Astrophysics Data System (ADS)

Giannoukos, Stamatios; Brkić, Boris; Taylor, Stephen; France, Neil

2015-02-01

A man-portable membrane inlet mass spectrometer has been built and tested to detect and monitor characteristic odors emitted from the human body and also from threat substances. In each case, a heated membrane sampling probe was used. During human scent monitoring experiments, data were obtained for inorganic gases and volatile organic compounds emitted from human breath and sweat in a confined space. Volatile emissions were detected from the human body at low ppb concentrations. Experiments with compounds associated with narcotics, explosives, and chemical warfare agents were conducted for a range of membrane types. Test compounds included methyl benzoate (odor signature of cocaine), piperidine (precursor in clandestine phencyclidine manufacturing processes), 2-nitrotoluene (breakdown product of TNT), cyclohexanone (volatile signature of plastic explosives), dimethyl methylphosphonate (used in sarin and soman nerve agent production), and 2-chloroethyl ethyl sulfide (simulant compound for sulfur mustard gas). Gas phase calibration experiments were performed allowing sub-ppb LOD to be established. The results showed excellent linearity versus concentration and rapid membrane response times.

Membrane inlet mass spectrometry for homeland security and forensic applications.

PubMed

Giannoukos, Stamatios; Brkić, Boris; Taylor, Stephen; France, Neil

2015-02-01

A man-portable membrane inlet mass spectrometer has been built and tested to detect and monitor characteristic odors emitted from the human body and also from threat substances. In each case, a heated membrane sampling probe was used. During human scent monitoring experiments, data were obtained for inorganic gases and volatile organic compounds emitted from human breath and sweat in a confined space. Volatile emissions were detected from the human body at low ppb concentrations. Experiments with compounds associated with narcotics, explosives, and chemical warfare agents were conducted for a range of membrane types. Test compounds included methyl benzoate (odor signature of cocaine), piperidine (precursor in clandestine phencyclidine manufacturing processes), 2-nitrotoluene (breakdown product of TNT), cyclohexanone (volatile signature of plastic explosives), dimethyl methylphosphonate (used in sarin and soman nerve agent production), and 2-chloroethyl ethyl sulfide (simulant compound for sulfur mustard gas). Gas phase calibration experiments were performed allowing sub-ppb LOD to be established. The results showed excellent linearity versus concentration and rapid membrane response times.

Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

PubMed

Wright, Linnzi K M; Lee, Robyn B; Vincelli, Nicole M; Whalley, Christopher E; Lumley, Lucille A

2016-01-22

Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX. Published by Elsevier Ireland Ltd.

Cholinesterases, a target of pharmacology and toxicology.

PubMed

Pohanka, Miroslav

2011-09-01

Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilhelm, Christina M., E-mail: wilhelmc@battelle.org; Snider, Thomas H., E-mail: snidert@battelle.org; Babin, Michael C., E-mail: babinm@battelle.org

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection atmore » the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl{sub 2}, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. - Highlights: • First comprehensive evaluation of leading AChE oxime reactivators • All oximes are compared against current U.S. therapy 2-PAM Cl. • Relative therapeutic oxime efficacies against OP CWNA and pesticides • Contribution to more effective antidotes for civilian and military populations.« less

Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders.

PubMed

Ohno, Kinji; Ohkawara, Bisei; Ito, Mikako

2017-10-01

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including myasthenia gravis, Lambert-Eaton myasthenic syndrome, Isaacs' syndrome, congenital myasthenic syndromes, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. Except for sarcopenia, all are orphan diseases. In addition, the NMJ signal transduction is impaired by tetanus, botulinum, curare, α-bungarotoxin, conotoxins, organophosphate, sarin, VX, and soman to name a few. Areas covered: This review covers the agrin-LRP4-MuSK signaling pathway, which drives clustering of acetylcholine receptors (AChRs) and ensures efficient signal transduction at the NMJ. We also address diseases caused by autoantibodies against the NMJ molecules and by germline mutations in genes encoding the NMJ molecules. Expert opinion: Representative small compounds to treat the defective NMJ signal transduction are cholinesterase inhibitors, which exert their effects by increasing the amount of acetylcholine at the synaptic space. Another possible therapeutic strategy to enhance the NMJ signal transduction is to increase the number of AChRs, but no currently available drug has this functionality.

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

PubMed

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.

Reversed enantioselectivity of diisopropyl fluorophosphatase against organophosphorus nerve agents by rational design.

PubMed

Melzer, Marco; Chen, Julian C-H; Heidenreich, Anne; Gäb, Jürgen; Koller, Marianne; Kehe, Kai; Blum, Marc-Michael

2009-12-02

Diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris is an efficient and robust biocatalyst for the hydrolysis of a range of highly toxic organophosphorus compounds including the nerve agents sarin, soman, and cyclosarin. In contrast to the substrate diisopropyl fluorophosphate (DFP) the nerve agents possess an asymmetric phosphorus atom, which leads to pairs of enantiomers that display markedly different toxicities. Wild-type DFPase prefers the less toxic stereoisomers of the substrates which leads to slower detoxification despite rapid hydrolysis. Enzyme engineering efforts based on rational design yielded two quadruple enzyme mutants with reversed enantioselectivity and overall enhanced activity against tested nerve agents. The reversed stereochemical preference is explained through modeling studies and the crystal structures of the two mutants. Using the engineered mutants in combination with wild-type DFPase leads to significantly enhanced activity and detoxification, which is especially important for personal decontamination. Our findings may also be of relevance for the structurally related enzyme human paraoxonase (PON), which is of considerable interest as a potential catalytic in vivo scavenger in case of organophosphorus poisoning.

A comparison of the neuroprotective efficacy of individual oxime (HI-6) and combinations of oximes (HI-6+trimedoxime, HI-6+K203) in soman-poisoned rats.

PubMed

Kassa, Jiri; Karasova, Jana Zdarova; Tesarova, Sandra

2011-07-01

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD₅₀ value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.

A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: Effects of epinephrine and oxygen therapies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gundavarapu, Sravanthi; Zhuang, Jianguo; Barrett, Edward G.

Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes includingmore » weakened response to hypoxia. We now show that LD{sub 50} sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24 h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD{sub 50} sarin-exposed animals were administered the bronchodilator epinephrine, > 90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD{sub 50} sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin. - Highlights: • Inhalation exposure of rats to LD{sub 50} sarin causes death through respiratory failure. • Severe bronchoconstriction is the major cause of sarin-induced respiratory failure. • Transfer of sarin exposed rats to 60% oxygen improves the mortality temporarily. • Epinephrine improves bronchoconstriction and mortality in LD{sub 50} sarin-exposed rats. • Both epinephrine and oxygen moderate the sarin-induced lung inflammatory response.« less

A Toolkit For CryoSat Investigations By The ESRIN EOP-SER Altimetry Team

NASA Astrophysics Data System (ADS)

Dinardo, Salvatore; Bruno, Lucas; Benveniste, Jerome

2013-12-01

The scope of this work is to feature the new tool for the exploitation of the CryoSat data, designed and developed entirely by the Altimetry Team at ESRIN EOP-SER (Earth Observation - Exploitation, Research and Development). The tool framework is composed of two separate components: the first one handles the data collection and management, the second one is the processing toolkit. The CryoSat FBR (Full Bit Rate) data is downlinked uncompressed from the satellite, containing un-averaged individual echoes. This data is made available in the Kiruna CalVal server in a 10 day rolling archive. Daily at ESRIN all the CryoSat FBR data, in SAR and SARin Mode, are downloaded (around 30 Gigabytes) catalogued and archived in local ESRIN EOP-SER workstations. As of March 2013, the total amount of FBR data is over 9 Terabytes, with CryoSat acquisition dates spanning January 2011 to February 2013 (with some gaps). This archive was built by merging partial datasets available at ESTEC and NOAA, that have been kindly made available for EOP-SER team. The on-demand access to this low level data is restricted to expert users with validated ESA P.I. credentials. Currently the main users of the archiving functionality are the team members of the Project CP4O (STSE- CryoSat Plus for Ocean), CNES and NOAA. The second component of the service is the processing toolkit. On the EOP-SER workstations there is internally and independently developed software that is able to process the FBR data in SAR/SARin mode to generate multi-looked echoes (Level 1B) and subsequently able to re-track them in SAR and SARin mode (Level 2) over open ocean, exploiting the SAMOSA model and other internally developed models. The processing segment is used for research & development scopes, supporting the development contracts awarded confronting the deliverables to ESA, on site demonstrations/training to selected users, cross- comparison against third part products (CLS/CNES CPP Products for instance), preparation to Sentinel-3 mission, publications, etc. Samples of these experimental SAR/SARin L1b/L2 Products can be provided to the scientific community for comparison with self-processed data, on-request. So far, the processing has been designed and optimized for open ocean studies and is fully functional only over this kind of surface but there are plans to augment this processing capacity over coastal zones, inland waters and over land in sight of maximizing the exploitation of the upcoming Sentinel-3 Topographic mission over all surfaces. There are also plans to make the toolkit fully accessible through software “gridification” to run in the ESRin GPod (Grid Processing on Demand) Service and to extend the tool's functionalities to support Sentinel-3 Mission (both Simulated and Real Data). Graphs and statistics about the spatial coverage and amount of FBR data actually archived on the EOP-SER workstations and some scientific results will be shown in this paper along with the tests that have been designed and performed to validate the products (tests against CryoSat Kiruna PDGS Products and against transponder data).

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs.

PubMed

Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Kabra, Kareem; Chanda, Soma; Oguntayo, Samuel; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2010-06-01

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m(3) concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m(3) soman survived, while animals exposed to 841, and 1121 mg/m(3) resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt(50) for soman determined by probit analysis was 827.2mg/m(3). A majority of the animals that died at 1121 mg/m(3) developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs. (c) 2010 Elsevier Inc. All rights reserved.

Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig.

PubMed

Chen, Kaizhen; Seng, Kok-Yong

2012-09-01

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE-soman and CaE-soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose-response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human. Copyright © 2011 John Wiley & Sons, Ltd.

Protection of human muscle acetylcholinesterase from soman by pyridostigmine bromide.

PubMed

Maselli, Ricardo A; Henderson, John D; Ng, Jarae; Follette, David; Graves, Gregory; Wilson, Barry W

2011-04-01

Pretreatment with pyridostigmine bromide (PB) of human intercostal muscle fibers exposed to the irreversible acetylcholinesterase (AChE) inhibitor soman was investigated. Muscles were pretreated with 3 × 10(-6) M PB or saline for 20 minutes, then exposed to 10(-7) M soman for 10 minutes. AChE of muscles treated with soman alone was inhibited >95%. In contrast, PB pretreatment of soman-exposed bundles protected 20% of AChE activity. AChE of bundles exposed to PB alone recovered after 4 hours, but bundles exposed to both PB and soman did not. Soman-induced reduction of resting membrane potentials and increment of amplitudes and decay times of miniature endplate potentials (MEPPs) were partially corrected by PB pretreatment. In vitro pretreatment of human muscles with PB protected up to 20% of muscle AChE and ameliorated some deleterious effects on endplate physiology induced by soman. Copyright © 2011 Wiley Periodicals, Inc.

Effect of Panpal pretreatment and antidotal treatment (HI-6 plus benactyzine) on respiratory and circulatory function in soman-poisoned rats.

PubMed

Kassa, J; Fusek, J

1997-10-01

1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.

Biological monitoring of exposure to nerve agents.

PubMed Central

Bajgar, J

1992-01-01

Changes in acetylcholinesterase activity in blood and some organs of rats after intoxication with sarin, soman, VX, and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV), in doses of roughly 2 x LD50 given intramuscularly, were obtained from published data and by experiment. The time course of inhibition of acetylcholinesterase in blood, regions of brain, and diaphragm and the occurrence of signs and symptoms of poisoning (none, salivation, disturbed ventilation and fasciculations, convulsions, or death) were summarised and compared. When blood enzyme activities were 70-100% normal, no obvious signs were seen; at 60-70%, salivation occurred; at less than 30-55%, disturbed ventilation and fasciculations were seen, and at 15-30%, convulsions occurred. Less than 10% was fatal. In experiments with narcotised dogs, the blood acetylcholinesterase activity and the ability to reactivate it with trimedoxime were determined after intoxication by intramuscular administration of the four compounds. It is concluded that acetylcholinesterase activity in the blood corresponds to that in the target organs and can be considered as an appropriate parameter for biological monitoring of exposure to nerve gases. Moreover, determination of reactivation of blood acetylcholinesterase gives more information than simple determination of enzyme activity. PMID:1390271

Miniaturized low-cost ion mobility spectrometer for fast detection of chemical warfare agents.

PubMed

Zimmermann, Stefan; Barth, Sebastian; Baether, Wolfgang K M; Ringer, Joachim

2008-09-01

Ion mobility spectrometry (IMS) is a well-known method for detecting hazardous compounds in air. Typical applications are the detection of chemical warfare agents, highly toxic industrial compounds, explosives, and drugs of abuse. Detection limits in the low part per billion range, fast response times, and simple instrumentation make this technique more and more popular. In particular, there is an increasing demand for miniaturized low-cost IMS for hand-held devices and air monitoring of public areas by sensor networks. In this paper, we present a miniaturized aspiration condenser type ion mobility spectrometer for fast detection of chemical warfare agents. The device is easy to manufacture and allows single substance identification down to low part per billion-level concentrations within seconds. The improved separation power results from ion focusing by means of geometric constraints and fluid dynamics. A simple pattern recognition algorithm is used for the identification of trained substances in air. The device was tested at the German Armed Forces Scientific Institute for Protection Technologies-NBC-Protection. Different chemical warfare agents, such as sarin, tabun, soman, US-VX, sulfur mustard, nitrogen mustard, and lewisite were tested. The results are presented here.

The Different Sensitive Behaviors of a Hydrogen-Bond Acidic Polymer-Coated SAW Sensor for Chemical Warfare Agents and Their Simulants

PubMed Central

Long, Yin; Wang, Yang; Du, Xiaosong; Cheng, Luhua; Wu, Penglin; Jiang, Yadong

2015-01-01

A linear hydrogen-bond acidic (HBA) linear functionalized polymer (PLF), was deposited onto a bare surface acoustic wave (SAW) device to fabricate a chemical sensor. Real-time responses of the sensor to a series of compounds including sarin (GB), dimethyl methylphosphonate (DMMP), mustard gas (HD), chloroethyl ethyl sulphide (2-CEES), 1,5-dichloropentane (DCP) and some organic solvents were studied. The results show that the sensor is highly sensitive to GB and DMMP, and has low sensitivity to HD and DCP, as expected. However, the sensor possesses an unexpected high sensitivity toward 2-CEES. This good sensing performance can’t be solely or mainly attributed to the dipole-dipole interaction since the sensor is not sensitive to some high polarity solvents. We believe the lone pair electrons around the sulphur atom of 2-CEES provide an electron-rich site, which facilitates the formation of hydrogen bonding between PLF and 2-CEES. On the contrary, the electron cloud on the sulphur atom of the HD molecule is offset or depleted by its two neighbouring strong electron-withdrawing groups, hence, hydrogen bonding can hardly be formed. PMID:26225975

Fragmentation of molecular ions in differential mobility spectrometry as a method for identification of chemical warfare agents.

PubMed

Maziejuk, M; Puton, J; Szyposzyńska, M; Witkiewicz, Z

2015-11-01

The subject of the work is the use of differential mobility spectrometry (DMS) for the detection of chemical warfare agents (CWA). Studies were performed for mustard gas, i.e., bis(2-chloroethyl)sulfide (HD), sarin, i.e., O-isopropyl methylphosphonofluoridate (GB) and methyl salicylate (MS) used as test compounds. Measurements were conducted with two ceramic DMS analyzers of different constructions allowing the generation of an electric field with an intensity of more than 120 Td. Detector signals were measured for positive and negative modes of operation in a temperature range from 0 to 80 °C. Fragmentations of ions containing analyte molecules were observed for all tested compounds. The effective temperatures of fragmentation estimated on the basis of dispersion plots were equal from about 148 °C for GB to 178 °C for MS. It was found that values of separation voltage (SV) and compensation voltage (CV) at which the fragmentation of sample ions is observed may be the parameters improving the certainty of detection for different analytes. The DMS analyzers enabling the observation of ion fragmentation can be successfully used for effective CWA detection. Copyright © 2015. Published by Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perkins, Michael W.; Pierre, Zdenka; Rezk, Peter

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m{sup 3} concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m{sup 3} soman survived, while animals exposed to 841, and 1121 mg/m{sup 3} resulted in 38% and 13% survival,more » respectively. The microinstillation inhalation exposure LCt{sub 50} for soman determined by probit analysis was 827.2 mg/m{sup 3}. A majority of the animals that died at 1121 mg/m{sup 3} developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.« less

Soman toxicity during and after exposure to different environmental temperatures.

PubMed

Wheeler, T G

1989-01-01

A systematic study has been conducted to determine physiological susceptibility to the potent anticholinesterase soman during and after exposure to different environmental temperatures. Rats were placed in an environmental chamber set at -1, 7, 15, 23, or 31 degrees C (80% relative humidity, RH) from 0000 to 0800 h. Soman injections were given subcutaneously (sc) at 0600 h (during thermal stress), or at 0810 h after removal from the chamber (injected and tested at 23 degrees C, 60% RH). The measures (taken 30 min after soman injection) included core temperature, grip strength, general state of health, and LD10 estimates (taken 2 h post injection). Soman exposure produced a dose-related effect on each measure under all thermal stress conditions. During thermal stress, soman exposure produced major changes in core temperature ranging from 26 to 41 degrees C, which were linearly related to the environmental temperature condition. After removal from the chamber, soman exposure reduced core temperature by only 1 degree C without regard to prior thermal stress temperature. Grip strength and subjective health rating were soman dose-related with only a minor chamber temperature influence. The toxicity of soman was increased during exposure to either cold or hot environments and after removal from the cold environments. The adrenal-cortical stress response to cold involves increased metabolism and oxygen requirement. The exception was the decreased toxicity observed when soman exposure occurred after removal from a hot environment, exacerbated by a failure in the respiratory system due to anticholinesterase exposure. The increased toxicity of soman while in or after removal from a cold environment is believed to be due to a generalized adrenal-cortical stress response. The increased soman toxicity while in a hot environment, but decreased toxicity after removal from the hot environment, provides an interesting subject for further research.

Rotational Spectrum of Sarin.

PubMed

Walker, A. R. Hight; Suenram, R. D.; Samuels, Alan; Jensen, James; Ellzy, Michael W.; Lochner, J. Michael; Zeroka, Daniel

2001-05-01

As part of an effort to examine the possibility of using molecular-beam Fourier-transform microwave spectroscopy to unambiguously detect and monitor chemical warfare agents, we report the first observation and assignment of the rotational spectrum of the nerve agent Sarin (GB) (Methylphosphonofluoridic acid 1-methyl-ethyl ester, CAS #107-44-8) at frequencies between 10 and 22 GHz. Only one of the two low-energy conformers of this organophosphorus compound (C(4)H(10)FO(2)P) was observed in the rotationally cold (T(rot)<2 K) molecular beam. The experimental asymmetric-rotor ground-state rotational constants of this conformer are A=2874.0710(9) MHz, B=1168.5776(4) MHz, C=1056.3363(4) MHz (Type A standard uncertainties are given, i.e., 1sigma), as obtained from a least-squares analysis of 74 a-, b-, and c-type rotational transitions. Several of the transitions are split into doublets due to the internal rotation of the methyl group attached to the phosphorus. The three-fold-symmetry barrier to internal rotation estimated from these splittings is 677.0(4) cm(-1). Ab initio electronic structure calculations using Hartree-Fock, density functional, and Moller-Plesset perturbation theories have also been made. The structure of the lowest-energy conformer determined from a structural optimization at the MP2/6-311G(**) level of theory is consistent with our experimental findings. Copyright 2001 Academic Press.

Rotational Spectrum of Sarin

NASA Astrophysics Data System (ADS)

Walker, A. R. Hight; Suenram, R. D.; Samuels, Alan; Jensen, James; Ellzy, Michael W.; Lochner, J. Michael; Zeroka, Daniel

2001-05-01

As part of an effort to examine the possibility of using molecular-beam Fourier-transform microwave spectroscopy to unambiguously detect and monitor chemical warfare agents, we report the first observation and assignment of the rotational spectrum of the nerve agent Sarin (GB) (Methylphosphonofluoridic acid 1-methyl-ethyl ester, CAS #107-44-8) at frequencies between 10 and 22 GHz. Only one of the two low-energy conformers of this organophosphorus compound (C4H10FO2P) was observed in the rotationally cold (Trot<2 K) molecular beam. The experimental asymmetric-rotor ground-state rotational constants of this conformer are A=2874.0710(9) MHz, B=1168.5776(4) MHz, C=1056.3363(4) MHz (Type A standard uncertainties are given, i.e., 1σ), as obtained from a least-squares analysis of 74 a-, b-, and c-type rotational transitions. Several of the transitions are split into doublets due to the internal rotation of the methyl group attached to the phosphorus. The three-fold-symmetry barrier to internal rotation estimated from these splittings is 677.0(4) cm-1. Ab initio electronic structure calculations using Hartree-Fock, density functional, and Moller-Plesset perturbation theories have also been made. The structure of the lowest-energy conformer determined from a structural optimization at the MP2/6-311G** level of theory is consistent with our experimental findings.

Soman poisoning increases neural progenitor proliferation and induces long-term glial activation in mouse brain.

PubMed

Collombet, Jean-Marc; Four, Elise; Bernabé, Denis; Masqueliez, Catherine; Burckhart, Marie-France; Baille, Valérie; Baubichon, Dominique; Lallement, Guy

2005-03-30

To date, only short-term glial reaction has been extensively studied following soman or other warfare neurotoxicant poisoning. In a context of cell therapy by neural progenitor engraftment to repair brain damage, the long-term effect of soman on glial reaction and neural progenitor division was analyzed in the present study. The effect of soman poisoning was estimated in mouse brains at various times ranging from 1 to 90 days post-poisoning. Using immunochemistry and dye staining techniques (hemalun-eosin staining), the number of degenerating neurons, the number of dividing neural progenitors, and microglial, astroglial or oligodendroglial cell activation were studied. Soman poisoning led to rapid and massive (post-soman day 1) death of mature neurons as assessed by hemalun-eosin staining. Following this acute poisoning phase, a weak toxicity effect on mature neurons was still observed for a period of 1 month after poisoning. A massive short-termed microgliosis peaked on day 3 post-poisoning. Delayed astrogliosis was observed from 3 to 90 days after soman poisoning, contributing to glial scar formation. On the other hand, oligodendroglial cells or their precursors were practically unaffected by soman poisoning. Interestingly, neural progenitors located in the subgranular zone of the dentate gyrus (SGZ) or in the subventricular zone (SVZ) of the brain survived soman poisoning. Furthermore, soman poisoning significantly increased neural progenitor proliferation in both SGZ and SVZ brain areas on post-soman day 3 or day 8, respectively. This increased proliferation rate was detected up to 1 month after poisoning.

Proceedings of the Symposium on Nuclear, Biological and Chemical Contamination Survivability (NBCCS). Developing Contamination-Survivable Defense Systems

DTIC Science & Technology

1994-10-01

34 78.8Sam GA (Tabun) GB (Sarin) True TrAjectory Angle , .Detsetor Window 45.0 d eu l -F None Defined D ( Mustard ) E roun .~uf ac Tg~ 1 S ($I".) Froud...Q0.25 ,10 VX.13--P.C.03 0,2siDS2 rl*40 awwhnm~madth.ii w I 0376 1 101 ɘ.25 1£e10 VN1 PCW po:tS ypd ~ihnja.og.lwum 1[T 03V]60l1-1.51 60.4 VX-14 P.C.0 1ot...The MICAD N8008 Program WWUIat ---- ACALSPAN j C N FUNCTIONAL PERFORMANCE TEST RESULTS block gas 02 aIOLcK3ICAL III VX TOD UASELIPIK POT PS UJIO pir O

Impact of ambient gases on the mechanism of [Cs8Nb6O19]-promoted nerve-agent decomposition.

PubMed

Kaledin, Alexey L; Driscoll, Darren M; Troya, Diego; Collins-Wildman, Daniel L; Hill, Craig L; Morris, John R; Musaev, Djamaladdin G

2018-02-28

The impact of ambient gas molecules (X), NO 2 , CO 2 and SO 2 on the structure, stability and decontamination activity of Cs 8 Nb 6 O 19 polyoxometalate was studied computationally and experimentally. It was found that Cs 8 Nb 6 O 19 absorbs these molecules more strongly than it adsorbs water and Sarin (GB) and that these interactions hinder nerve agent decontamination. The impacts of diamagnetic CO 2 and SO 2 molecules on polyoxoniobate Cs 8 Nb 6 O 19 were fundamentally different from that of NO 2 radical. At ambient temperatures, weak coordination of the first NO 2 radical to Cs 8 Nb 6 O 19 conferred partial radical character on the polyoxoniobate and promoted stronger coordination of the second NO 2 adsorbent to form a stable diamagnetic Cs 8 Nb 6 O 19 /(NO 2 ) 2 species. Moreover, at low temperatures, NO 2 radicals formed stable dinitrogen tetraoxide (N 2 O 4 ) that weakly interacted with Cs 8 Nb 6 O 19 . It was found that both in the absence and presence of ambient gas molecules, GB decontamination by the Cs 8 Nb 6 O 19 species proceeds via general base hydrolysis involving: (a) the adsorption of water and the nerve agent on Cs 8 Nb 6 O 19 /(X), (b) concerted hydrolysis of a water molecule on a basic oxygen atom of the polyoxoniobate and nucleophilic addition of the nascent OH group to the phosphorus center of Sarin, and (c) rapid reorganization of the formed pentacoordinated-phosphorus intermediate, followed by dissociation of either HF or isopropanol and formation of POM-bound isopropyl methyl phosphonic acid (i-MPA) or methyl phosphonofluoridic acid (MPFA), respectively. The presence of the ambient gas molecules increases the energy of the intermediate stationary points relative to the asymptote of the reactants and slightly increases the hydrolysis barrier. These changes closely correlate with the Cs 8 Nb 6 O 19 -X complexation energy. The most energetically stable intermediates of the GB hydrolysis and decontamination reaction were found to be Cs 8 Nb 6 O 19 /X-MPFA-(i-POH) and Cs 8 Nb 6 O 19 /X-(i-MPA)-HF both in the absence and presence of ambient gas molecules. The high stability of these intermediates is due to, in part, the strong hydrogen bonding between the adsorbates and the protonated [Cs 8 Nb 6 O 19 /X/H] + -core. Desorption of HF or/and (i-POH) and regeneration of the catalyst required deprotonation of the [Cs 8 Nb 6 O 19 /X/H] + -core and protonation of the phosphonic acids i-MPA and MPFA. This catalyst regeneration is shown to be a highly endothermic process, which is the rate-limiting step of the GB hydrolysis and decontamination reaction both in the absence and presence of ambient gas molecules.

A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K727, K733) with the oxime HI-6 and obidoxime in sarin-poisoned rats and mice.

PubMed

Kassa, Jiri; Sepsova, Vendula; Matouskova, Lenka; Horova, Anna; Musilek, Kamil

2015-03-01

The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.

Binding and hydrolysis of soman by human serum albumin.

PubMed

Li, Bin; Nachon, Florian; Froment, Marie-Thérèse; Verdier, Laurent; Debouzy, Jean-Claude; Brasme, Bernardo; Gillon, Emilie; Schopfer, Lawrence M; Lockridge, Oksana; Masson, Patrick

2008-02-01

Human plasma and fatty acid free human albumin were incubated with soman at pH 8.0 and 25 degrees C. Four methods were used to monitor the reaction of albumin with soman: progressive inhibition of the aryl acylamidase activity of albumin, the release of fluoride ion from soman, 31P NMR, and mass spectrometry. Inhibition (phosphonylation) was slow with a bimolecular rate constant of 15 +/- 3 M(-1) min (-1). MALDI-TOF and tandem mass spectrometry of the soman-albumin adduct showed that albumin was phosphonylated on tyrosine 411. No secondary dealkylation of the adduct (aging) occurred. Covalent docking simulations and 31P NMR experiments showed that albumin has no enantiomeric preference for the four stereoisomers of soman. Spontaneous reactivation at pH 8.0 and 25 degrees C, measured as regaining of aryl acylamidase activity and decrease of covalent adduct (pinacolyl methylphosphonylated albumin) by NMR, occurred at a rate of 0.0044 h (-1), indicating that the adduct is quite stable ( t1/2 = 6.5 days). At pH 7.4 and 22 degrees C, the covalent soman-albumin adduct, measured by MALDI-TOF mass spectrometry, was more stable ( t1/2 = 20 days). Though the concentration of albumin in plasma is very high (about 0.6 mM), its reactivity with soman (phosphonylation and phosphotriesterase activity) is too slow to play a major role in detoxification of the highly toxic organophosphorus compound soman. Increasing the bimolecular rate constant of albumin for organophosphates is a protein engineering challenge that could lead to a new class of bioscavengers to be used against poisoning by nerve agents. Soman-albumin adducts detected by mass spectrometry could be useful for the diagnosis of soman exposure.

Impact of ambient gases on the mechanism of [Cs8Nb6O19]-promoted nerve-agent decomposition† †Dedicated to the memory of Prof. Keiji Morokuma. ‡ ‡Electronic supplementary information (ESI) available: (1) The calculated transition states, intermediates and products of the GB hydrolysis and their important geometry parameters (in Å) for X = SO2, (2) the calculated adsorption energies (in kcal mol–1) of NO2 radicals to Cs8Nb6O19, (3) Cartesian coordinates for all reported structures in xyz format. (structure.xyz). See DOI: 10.1039/c7sc04997h

PubMed Central

Kaledin, Alexey L.; Driscoll, Darren M.; Troya, Diego; Collins-Wildman, Daniel L.

2018-01-01

The impact of ambient gas molecules (X), NO2, CO2 and SO2 on the structure, stability and decontamination activity of Cs8Nb6O19 polyoxometalate was studied computationally and experimentally. It was found that Cs8Nb6O19 absorbs these molecules more strongly than it adsorbs water and Sarin (GB) and that these interactions hinder nerve agent decontamination. The impacts of diamagnetic CO2 and SO2 molecules on polyoxoniobate Cs8Nb6O19 were fundamentally different from that of NO2 radical. At ambient temperatures, weak coordination of the first NO2 radical to Cs8Nb6O19 conferred partial radical character on the polyoxoniobate and promoted stronger coordination of the second NO2 adsorbent to form a stable diamagnetic Cs8Nb6O19/(NO2)2 species. Moreover, at low temperatures, NO2 radicals formed stable dinitrogen tetraoxide (N2O4) that weakly interacted with Cs8Nb6O19. It was found that both in the absence and presence of ambient gas molecules, GB decontamination by the Cs8Nb6O19 species proceeds via general base hydrolysis involving: (a) the adsorption of water and the nerve agent on Cs8Nb6O19/(X), (b) concerted hydrolysis of a water molecule on a basic oxygen atom of the polyoxoniobate and nucleophilic addition of the nascent OH group to the phosphorus center of Sarin, and (c) rapid reorganization of the formed pentacoordinated-phosphorus intermediate, followed by dissociation of either HF or isopropanol and formation of POM-bound isopropyl methyl phosphonic acid (i-MPA) or methyl phosphonofluoridic acid (MPFA), respectively. The presence of the ambient gas molecules increases the energy of the intermediate stationary points relative to the asymptote of the reactants and slightly increases the hydrolysis barrier. These changes closely correlate with the Cs8Nb6O19–X complexation energy. The most energetically stable intermediates of the GB hydrolysis and decontamination reaction were found to be Cs8Nb6O19/X-MPFA-(i-POH) and Cs8Nb6O19/X-(i-MPA)-HF both in the absence and presence of ambient gas molecules. The high stability of these intermediates is due to, in part, the strong hydrogen bonding between the adsorbates and the protonated [Cs8Nb6O19/X/H]+-core. Desorption of HF or/and (i-POH) and regeneration of the catalyst required deprotonation of the [Cs8Nb6O19/X/H]+-core and protonation of the phosphonic acids i-MPA and MPFA. This catalyst regeneration is shown to be a highly endothermic process, which is the rate-limiting step of the GB hydrolysis and decontamination reaction both in the absence and presence of ambient gas molecules. PMID:29719688

Pre- and post-treatment effect of physostigmine on soman-inhibited human erythrocyte and muscle acetylcholinesterase in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herkert, N.M.; Schulz, S.; Wille, T.

2011-05-15

Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before ormore » after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by decarbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors.« less

Aerosolized scopolamine protects against microinstillation inhalation toxicity to sarin in guinea pigs.

PubMed

Che, Magnus M; Chanda, Soma; Song, Jian; Doctor, Bhupendra P; Rezk, Peter E; Sabnekar, Praveena; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

2011-07-01

Sarin is a volatile nerve agent that has been used in the Tokyo subway attack. Inhalation is predicted to be the major route of exposure if sarin is used in war or terrorism. Currently available treatments are limited for effective postexposure protection against sarin under mass casualty scenario. Nasal drug delivery is a potential treatment option for mass casualty under field conditions. We evaluated the efficacy of endotracheal administration of muscarinic antagonist scopolamine, a secretion blocker which effectively crosses the blood-brain barrier for protection against sarin inhalation toxicity. Age and weight matched male Hartley guinea pigs were exposed to 677.4 mg/m³ or 846.5 mg/ m³ (1.2 × LCt₅₀) sarin by microinstillation inhalation exposure for 4 min. One minute later, the animals exposed to 846.5 mg/ m³ sarin were treated with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 h for efficacy evaluation. The results showed that treatment with scopolamine increased the survival rate from 20% to 100% observed in untreated sarin-exposed animals. Behavioral symptoms of nerve agent toxicity including, convulsions and muscular tremors were reduced in sarin-exposed animals treated with scopolamine. Sarin-induced body weight loss, decreased blood O₂ saturation and pulse rate were returned to basal levels in scopolamine-treated animals. Increased bronchoalveolar lavage (BAL) cell death due to sarin exposure was returned to normal levels after treatment with scopolamine. Taken together, these data indicate that postexposure treatment with aerosolized scopolamine prevents respiratory toxicity and protects against lethal inhalation exposure to sarin in guinea pigs.

The evaluation of prophylactic efficacy of newly developed reversible inhibitors of acetylcholinesterase in soman-poisoned mice - a comparison with commonly used pyridostigmine.

PubMed

Kassa, Jiri; Korabecny, Jan; Sepsova, Vendula; Tumova, Martina

2014-12-01

The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Kinetics and metabolism of physostigmine in rat in the presence of soman

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khalique, A.; Somani, S.M.

1986-03-01

The effect of soman (105 ..mu..g/kg; 1.5 LD/sub 50/ s.c.) administration on pharmacokinetics and metabolism of /sup 3/H-physostigmine (Phy) was studied in rats. The rats were pretreated with either Phy 100 ..mu..g/kg i.v. or 500 ..mu..g/kg i.m., 5 or 15 min prior to soman administration. Phy and metabolites were determined in plasma and brain by HPLC. The half-life of Phy in plasma after i.v. administration was 15.5 min both in the presence and absence of soman, however the t/sub 1/2/ in brain was 11 min and 13 min, respectively. Clearance was 71.4 ml/min/kg in the Phy treated rat and 90more » ml/min/kg in the presence of soman. The half-life of Phy in plasma was 18 min and 17 min, and in brain 17 min and 15 min, respectively in the absence and presence of soman after i.m. dose of Phy. Clearance after Phy treatment was 85.2 mlmin/kg however in the presence of soman, it was 66.7 ml/min/kg. Phy was slightly less metabolized to eseroline and two other metabolites, M/sub 1/ and M/sub 2/, in the presence of soman after i.v. as well as after i.m. administration in plasma and brain. The soman administration does not change the pharmacokinetics of Phy by the two different dosages and routes of administration.« less

Mechanism of soman-induced contractions in canine tracheal smooth muscle. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adler, M.; Moore, D.H.; Filbert, M.G.

1992-12-31

The actions of the irreversible organophosphorus cholinesterase (ChE) inhibitor soman were investigated on canine trachea smooth muscle in vitro. Concentrations of soman > or - 1 nM increased the amplitude and decay of contractions elicited by electric field stimulation. The effect on decay showed a marked dependence on stimulation frequency, undergoing a 2.4-fold increase between 3 and 60 Hz. Soman also potentiated tensions due to bath applied acetylcholine (ACh). Little or no potentiation was observed for contractions elicited by carbamylcholine, an agonist that is not hydrolyzed by ChE. Concentration of soman > or - 3 nM led to the appearancemore » of sustained contractures. These contractures developed with a delayed onset and were well correlated with ChE activity. Alkylation of muscarinic receptors by propylbenzilylcholine mustard antagonized the actions of soman on both spontaneous and electrically-evoked muscle contractions. The results are consistent with a mechanism in which the toxic actions of soman are mediated by accumulation of neurally-released ACh secondary to inhibition of ChE activity. An important factor in this accumulation is suggested to be the buffering effect of the muscarinic receptors on the efflux of ACh from the neuroeffector junction. Tracheal smooth muscle, Cholinesterase inhibitors, Muscarinic receptor, Soman, Organophosphate.« less

Alterations in brain glutathione homeostasis induced by the nerve gas soman.

PubMed

Klaidman, Lori K; Adams, James D; Cross, Robert; Pazdernik, Thomas L; Samson, Fred

2003-01-01

Public awareness of the dangers of chemical and biological warfare has been heightened in recent times. In particular, chemical nerve agents such as soman and its analogs have been developed and used in war as well as recent incidents, such as in Iraq and Japan. Soman, a rapid acting acetylcholinesterase inhibitor, produces a status epilepticus that leads to extensive neuropathology in vulnerable brain regions (eg, piriform cortex and hippocampus). This study was undertaken to determine whether oxidative mechanisms are involved in brain pathology during soman toxicity. Intracellular thiols such as glutathione (GSH) and protein sulfhydryls (PrSH) are among the most critical antioxidants used to combat oxidative stress. Here we report that during the seizure phase (1 h post soman exposure), PrSH levels in piriform cortex and hippocampus were decreased without changes in glutathione (GSH) levels. However, by 24 h post soman exposure (pathology phase), GSH levels were decreased by nearly 50% in the piriform cortex with a corresponding decrease in PrSH groups. The shift to a more oxidized thiol status indicates that oxygen free radicals likely participate in the neuropathology associated with soman-induced seizures.

Variable effects of soman on macromolecular secretion by ferret trachea

DOE Office of Scientific and Technical Information (OSTI.GOV)

McBride, R.K.; Zwierzynski, D.J.; Stone, K.K.

1991-01-01

The purpose of this study was to examine the effect of the anticholinesterase agent, soman, on macromolecular secretion by ferret trachea, in vitro. We mounted pieces of ferret trachea in Ussing-type chambers. Secreted sulfated macromolecules were radiolabeled by adding 500 microCi of {sup 35}SO{sub 4} to the submucosal medium and incubating for 17 hr. Soman added to the submucosal side produced a concentration-dependent increase in radiolabeled macromolecular release with a maximal secretory response (mean +/- SD) of 202 +/- 125% (n = 8) relative to the basal secretion rate at a concentration of 10{sup {minus} 7} M. The addition ofmore » either 10{sup {minus}6} M pralidoxime (acetylcholinesterase reactivator) or 10{sup {minus}6} M atropine blocked the response to 10{sup {minus}7} M soman. At soman concentrations greater than 10{sup {minus}7} M, secretion rate decreased and was not significantly different from basal secretion. Additional experiments utilizing acetylcholine and the acetylcholinesterase inhibitor, physostigmine, suggest that inhibition of secretion by high concentrations of soman may be due to a secondary antagonistic effect of soman on muscarinic receptors.« less

Quantitative proteomic analysis of the brainstem following lethal sarin exposure.

PubMed

Meade, Mitchell L; Hoffmann, Andrea; Makley, Meghan K; Snider, Thomas H; Schlager, John J; Gearhart, Jeffery M

2015-06-22

The brainstem represents a major tissue area affected by sarin organophosphate poisoning due to its function in respiratory and cardiovascular control. While the acute toxic effects of sarin on brainstem-related responses are relatively unknown, other brain areas e.g., cortex or cerebellum, have been studied more extensively. The study objective was to analyze the guinea pig brainstem toxicology response following sarin (2×LD50) exposure by proteome pathway analysis to gain insight into the complex regulatory mechanisms that lead to impairment of respiratory and cardiovascular control. Guinea pig exposure to sarin resulted in the typical acute behavior/physiology outcomes with death between 15 and 25min. In addition, brain and blood acetylcholinesterase activity was significantly reduced in the presence of sarin to 95%, and 89%, respectively, of control values. Isobaric-tagged (iTRAQ) liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 198 total proteins of which 23% were upregulated, and 18% were downregulated following sarin exposure. Direct gene ontology (GO) analysis revealed a sarin-specific broad-spectrum proteomic profile including glutamate-mediated excitotoxicity, calcium overload, energy depletion responses, and compensatory carbohydrate metabolism, increases in ROS defense, DNA damage and chromatin remodeling, HSP response, targeted protein degradation (ubiquitination) and cell death response. With regards to the sarin-dependent effect on respiration, our study supports the potential interference of sarin with CO2/H(+) sensitive chemoreceptor neurons of the brainstem retrotrapezoid nucleus (RTN) that send excitatory glutamergic projections to the respiratory centers. In conclusion, this study gives insight into the brainstem broad-spectrum proteome following acute sarin exposure and the gained information will assist in the development of novel countermeasures. Published by Elsevier B.V.

A comparison of organophosphate degradation genes and bioremediation applications.

PubMed

Iyer, Rupa; Iken, Brian; Damania, Ashish

2013-12-01

Organophosphates (OPs) form the bulk of pesticides that are currently in use around the world accounting for more than 30% of the world market. They also form the core for many nerve-based warfare agents including sarin and soman. The widespread use and the resultant build-up of OP pesticides and chemical nerve agents has led to the development of major health problems due to their extremely toxic interaction with any biological system that encounters them. Growing concern over the accumulation of OP compounds in our food products, in the soils from which they are harvested and in wastewater run-off has fuelled a growing interest in microbial biotechnology that provides cheap, efficient OP detoxification to supplement expensive chemical methods. In this article, we review the current state of knowledge of OP pesticide and chemical agent degradation and attempt to clarify confusion over identification and nomenclature of two major families of OP-degrading enzymes through a comparison of their structure and function. The isolation, characterization, utilization and manipulation of the major detoxifying enzymes and the molecular basis of degradation of OP pesticides and chemical nerve agents are discussed as well as the achievements and technological advancements made towards the bioremediation of such compounds. © 2013 John Wiley & Sons Ltd and Society for Applied Microbiology.

Method Of Signal Amplification In Multi-Chromophore Luminescence Sensors

DOEpatents

Levitsky, Igor A.; Krivoshlykov, Sergei G.

2004-02-03

A fluorescence-based method for highly sensitive and selective detection of analyte molecules is proposed. The method employs the energy transfer between two or more fluorescent chromophores in a carefully selected polymer matrix. In one preferred embodiment, signal amplification has been achieved in the fluorescent sensing of dimethyl methylphosphonate (DMMP) using two dyes, 3-aminofluoranthene (AM) and Nile Red (NR), in a hydrogen bond acidic polymer matrix. The selected polymer matrix quenches the fluorescence of both dyes and shifts dye emission and absorption spectra relative to more inert matrices. Upon DMMP sorption, the AM fluorescence shifts to the red at the same time the NR absorption shifts to the blue, resulting in better band overlap and increased energy transfer between chromophores. In another preferred embodiment, the sensitive material is incorporated into an optical fiber system enabling efficient excitation of the dye and collecting the fluorescent signal form the sensitive material on the remote end of the system. The proposed method can be applied to multichromophore luminescence sensor systems incorporating N-chromophores leading to N-fold signal amplification and improved selectivity. The method can be used in all applications where highly sensitive detection of basic gases, such as dimethyl methylphosphonate (DMMP), Sarin, Soman and other chemical warfare agents having basic properties, is required, including environmental monitoring, chemical industry and medicine.

Naloxone Antagonizes Soman-induced Central Respiratory Depression in Rats.

PubMed

Škrbić, Ranko; Stojiljković, Miloš P; Ćetković, Slavko S; Dobrić, Silva; Jeremić, Dejan; Vulović, Maja

2017-06-01

The influence of naloxone on respiration impaired by the highly toxic organophosphate nerve agent soman in anaesthetized rats was investigated. Soman, administered in a dose that was ineffective in blocking the electrically induced contractions of the phrenic nerve-diaphragm preparation in situ, induced a complete block of the spontaneous respiratory movements of the diaphragm, indicating the domination of central over the peripheral effects. Naloxone dose-dependently antagonized the soman-induced respiratory blockade. Atropine, at a dose that was per se ineffective in counteracting soman-induced respiratory depression, potentiated the protective effects of naloxone and completely restored respiration. Naloxone remained completely ineffective in antagonizing respiratory depression induced by the muscarinic receptor agonist the oxotremorine. It is assumed that naloxone antagonizes soman-induced respiratory inhibition by blocking endogenous opioidergic respiratory control pathways that are independent of the stimulation of muscarinic receptors. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

[Comparison of the reactivating effect of BI-6, a new asymmetrical bispyridinium oxime, with oxime HI-6 and obidoxime on soman-inhibited acetylcholinesterase in the diaphragm and various parts of the brain in rats].

PubMed

Kassa, J; Bajgar, J

1999-08-30

Acute poisoning with the highly toxic organophosphorus agent, soman, is not treated satisfactorily even by the most modern antidotes. In experiments on rats, the reactivating effect of a new asymmetric bispyridinium oxime BI-6 was compared with widely used oximes HI-6 and obidoxime by investigating the changes of soman-inhibited acetylcholinesterase activity in the diaphragm and various parts of the brain in rats up to three hours following soman challenge. Our findings confirm that the new oxime BI-6 is a more effective reactivator of soman-inhibited acetylcholinesterase than obidoxime but not as effective as the oxime HI-6 especially in the peripheral compartment. The new oxime BI-6 is not as effective as HI-6 which seems to have definite advantages over other oximes in the treatment of soman poisoning.

A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

PubMed Central

Fattebert, Jean-Luc; Emigh, Aiyana

2015-01-01

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures. PMID:25874456

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

DOE PAGES

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; ...

2015-04-13

Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone andmore » sidechain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.« less

Neuroimmune Effects of Inhaling Low Dose Sarin

DTIC Science & Technology

2008-02-01

system Because two of the Japanese sarin terrorism survivors succumbed to Legionella infection nearly two years after the sarin exposure (Kamimura...lung organism, Legionella . However, our results indicated that both adaptive (antibody and T cell receptor-mediated responses) as well inflammatory...H. Niino, K. Saitoh, and A. Saitoh. 1998. Legionella pneumonia caused by aspiration of hot spring water after sarin exposure. Nihon. Kokyuki. Gakkai

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice.

PubMed

Kassa, Jiří; Korábečný, Jan; Nepovimová, Eugenie

The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2.

A comparison of the efficacy of newly developed reversible inhibitors of acetylcholinesterase with commonly used pyridostigmine as pharmacological pre-treatment of soman-poisoned mice.

PubMed

Kassa, Jiri; Musilek, Kamil; Koomlova, Marketa; Bajgar, Jiri

2012-04-01

The ability of three newly developed reversible inhibitors of acetylcholinesterase (AChE) (K298, K344 and K474) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was compared. Neither pyridostigmine nor new reversible inhibitors of AChE were able to increase the LD(50) value of soman. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of AChE was not able to protect mice against soman-induced lethal acute toxicity. The pharmacological pre-treatment with pyridostigmine alone or with K474 was able to slightly increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice, but the increase in the efficacy of antidotal treatment was not significant. The other newly developed reversible inhibitors of AChF (K298, K344) were completely ineffective. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of AChF is not promising. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.

Interleukin-18 Expression Increases in Response to Neurovascular Damage Following Soman-induced Status Epilepticus in Rats

DTIC Science & Technology

2015-07-22

CONTRACT NUMBER soman-induced status epilepticus in rats 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Johnson, EA, Guignet, MA, Dao...See reprint. 15. SUBJECT TERMS Interleukin 18, Status epilepticus , Soman (GD), Macrophage, T-cell, Neutrophil, Piriform cortex, Hippocampus...following soman-induced status epilepticus in rats Erik A. Johnson1*, Michelle A. Guignet1, Thuy L. Dao1, Tracey A. Hamilton2 and Robert K. Kan1 Abstract

Histopathologic Changes in the Brain, Heart, and Skeletal Muscle of Rhesus Macaques, Ten Days After Exposure to Soman (An Organophosphorus Nerve Agent)

DTIC Science & Technology

2000-04-01

Center, Washington DC. 2. Koplovitz, I., S. Schulz, M. Shutz, et al. 1997. Memantine ef- fects on soman-induced seizures and seizure-related brain dam...neuronal culture as a model for soman-in- duced neurotoxicity and effectiveness of memantine as a neuroprotective drug. Arch. Toxicol. 69:384-390...for soman induced neurotoxicity and effectiveness of memantine as a neuroprotective drug. Drug Dev. Rev. 30:45-53. 27. Bredlow, J. D., G. F

Time course of cholinesterase activity in plasma, brain and muscle of rat pretreated with physostigmine, and then soman

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giacobini, E.; Boyer, A.; Somani, S.M.

1986-03-05

Time course of /sup 3/H-physostigmine (Phy) concentration and cholinesterase (ChE) activity in plasma and tissues was studied in rats pretreated with Phy and then soman. Rats were dosed with Phy (100 ..mu..g/kg, i.v.), 5 or 15 min prior to soman (105 ..mu..g/kg, 1.5 LD/sub 50/, s.c.) treatment and were sacrificed at various times; Phys conc. and ChE activity were determined. BuChE activity in plasma was 5% of control from 7-30 min after Phy i.v. pretreatment and soman or soman alone treatment. Plasma Phy conc. steadily declined (32.6 ng/ml at 7 min) to 15 ng/ml at 30 min. ChE activity inmore » muscle was 60-50% of control for Phy pretreated but soman alone gave 85-72% activity from 2-30 min. Brain ChE activity was about 5% of control within 2 min after soman treatment; however, with Phy pretreatment, the activity was about 52% at 7 min, 40% at 22 min, which recovered to 45% of control at 35 min, indicating that Phy protected brain ChE. Brain Phy conc. steadily declined (58.6 ng/g at 7 min) to 11.7 ng/g at 30 min. However, pretreatment of rat with a higher dose of Phy and then soman showed BuChE in plasma and ChE in brain and muscle to be about 25, 35 and 51%, in comparison to about 5% in plasma and brain with soman alone treatment, indicating higher protection of ChE enzyme with higher conc. of Phy in plasma and brain.« less

Effectiveness of Donepezil, Rivastigmine, and (±)Huperzine A in Counteracting the Acute Toxicity of Organophosphorus Nerve Agents: Comparison with Galantamine

PubMed Central

Aracava, Yasco; Pereira, Edna F. R.; Akkerman, Miriam; Adler, Michael

2009-01-01

Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (±)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 × LD50 soman (42 μg/kg s.c.). All animals that were pretreated with galantamine (6–8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 × LD50 soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 × LD50 soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 × LD50 soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman. PMID:19741148

Measurement of various respiratory dynamics parameters following acute inhalational exposure to soman vapor in conscious rats.

PubMed

Perkins, Michael W; Wong, Benjamin; Rodriguez, Ashley; Devorak, Jennifer; Sciuto, Alfred M

2015-01-01

Respiratory dynamics were investigated in head-out plethysmography chambers following inhalational exposure to soman in untreated, non-anesthetized rats. A multipass saturator cell was used to generate 520, 560 and 600 mg × min/m(3) of soman vapor in a customized inhalational exposure system. Various respiratory dynamic parameters were collected from male Sprague-Dawley rats (300--350 g) during (20 min) and 24 h (10 min) after inhalational exposure. Signs of CWNA-induced cholinergic crisis were observed in all soman-exposed animals. Percentage body weight loss and lung edema were observed in all soman-exposed animals, with significant increases in both at 24 h following exposure to 600 mg × min/m(3). Exposure to soman resulted in increases in respiratory frequency (RF) in animals exposed to 560 and 600 mg × min/m(3) with significant increases following exposure to 560 mg × min/m(3) at 24 h. No significant alterations in inspiratory time (IT) or expiratory time (ET) were observed in soman-exposed animals 24 h post-exposure. Prominent increases in tidal volume (TV) and minute volume (MV) were observed at 24 h post-exposure in animals exposed to 600 mg × min/m(3). Peak inspiratory (PIF) and expiratory flow (PEF) followed similar patterns and increased 24 h post-exposure to 600 mg × min/m(3) of soman. Results demonstrate that inhalational exposure to 600 mg × min/m(3) soman produces notable alterations in various respiratory dynamic parameters at 24 h. The following multitude of physiological changes in respiratory dynamics highlights the need to develop countermeasures that protect against respiratory toxicity and lung injury.

Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.

PubMed

Aracava, Yasco; Pereira, Edna F R; Akkerman, Miriam; Adler, Michael; Albuquerque, Edson X

2009-12-01

Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (+/-)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 x LD(50) soman (42 microg/kg s.c.). All animals that were pretreated with galantamine (6-8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.

NEUROBEHAVIORAL TERATOGENICITY OF SARIN IN AN AVIAN MODEL

PubMed Central

Yanai, Joseph; Pinkas, Adi; Seidler, Frederic J.; Ryde, Ian T.; Van der Zee, Eddy A.; Slotkin, Theodore A.

2009-01-01

Nerve gas organophosphates like sarin are likely to be used in urban terrorism, leading to widespread exposures of pregnant women and young children. Here, we established a model for sarin neurobehavioral teratogenicity in the developing chick so as to explore the consequences of apparently subtoxic sarin exposure and the mechanisms underlying synaptic and behavioral deficits. Chicken eggs were injected with sarin (2, 6 and 12 μg/kg) on incubation days 2 and 6, treatments that did not decrease hatching and did not evoke dysmorphology. After hatching the chicks were tested for filial imprinting and neurochemical markers known to be critical for imprinting. Imprinting was reduced at 2 and 6 μg/kg but not at the highest dose. Acetylcholinesterase and choline acetyltransferase were unaffected but sarin reduced the concentration of the high-affinity choline transporter, the rate-limiting factor in acetylcholine utilization. The concentration of PKC isoforms was assessed in the imprinting-related intermediate part of the medial hyperstriatum ventrale, the region most closely associated with cholinergic function in imprinting behavior. Sarin reduced the concentration of all isoforms (α, β, γ) with a similar, biphasic dose-response curve to that seen for behavioral performance, a relationship noted in previous work with organophosphate pesticides. Our results indicate that otherwise subtoxic exposures to sarin produce neurodevelopmental deficits; since we utilized a chick model, which is devoid of maternal confounds that are present in mammalian development, the adverse effects of sarin are mediated directly in the developing organism. PMID:19660543

The effects of repeated low-dose sarin exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shih, T.-M.; Hulet, S.W.; McDonough, J.H.

2006-09-01

This project assessed the effects of repeated low-dose exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the established LD{sub 5} dose of sarin (42 {mu}g/kg, s.c.). The animals were assessed for changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels, neurobehavioral reactions to a functional observational battery (FOB), cortical electroencephalographic (EEG) power spectrum, and intrinsic acetylcholine (ACh) neurotransmitter (NT) regulation over the 2 weeks of sarin exposure and for up to 12 days postinjection.more » No guinea pig receiving 0.3, 0.4 or 0.5 x LD{sub 5} of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline, while seizures were evident in animals receiving 0.6 x LD{sub 5} of sarin as early as the second day; subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD{sub 5} sarin showed obvious signs of cholinergic toxicity; overall, 2 of 13 animals receiving 0.5 x LD{sub 5} sarin died before all 10 injections were given, and there was a significant increase in the angle of gait in the animals that lived. By the 10th day of injection, the animals receiving saline were significantly easier to remove from their cages and handle and significantly less responsive to an approaching pencil and touch on the rump in comparison with the first day of testing. In contrast, the animals receiving 0.4 x LD{sub 5} sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared with the first day. The 0.5 x LD{sub 5} sarin animals also failed to show any significant changes to the approach and touch responses and did not adjust to handling or removal from the cage from the first day of injections to the last day of handling. Thus, the guinea pigs receiving the 0.4 and 0.5 x LD{sub 5} doses of sarin failed to habituate to some aspects of neurobehavioral testing. Spectral analysis of EEG data suggested that repeated sarin exposure may disrupt normal sleeping patterns (i.e., lower frequency bandwidths). While these EEG changes returned to relative normalcy 6 days after the last injection in animals receiving 0.4 x LD{sub 5} sarin, these changes were still observed in the animals that received 0.5 x LD{sub 5} sarin. Ten to twelve days after the last sarin injection (in 0.4 x LD{sub 5} group only), neurochemical data showed that striatal choline levels were reduced in comparison to the saline group. At this time, atropine sulfate (5 mg/kg, i.p.) challenge resulted in a transient elevation in striatal ACh levels in animals exposed to repeated 0.4 x LD{sub 5} sarin as well as in control animals. No evidence of brain or heart pathology was found in any guinea pig that survived all 10 sarin injections.« less

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Final summary report, 1 October 1981-29 February 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of Soman and paraoxon on cerebral metabolic rate (CMRg) and the levels of various metabolites in rate brain were investigated. In non-convulsing animals, 0.8 of the paraoxon LD50 and 0.5 of the Soman LD50 tended to lower CMRg. A higher dose of Soman, 0.8-0.95 of the LD50, resulted in convulsive seizures in some but not all of the animals. In convulsing rats the CMRg and lactate levels were elevated primarily in the cortex and thalamus/basal ganglia. Decreased ATP and glucose levels with an elevated CMRg and lactate concentration was observed in the cortex, suggesting that Soman may bemore » uncoupling oxidative phosphorylation. Pretreatment with atropine prevented the behavioral manifestations and the elevated CMRg but not the hyperglycemia produced by an 0.8 LD50 dose of Soman. These results suggest that Soman-induced convulsions are similar to those produced by other central nervous system (CNS) excitatory agents in that only certain brain regions are affected. The use of atropine to block the CNS disturbances produced by Soman appears to be effective also does not result in the extensive depression of CMRg observed with TAB, a mixture of trimedoxime, atropine and benactyzine.« less

Diet composition exacerbates or attenuates soman toxicity in rats: implied metabolic control of nerve agent toxicity.

PubMed

Myers, Todd M; Langston, Jeffrey L

2011-06-01

To evaluate the role of diet composition on nerve agent toxicity, rats were fed four distinct diets ad libitum for 28 d prior to challenge with 110 μg/kg (1.0 LD(50), sc) soman. The four diets used were a standard rodent diet, a choline-enriched diet, a glucose-enriched diet, and a ketogenic diet. Body weight was recorded throughout the study. Toxic signs and survival were evaluated at key times for up to 72 h following soman exposure. Additionally, acquisition of discriminated shuttlebox avoidance performance was characterized beginning 24h after soman challenge and across the next 8 d (six behavioral sessions). Prior to exposure, body weight was highest in the standard diet group and lowest in the ketogenic diet group. Upon exposure, differences in soman toxicity as a function of diet became apparent within the first hour, with mortality in the glucose-enriched diet group reaching 80% and exceeding all other groups (in which mortality ranged from 0 to 6%). At 72 h after exposure, mortality was 100% in the glucose-enriched diet group, and survival approximated 50% in the standard and choline-enriched diet groups, but equaled 87% in the ketogenic diet group. Body weight loss was significantly reduced in the ketogenic and choline-enriched diet groups, relative to the standard diet group. At 1 and 4h after exposure, rats in the ketogenic diet group had significantly lower toxic sign scores than all other groups. The ketogenic diet group performed significantly better than the standard diet group on two measures of active avoidance performance. The exacerbated soman toxicity observed in the glucose-enriched diet group coupled with the attenuated soman toxicity observed in the ketogenic diet group implicates glucose availability in the toxic effects of soman. This increased glucose availability may enhance acetylcholine synthesis and/or utilization, thereby exacerbating peripheral and central soman toxicity. Published by Elsevier B.V.

Aum Shinrikyo's Chemical and Biological Weapons: More Than Sarin.

PubMed

Tu, A T

2014-07-01

The radical religious group Aum Shinrikyo was founded in Japan in the 1980s and grew rapidly in the 1990s. Aum members perpetrated a mass murder in Matsumoto City in 1994, where they used sarin as a chemical weapon to poison approximately 500 civilians. On March 20, 1995, Aum deployed sarin in an even larger terrorist attack on the Tokyo Subway System, which poisoned some 6,000 people. After the Tokyo Subway attack, the Japanese Police arrested the sect's senior members. From 2005 through 2011, 13 of these senior members were sentenced to death. In this article, aspects of Aum's chemical and biological terrorism are reviewed. Sarin production efforts by the sect are described, including how the degradation product of sarin in soil, methylphosphonic acid, enabled the detection of sarin production sites. Also, Aum's chemical-warfare agents other than sarin are described, as are its biological weapons. The author was permitted by the Japanese government to interview Dr. Tomomasa Nakagawa, one of the senior members of Aum Shinrikyo. From Dr. Nakagawa the author obtained valuable inside information about Aum's chemical and biological weapons programs. Copyright © 2014 Central Police University.

Effects of organophosphorus anticholinesterase compounds on brain glucose and energy metabolism. Annual summary report, 1 October 1982-29 February 1984

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medina, M.A.; Miller, A.L.

1984-09-01

The effects of paraoxon and Soman on glucose utilization and of Soman on the levels of intermediary metabolites were investigated in rat brain. The rate of glucose utilization and the levels of intermediary metabolites were determined in six brain areas at varying time periods after administration of 0.5 or 0.8 of the paraoxon or Soman LD50. Behavioral changes were observed only with the 0.8 LD50 dose of both compounds and some of the animals exhibited convulsive activity with this dose of Soman. Brain glucose utilization tended to be decreased by 0.8 LD50 paraoxon and 0.5 LD50 Soman. Some alterations inmore » metabolite levels were observed but these were not consistent and could not be correlated with the rate of glucose utilization. In animals with Soman-induced convulsions, glucose utilization and lactate levels were elevated only in the cortex and thalamus/basal ganglia. ATP, creatine phosphate and glucose levels were decreased in the cortex but not in other brain areas, suggesting the possibility of uncoupling of oxidative phosphorylation. Pretreatment with atropine prevented the behavioral responses and the changes in glucose utilization previously observed with 0.8 Soman LD50. Our results in convulsing animals are similar to those which have been observed with the excitatorytoxins kainic acid and bicuculline.« less

Protective effects of S+ ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs.

PubMed

Dorandeu, Frederic; Baille, Valerie; Mikler, John; Testylier, Guy; Lallement, Guy; Sawyer, Thomas; Carpentier, Pierre

2007-05-20

Soman poisoning is known to induce full-blown tonic-clonic seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Previous studies in guinea-pigs have shown that racemic ketamine (KET), with atropine sulfate (AS), is very effective in preventing death, stopping seizures and protecting sensitive brain areas when given up to 1h after a supra-lethal challenge of soman. The active ketamine isomer, S(+) ketamine (S-KET), is more potent than the racemic mixture and it also induces less side-effects. To confirm the efficacy of KET and to evaluate the potential of S-KET for delayed medical treatment of soman-induced SE, we studied different S-KET dose regimens using the same paradigm used with KET. Guinea-pigs received pyridostigmine (26 microg/kg, IM) 30min before soman (62 microg/kg, 2 LD(50), IM), followed by therapy consisting of atropine methyl nitrate (AMN) (4 mg/kg, IM) 1min following soman exposure. S-KET, with AS (10mg/kg), was then administered IM at different times after the onset of seizures, starting at 1h post-soman exposure. The protective efficacy of S-KET proved to be comparable to KET against lethality and SRBD, but at doses two to three times lower. As with KET, delaying treatment by 2h post-poisoning greatly reduced efficacy. Conditions that may have led to an increased S-KET brain concentration (increased doses or number of injections, adjunct treatment with the oxime HI-6) did not prove to be beneficial. In summary, these observations confirm that ketamine, either racemic or S-KET, in association with AS and possibly other drugs, could be highly effective in the delayed treatment of severe soman intoxication.

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shih, T.M.

1993-12-31

The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 ttg/kg. SC; equivalent to 0.9 x LDs0 dose) and treated 1 min later with one of these oximes (100 or 200 ttmo1/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93 - 96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (rangingmore » from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. in contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than Hl-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximesreactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. 111-6 reactivated soman-inhibited ChE in all tis- sues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in Intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Che, Magnus M.; Conti, Michele; Chanda, Soma

We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m{sup 3} sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarinmore » exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.« less

Using Metal Complex Ion-Molecule Reactions in a Miniature Rectilinear Ion Trap Mass Spectrometer to Detect Chemical Warfare Agents

NASA Astrophysics Data System (ADS)

Graichen, Adam M.; Vachet, Richard W.

2013-06-01

The gas-phase reactions of a series of coordinatively unsaturated [Ni(L)n]y+ complexes, where L is a nitrogen-containing ligand, with chemical warfare agent (CWA) simulants in a miniature rectilinear ion trap mass spectrometer were investigated as part of a new approach to detect CWAs. Results show that upon entering the vacuum system via a poly(dimethylsiloxane) (PDMS) membrane introduction, low concentrations of several CWA simulants, including dipropyl sulfide (simulant for mustard gas), acetonitrile (simulant for the nerve agent tabun), and diethyl phosphite (simulant for nerve agents sarin, soman, tabun, and VX), can react with metal complex ions generated by electrospray ionization (ESI), thereby providing a sensitive means of detecting these compounds. The [Ni(L)n]2+ complexes are found to be particularly reactive with the simulants of mustard gas and tabun, allowing their detection at low parts-per-billion (ppb) levels. These detection limits are well below reported exposure limits for these CWAs, which indicates the applicability of this new approach, and are about two orders of magnitude lower than electron ionization detection limits on the same mass spectrometer. The use of coordinatively unsaturated metal complexes as reagent ions offers the possibility of further tuning the ion-molecule chemistry so that desired compounds can be detected selectively or at even lower concentrations.

Tyrosines of Human and Mouse Transferrin Covalently Labeled by Organophosphorus Agents: A New Motif for Binding to Proteins that Have No Active Site Serine

PubMed Central

Li, Bin; Schopfer, Lawrence M.; Grigoryan, Hasmik; Thompson, Charles M.; Hinrichs, Steven H.; Masson, Patrick; Lockridge, Oksana

2009-01-01

The expectation from the literature is that organophosphorus (OP) agents bind to proteins that have an active site serine. However, transferrin, a protein with no active site serine, was covalently modified in vitro by 0.5mM 10-fluoroethoxyphosphinyl-N-biotinamido pentyldecanamide, chlorpyrifos oxon, diisopropylfluorophosphate, dichlorvos, sarin, and soman. The site of covalent attachment was identified by analyzing tryptic peptides in the mass spectrometer. Tyr 238 and Tyr 574 in human transferrin and Tyr 238, Tyr 319, Tyr 429, Tyr 491, and Tyr 518 in mouse transferrin were labeled by OP. Tyrosine in the small synthetic peptide ArgTyrThrArg made a covalent bond with diisopropylfluorophosphate, chlorpyrifos oxon, and dichlorvos at pH 8.3. These results, together with our previous demonstration that albumin and tubulin bind OP on tyrosine, lead to the conclusion that OP bind covalently to tyrosine, and that OP binding to tyrosine is a new OP-binding residue. The OP-reactive tyrosines are activated by interaction with Arg or Lys. It is suggested that many proteins in addition to those already identified may be modified by OP on tyrosine. The extent to which tyrosine modification by OP can occur in vivo and the toxicological implications of such modifications require further investigation. PMID:18930948

Efficacy comparison of scopolamine and diazepam against soman-induced debilitation in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, D.R.; Gennings, C.; Carter, W.H.

1994-12-31

The efficacy of diazepam (DZ) and scopolamine (SCP), in combination with atropine (ATR) + oxime therapy, against soman-induced seizure/convulsive activity and associated brain damage has been demonstrated, but the efficacy of each against the incapacitating effects of soman has not been addressed. Thus, the therapeutic efficacies of SCP (5 doses; 0-0.86 mg/kg) and DZ (5 doses; 0-5 mg/kg), when each was used in conjunction with ATR (3 doses; 0.5-8 mg/kg) + 2-PAM (25 mg/kg) therapy, were compared in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5, or 3.2 LD5Os of soman. Response surface methodology was employed tomore » describe the relationship between soman-induced incapacitation and the ATR/DZ or ATRISCP dosages. Incapacitation was measured by toxicity scores assigned by three graders to test animals at 60 min postsoman. Results show that as the dosage of SCP increased, the mean toxicity scores decreased. Also, within the indicated dose ranges used, the efficacy of SCP was not dependent on the presence of ATR. In contrast, ATR alone was found to be more effective than when combined with DZ at any dose, and indicates that DZ might be temporarily contributing to soman-induced incapacitation. These findings suggest that in guinea pigs, SCP could replace ATR or DZ, or both, as therapy against soman-induced incapacitation.« less

Action of cholinergic poisons on the central nervous system and effectiveness of potential antidotes. Annual report 1 Jul 81-30 Jun 82

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samson, F.; Nelson, S.

The research aim was to determine the effects of soman, related organophosphate toxins and potential antidotes on brain regional functions in rats: The (/sup 14/C)-2-deoxyglucose procedure (2-DG) was used for mapping brain regional glucose use. Quantitative autoradiography was used for muscarinic and nicotinic cholinergic receptors. The 2-DG procedure gives a quantitative measure of glucose utilization in brain regions and is in index of the 'functional activity' in brain regions and systems. Values were determined in controls, rats with soman induced seizures, seizures induced by convulsants (DFP, strychnine, picrotoxin, pentylenetetrazol, penicillin) and soman pretreated with TAB. Brain regional cholinergic receptor mapsmore » were prepared and some regional muscarinic and nicotinic receptor densities have been quantified. Soman (112 micrograms/kg i.m.) causes strong, continuous seizures and a dramatic (2-6 fold) increase in the rate of glucose use in 10 major brain regions. Most intense increases were in septum, substants nigra reticularis and outer layer of hippcampal dendata gyrus. The overt seizures of rats induced by convulsants DFP, strychnine, picrotoxin, pentylenetetrazol and penicillin (in hippocampus) were strikingly different from that of rats with soman seizures. High doses (2X LD50) of soman in rats protected with TAB caused a 50% depression of glucose use in most brain regions. The effects of repeated soman exposure on muscarinic and nicotinic receptors are under study.« less

Blood and bronchoalveolar lavage fluid acetylcholinesterase levels following microinstillation inhalation exposure to sarin in Guinea pigs.

PubMed

Che, Magnus M; Conti, Michele; Boylan, Megan; Sciuto, Alfred M; Gordon, Richard K; Nambiar, Madhusoodana P

2008-07-01

We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m(3)) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt(50) for sarin using the microinstillation technique was determined to be close to 677.4 mg/m(3). Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m(3) sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m(3) sarin exposure but a marginal inhibition at 169.3 mg/m(3). In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m(3) in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m(3) and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.

Cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning.

PubMed

Joosen, Marloes J A; Bueters, Tjerk J H; van Helden, Herman P M

2004-01-01

Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 micro g/kg s.c., approximately 2 x LD50) in rats is completely prevented by treatment with the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A1 receptor antagonist 8- p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A1 receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.

Neuroprotective mechanisms activated in non-seizing rats exposed to sarin.

PubMed

Te, Jerez A; Spradling-Reeves, Kimberly D; Dillman, James F; Wallqvist, Anders

2015-08-27

Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures. Published by Elsevier B.V.

Effects of carbamates on whole blood cholinesterase activity: chemical protection against soman.

PubMed

Heyl, W C; Harris, L W; Stitcher, D L

1980-01-01

The toxicity (LD50) of several carbamates, all reversible inhibitors of cholinesterase (ChE), were determined in male rabbits. These include isopropyl methylphenyl carbamate (IMPC), pyridostigmine, neostigmine, benzpyrinium and physostigmine. When 1/9 of the LD50 of the above carbamates was individually combined with atropine (A) and benactyzine (B), mecamylamine (M) or chloropromazine (CPZ) and administered to rabbits in a pretreatment regimen, most animals could be protected from a 10 LD50 challenge of Soman. If CPZ, M or B was omitted from this regimen, no rabbits survived this challenge of Soman. The protection afforded against Soman was found to be related to reversible inhibition of ChE by the carbamates; reversible ChE inhibition varied with the route of injection and with the physical properties of the carbamate. Oral administration of pyridostigmine, a quaternary carbamate, provided protection for 24 hours. When the pretreatment included four components (pyridostigmine, A, M and B), the LD50 of Soman was raised 30.8 times in rabbits.

Skin decontamination with mineral cationic carrier against sarin determined in vivo.

PubMed

Vucemilović, Ante; Hadzija, Mirko; Jukić, Ivan

2009-06-01

Our Institute's nuclear, biological, and chemical defense research team continuously investigates and develops preparations for skin decontamination against nerve agents. In this in vivo study, we evaluated skin decontamination efficacy against sarin by a synthetic preparation called Mineral Cationic Carrier (MCC) with known ion exchange, absorption efficacy and bioactive potential. Mice were treated with increasing doses of sarin applied on their skin, and MCC was administered immediately after contamination. The results showed that decontamination with MCC could achieve therapeutic efficacy corresponding to 3 x LD(50) of percutaneous sarin and call for further research.

Microfluidic chip with optical sensor for rapid detection of nerve agent Sarin in water samples

NASA Astrophysics Data System (ADS)

Tan, Hsih Yin; Nguyen, Nam-Trung; Loke, Weng Keong; Tan, Yong Teng

2007-12-01

The chemical warfare agent Sarin is an organophosphate that is highly toxic to humans as they can act as cholinesterase inhibitors, that disrupts neuromuscular transmission. As these nerve agents are colorless, odorless and highly toxic, they can be introduced into drinking water as a means of terrorist sabotage. Hence, numerous innovative devices and methods have been developed for rapid detection of these organophosphates. Microfluidic technology allows the implementation of fast and sensitive detection of Sarin. In this paper, a micro-total analysis systems (TAS), also known as Lab-on-a-chip, fitted with an optical detection system has been developed to analyze the presence of the nerve agent sarin in water samples. In the present set-up, inhibition of co-introduced cholinesterase and water samples containing trace amounts of nerve agent sarin into the microfluidic device was used as the basis for selective detection of sarin. The device was fabricated using polymeric micromachining with PMMA (poly (methymethacrylate)) as the substrate material. A chromophore was utilized to measure the activity of remnant cholinesterase activity, which is inversely related to the amount of sarin present in the water samples. Comparisons were made between two different optical detection techniques and the findings will be presented in this paper. The presented measurement method is simple, fast and as sensitive as Gas Chromatography.

Neuroprotective Effects of Galantamine on Nerve Agent-Induced Neuroglial and Biochemical Changes.

PubMed

Golime, RamaRao; Palit, Meehir; Acharya, J; Dubey, D K

2018-05-01

Neuroprotection from nerve agent such as soman-induced neural damage is a major challenge for existing drugs. Nerve agent exposure can cause many neural effects in survivors arising mainly due to acetylcholinesterase (AChE) inhibition or death within minutes. Unraveling the mechanisms underlying the nerve agent-induced multiple neurological effects is useful to develop better and safe drugs. The present study aimed to understand the molecular response during soman exposure and to evaluate the neuroprotective efficacy of galantamine on nerve agent-induced neurotoxic changes. mRNA expression studies using quantitative real-time PCR revealed significant changes in S-100β, Gfap, c-fos, and Bdnf in the hippocampus and piriform cortex after soman (90 μg/kg, s.c) exposure. Immunoblot analysis showed acute soman exposure significantly increased the protein levels of neuroglial markers (S100-β and GFAP); c-Fos and protein oxidation in discrete rat brain areas indicate their role in nerve agent-induced neurotoxicity. Induction of BDNF levels during soman exposure may indicate the recovery mechanisms activation. AChE was inhibited in the blood and brain up to 82% after soman exposure. Antidotal treatment with galantamine alone (3 mg/kg) and galantamine plus atropine (10 mg/kg) has protected animals from nerve agent-induced intoxication, death, and soman-inhibited AChE up to 45% in the blood and brain. Animal received galantamine displayed increased levels of neuroprotective genes (nAChRα-7, Bcl-2, and Bdnf) in the brain suggest the neuroprotective value of galantamine. Neuroglial changes, c-Fos, and protein oxidation levels significantly reduced after galantamine and galantamine plus atropine treatment indicate their potential antidotal value in nerve agent treatment.

Distortion product otoacoustic emissions as non-invasive biomarkers and predictors of soman-induced central neurotoxicity: a preliminary study.

PubMed

Job, Agnès; Baille, Valérie; Dorandeu, Frédéric; Pouyatos, Benoît; Foquin, Annie; Delacour, Claire; Denis, Josiane; Carpentier, Pierre

2007-09-05

The organophosphorus nerve agent soman is an irreversible cholinesterase (ChE) inhibitor that can produce long-lasting seizures and brain damage in which the neurotransmitters acetylcholine and glutamate are involved. These same neurotransmitters play key-roles in the auditory function. It was then assumed that exploring the hearing function may provide markers of the central events triggered by soman intoxication. In the present study, distortion product otoacoustic emissions (DPOAEs), a non-invasive audiometric method, were used to monitor cochlear functionality in rats administered with a moderate dose of soman (45 microg/kg). DPOAEs were investigated either 4h or 24h post-challenge. In parallel, the effects of soman on whole blood and brain ChE activity and on brain histology were also studied. The first main result is that DPOAE intensities were significantly decreased 4h post-soman and returned to baseline at 24h. The amplitude changes were well related to the severity of symptoms, with the greatest change being recorded in the rats that survived long-lasting convulsions. The second main result is that baseline DPOAEs recorded 8 days before soman appear to predict the severity of symptoms produced by the intoxication. Indeed, the lowest baseline DPOAEs corresponded to the occurrence of long-lasting convulsions and brain damage and to the greatest inhibition in central ChE. These results thus suggest that DPOAEs represent a promising non-invasive tool to assess and predict the central consequences of nerve agent poisoning. Further investigations will be carried out to assess the potential applications and the limits of this non-invasive method.

The by-products generated during sarin synthesis in the Tokyo sarin disaster induced inhibition of natural killer and cytotoxic T lymphocyte activity.

PubMed

Li, Q; Hirata, Y; Piao, S; Minami, M

2000-05-05

More than 5000 passengers on Tokyo subway trains were injured by the nerve gas, sarin and its by-products. Analysis of phosphor-carrying metabolites of sarin and its by-products in urine samples from the victims suggested that they were exposed not only to sarin, but also by-products generated during sarin synthesis, i.e. diisopropyl methylphosphonate (DIMP) and diethyl methylphosphonate (DEMP). We suspected genetic after-effects due to sarin by-products, thus, we checked the frequency of sister chromatid exchange (SCE) and found that SCE was significantly higher in the victims than in a control group, and that DIMP and DEMP significantly induced human lymphocyte SCE in vitro. In the present study, to explore whether DIMP and DEMP, which induced a high frequency of SCE of lymphocytes, also affected the lymphocyte functions, we examined the effect of DIMP and DEMP on splenic natural killer (NK) and splenic cytotoxic T lymphocyte (CTL) activity in mice, and NK activity of human lymphocytes in vitro. We found that DIMP and DEMP significantly inhibited NK and CTL activity in a dose-dependent manner. The inhibition induced by DIMP was stronger than that by DEMP. The effect of DIMP and DEMP on the splenic NK activity of mice was stronger than on the splenic CTL activity, and the human lymphocytes is more sensitive to DIMP and DEMP than the splenocytes of mice.

Organophosphorus acid anhydrolase in slime mold, duckweed and mung bean: a continuing search for a physiological role and a natural substrate.

PubMed

Hoskin, F C; Walker, J E; Mello, C M

1999-05-14

Recently, and for the first time, a diisopropylphosphorofluoridate (DFP)-hydrolyzing enzyme, i.e. an organophosphorus acid anhydrolase (OPAA), has been reported in a plant-source. Based on this and other suggestive evidence, the ability of three plant sources and a protist to hydrolyze DFP and 1,2,2-trimethylpropyl methylphosphonofluoridate (Soman) were tested, and the effects of Mn2+ and ethylenediamine tetraacetate (EDTA) on this activity. The plants are duckweed (Lemna minor), giant duckweed (Spirodela oligorhiza), and germinated mung bean (Vigna radiata); the protist is a slime mold (Dictyostelium discoidium). The tests are based on a crude classification of OPAAs as 'squid type' (DFP hydrolyzed more rapidly than Soman) and all of the others termed by us, with questionable justification, as 'Mazur type' (Soman hydrolyzed more rapidly than DFP). Of the two duckweeds, Spirodela oligorhiza hydrolyzes Soman but not DFP, and Lemna minor does not hydrolyze either substrate. In contrast to the report of Yu and Sakurai, mung bean does not hydrolyze DFP and hydrolyzes Soman with a 5-fold stimulation by Mn2+ and a marked inhibition by EDTA. The slime mold hydrolyzes Soman more rapidly than DFP (but does hydrolyze DFP) and the hydrolysis is Mn2+ stimulated. The failure of these plant sources to hydrolyze DFP is similar to the behavior of OPAA from Bacillus stearothermophilus.

Efficacy evaluation of physostigmine and anticholinergic adjuncts as a pretreatment for nerve agent intoxication. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

von Bredow, J.; Corcoran, K.; Maitland, G.

1991-12-31

Pretreatment of nonhuman primates with physostigmine (Phy) and scopolamine or physostigmine and trihexyphenidyl 25 min before exposure to 2 LD50 soman im resulted in complete survival without convulsions or loss of consciousness. When identically pretreated animals were challenged with 5 LD50s of soman followed by atropine and 2-PAM therapy 1 min later, all animals experienced a loss of consciousness for approximately 10 min followed by functional recovery within an additional 20 min. These findings indicated that a pretreatment regimen composed of Phy and cholinolytic is capable of protecting primates from an absolute lethal dose of soman with rapid recovery frommore » incapacitation. Physostigmine, nerve agent pretreatment, cynomolgus monkeys soman (GD).« less

Diet composition modifies the toxicity of repeated soman exposure in rats.

PubMed

Langston, Jeffrey L; Myers, Todd M

2011-12-01

It was previously demonstrated that diet potently modulates the toxic effects of an acute lethal dose of the nerve agent soman. The current investigation was undertaken to examine the influence of diet on the cumulative toxicity of repeated soman administration. Rats were fed one of four distinct diets (standard, choline-enriched, glucose-enriched, or ketogenic) for four weeks prior to and throughout a repeated soman dosing and recovery regimen. Each diet group included animals exposed to an equivalent volume of saline that served as negative controls. In exposure Week 1, animals received three consecutive daily doses of 0.4 LD(50) soman. In exposure Week 2, animals received four consecutive daily doses of 0.5 LD(50) soman. In exposure Week 3, animals received five consecutive daily doses of 0.5 LD(50) soman. Week 4 constituted a post-exposure recovery evaluation. Throughout the experiment, behavioral function was assessed by a discriminated avoidance test that required intact sensory and motor function. Survival and body weight changes were recorded daily. Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group. Avoidance performance and weight loss measures corroborated the differential toxicity observed across diet groups. Upon cessation of soman exposure during the final week, recovery of weight and avoidance performance in survivors was comparable across diet groups. These results systematically replicate previous findings demonstrating that diet composition exacerbates or attenuates toxicity in rodents exposed acutely to organophosphorus compounds. Published by Elsevier B.V.

Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack.

PubMed

Nishiwaki, Y; Maekawa, K; Ogawa, Y; Asukai, N; Minami, M; Omae, K

2001-11-01

Although the clinical manifestations of acute sarin poisoning have been reported in detail, no comprehensive study of the chronic physical and psychiatric effects of acute sarin poisoning has been carried out. To clarify the chronic effects of sarin on the nervous system, a cross-sectional epidemiologic study was conducted 3 years after the Tokyo subway sarin attack. Subjects consisted of the rescue team staff members and police officers who had worked at the disaster site. Subjects consisted of 56 male exposed subjects and 52 referent subjects matched for age and occupation. A neurobehavioral test, stabilometry, and measurement of vibration perception thresholds were performed, as well as psychometric tests to assess traumatic stress symptoms. The exposed group performed less well in the backward digit span test than the referent group in a dose-effect manner. This result was the same after controlling for possible confounding factors and was independent of traumatic stress symptoms. In other tests of memory function, except for the Benton visual retention test (mean correct answers), effects related to exposure were also suggested, although they were not statistically significant. In contrast, the dose-effect relationships observed in the neurobehavioral tests (psychomotor function) were unclear. None of the stabilometry and vibration perception threshold parameters had any relation to exposure. Our findings suggest the chronic decline of memory function 2 years and 10 months to 3 years and 9 months after exposure to sarin in the Tokyo subway attack, and further study is needed.

Effects of sarin on the nervous system in rescue team staff members and police officers 3 years after the Tokyo subway sarin attack.

PubMed Central

Nishiwaki, Y; Maekawa, K; Ogawa, Y; Asukai, N; Minami, M; Omae, K

2001-01-01

Although the clinical manifestations of acute sarin poisoning have been reported in detail, no comprehensive study of the chronic physical and psychiatric effects of acute sarin poisoning has been carried out. To clarify the chronic effects of sarin on the nervous system, a cross-sectional epidemiologic study was conducted 3 years after the Tokyo subway sarin attack. Subjects consisted of the rescue team staff members and police officers who had worked at the disaster site. Subjects consisted of 56 male exposed subjects and 52 referent subjects matched for age and occupation. A neurobehavioral test, stabilometry, and measurement of vibration perception thresholds were performed, as well as psychometric tests to assess traumatic stress symptoms. The exposed group performed less well in the backward digit span test than the referent group in a dose-effect manner. This result was the same after controlling for possible confounding factors and was independent of traumatic stress symptoms. In other tests of memory function, except for the Benton visual retention test (mean correct answers), effects related to exposure were also suggested, although they were not statistically significant. In contrast, the dose-effect relationships observed in the neurobehavioral tests (psychomotor function) were unclear. None of the stabilometry and vibration perception threshold parameters had any relation to exposure. Our findings suggest the chronic decline of memory function 2 years and 10 months to 3 years and 9 months after exposure to sarin in the Tokyo subway attack, and further study is needed. PMID:11713003

Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides.

PubMed

Musilek, Kamil; Dolezal, Martin; Gunn-Moore, Frank; Kuca, Kamil

2011-07-01

Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and heterogeneous group of organophosphorus compounds. Their biological activity of inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) ranks them as life endangering agents. The necessary treatment after OPP exposure involves the use of parasympatolytics (e.g. atropine), oxime reactivators (e.g. obidoxime), and anticonvulsive drugs (e.g. diazepam). Therefore, the reactivators of AChE are essential compounds in the treatment of OPP intoxications. Commercial AChE reactivators (e.g. pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) were originally developed for other members of the organophosphate family, such as nerve agents (e.g. sarin, soman, tabun, VX). Pralidoxime, HI-6, and methoxime were found to be weak reactivators of OPP-inhibited AChE. Obidoxime and trimedoxime showed satisfactory reactivation against various OPPs with minor toxicity issues. During the last two decades, the treatment of OPP exposure has become more widely discussed because of growing agricultural production, industrialization, and harmful social issues (e.g. suicides). In this review is the summarized design, evaluation, and structure-activity relationship studies of recently produced AChE reactivators. Since pralidoxime, over 300 oximes have been produced or tested against OPP poisoning, and several novel compounds show very promising abilities as comparable (or higher) to commercial oximes. Some of these are highlighted for their further testing of OPP exposure and, additionally, the main structure-activity relationship of AChE reactivators against OPP is discussed. © 2009 Wiley Periodicals, Inc.

Contaminant characterization on hair and fiber surfaces using imaging TOF-SIMS

NASA Astrophysics Data System (ADS)

Groenewold, Gary S.; Gresham, Garold L.; Gianotto, Anita K.; Avci, Recep

1999-02-01

Imaging time-of-flight secondary ion mass spectrometry (SIMS) was used to evaluate the detection of contaminant chemicals on the surfaces of single synthetic textile and canine hair fibers. The results of the study showed that a variety of chemical classes can be detected. Both cocaine and heroin could be easily observed as intact protonated molecules ([M + H]+) in the cation spectra acquired from textile fibers. Two organophosphates were evaluated: malathion, which is a common pesticide, and pinacolyl methyl phosphonic acid (PMPA), which is the principal degradation product of the nerve agent soman (a close relative of sarin). Malathion could be observed as (CH3O)2P(equalsS)S-, which is formed by thiophosphate cleavage of the intact malathion. PMPA is observed as the conjugate base ([PMPA - H]-). Surfactant chemicals found in hair care products were successfully detected on single hair fibers. Specifically, alkyl sulfates, ethoxylated alkyl sulfates, silicones, and alkylammonium compounds could be readily identified in spectra acquired from single hair fiber samples exposed to shampoo and/or conditioner. Generally, the results of the study show that imaging SIMS is applicable to single fiber analysis, for a range of adsorbed compound types. The forensic application of this instrumental approach has not been widely recognized. However, the ability of the technique to acquire specific chemical information from trace samples clearly points to applications where the need for chemical analysis is great, but the amount of sample is limited.

Effects of injectable anticholinergic drugs on soman-induced lethality and convulsant/subconvulsant activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Anderson, D.R.; Lennox, W.J.

1993-05-13

FDA approved, injectable preparations of candidate compounds BENZTROPINE (BZT), 1.0 mg/ml; biperiden (BIP), 5.0 mg/ml; dicyclomine (DCL), 10 mg/ml; 1-hyoscyamine (HYO), 0.5 mg/ml; orphenadrine (ORP), 30 mg/ml; scopolamine (SCP), 1.0 mg/ml were tested in parallel with diazepam (DZ, the standard) in male guinea pigs against ongoing soman induced convulsive (CV)/sub-CV activity. Three trained graders concurrently assigned CV/sub-CV scores (12 - convulsions; 0 normal) to each animal. Animals received (im) pyridostigmine (PYR; 26 ug/kg) 30 min before soman (56 ug/kg; 2 LD50), atropine (2 mg/kg) admixed with 2-PAM (25 mg/kg) at one min after soman, and the candidate drug preparation atmore » 5.67 min post soman, a time when CV activity is assured. BIP and SCP demonstrated efficacy over dosage ranges between 10 and 0.3 and 1.0 and 0.13 mg/kg, respectively, while the other preparations were less effective at their respective maximum dosages. At optimal dosages of SCP (0.5 mg/kg) and BIP (10 mg/kg), the CV/sub-CV scores were significantly lower (p < 0.05) than those of DZ.« less

Treatment with endotracheal therapeutics after sarin microinstillation inhalation exposure increases blood cholinesterase levels in guinea pigs.

PubMed

Che, Magnus M; Song, Jian; Oguntayo, Samuel; Doctor, Bhupendra P; Rezk, Peter; Perkins, Michael W; Sciuto, Alfred M; Nambiar, Madhusoodana P

2012-05-01

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4 mg/m(3) or 846.5 mg/m(3) (1.2 LCt(50)) sarin for 4 min using a microinstillation inhalation exposure technique and treated 1 min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24 h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45-60%) compared to sarin-exposed animals (p < 0.05). Similarly, treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p < 0.05). BChE activity was increased after treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases.

Effects of pyridostigmine and cholinolytics on cholinesterase and acetylcholine in Soman poisoned rats.

PubMed

Stitcher, D L; Harris, L W; Heyl, W C; Alter, S C

1978-01-01

Soman reduced blood and brain cholinesterase (ChE) activity to less than 15% and increased cerebral acetylcholine (ACh) levels to 137.4% of control. When pyridostigmine (P) was used as a prophylactic adjunct, it reduced blood ChE activity to 31.6% of control, failed to significantly alter brain ChE activity, and protected more than 70% of the blood (but not brain enzyme) from phosphonylation by soman. Benactyzine (B) was more effective than atropine (A) in reducing cerebral ACh concentrations, while a combination of the two was more effective than either alone. A prophylaxis of P + A + B was effective in controlling ACh levels in rats poisoned with one LD50 dose of Soman. Since P did not diminish the effects of the cholinolytics on cerebral ACh, this (together with the enzyme data) suggests that the two cholinolytics alone provided the central protection.

The Potential Neurotoxic Effects of Low-Dose Sarin Exposure in a Guinea Pig Model

DTIC Science & Technology

2002-01-01

1 THE POTENTIAL NEUROTOXIC EFFECTS OF LOW-DOSE SARIN EXPOSURE IN A GUINEA PIG MODEL Melinda R. Roberson, PhD, Michelle B. Schmidt...Proving Ground, MD 21010 USA ABSTRACT This study is assessing the effects in guinea pigs of repeated low-dose exposure to the nerve...COVERED - 4. TITLE AND SUBTITLE The Potential Neurotoxic Effects Of Low-Dose Sarin Exposure In A Guinea Pig Model 5a. CONTRACT NUMBER 5b

Interaction between physostigmine and soman on brain regional cholinesterase activity and /sup 3/H-physostigmine distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallak, M.E.; Woodruff, E.; Giacobini, E.

1986-03-05

Physostigmine (Phy) concentrations (as radioactivity) were studied in various brain areas after /sup 3/H-Phy administration as a function of time. Five min after 500 ..mu..g/kg i.m., cortex (CX) and total brain showed similar concentrations (370 ng/g) which were 50-90% higher than those of other brain regions (striatum, hippocampus, and medulla oblongata). Soman did not affect Phy levels in whole brain after pretreatment with Phy (100 or 500 ..mu..g/kg), however, the regional distribution of Phy was altered by soman as was ChE inhibition. A significant increase in Phy concentration was seen in HC (22 and 45% at 5 and 30 min,more » respectively) and CX (21% at 30 min). ChE activity in total brain was 12, 30, and 24% (5, 15 and 30 min after soman administration) lower than after Phy alone. If the pretreatment dose of Phy was increased to 500 ..mu..g/kg /sup 3/H-Phy, ChE activity was further reduced to 4, 13 and 19%. This might indicate that higher doses of Phy provide more protection of the enzyme from soman than lower doses. The protective role of Phy seen in total brain was not consistent for all brain regions. Soman alone produced a 95% ChE inhibition and there were no differences in its effect between total brain or brain areas. Pretreatment of the rat with Phy produced a protective effect upon ChE activity up to 30 min. However, no protective effect on survival was observed.« less

Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by Soman. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sparenborg, S.; Brennecke, L.H.; Jaax, N.K.

1992-12-31

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a post treatment (30, 100 or 300 micron g/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions andmore » electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Post treatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity....Seizure-related brain damage, Organophosphorus compound, Nerve agent, Cholinesterase inhibition, Excitotoxicity, Guinea pig.« less

A System Dynamics Approach to the Efficacy of Oxime Therapy in Sub Lethal Exposure to Sarin Gas

DTIC Science & Technology

2015-06-18

effective treatments , including antidotes, is considered to contribute to this high mortality rate (Buckley et al., 2004:1231). The efficacy of current...officials to reduce the risk associated with high -consequence threats”. Nerve agents, such as Sarin gas, are considered high consequence threats...The threat of use of agents such as Sarin is as much a threat today as any other time in our history. However, the suggested treatment protocol is

(-)-Phenserine Attenuates Soman-Induced Neuropathology

PubMed Central

Chen, Jun; Pan, Hongna; Chen, Cynthia; Wu, Wei; Iskandar, Kevin; He, Jeffrey; Piermartiri, Tetsade; Jacobowitz, David M.; Yu, Qian-Sheng; McDonough, John H.; Greig, Nigel H.; Marini, Ann M.

2014-01-01

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy. PMID:24955574

Effects of inhibitors of acetylcholine synthesis on brain acetylcholine and survival in soman-intoxicated animals.

PubMed

Harris, L W; Stitcher, D L; Hey, W C

1982-05-31

The effects of hemicholinium-3 (HC-3) or 4-(l-naphthylvinyl)pyridine (4-NVP) alone and together with cholinolytics and/or cholinesterase inhibitors on brain acetylcholine (ACh) levels and survival were studied. Intracerebroventricular (ICVT) injection of 10 micrograms HC-3 280 min before euthanasia by microwave irradiation reduced rat cerebral ACh levels from 28.4 to 5.4 nmoles ACh/g wet tissue. In rats pretreated with HC-3 alone or with other pretreatment drugs prior to giving up to 2.7 LD50 of soman, iv, cerebral ACh levels increased very little, but in animals not receiving HC-3, brain ACh levels increased to 67.1 nmoles. Treatment of unpoisoned rats with 4-NVP resulted in a significant (26%) reduction in ACh. The inclusion of atropine with 4-NVP caused sign-free doses of physostigmine to produce toxic signs in rabbits and did not enhance the efficacy of carbamate pretreatment against soman. Pretreatment of rabbits with pyridostigmine and atropine methyl nitrate (AMN) failed to provide any protection against soman, but when HC-3, ICVT, was included with those drugs, the protective ratio (PR), against soman was increased excess ACh is a primary lesion in organophosphorus anticholinesterase intoxication and that the central nervous system is quite sensitive to excesses of ACh.

How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

2015-01-01

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deshpande, S.S.; Smith, C.D.; Filbert, M.G.

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-12Omin at 0.1 %M concentration caused almost complete inhibition ( > 90%) of acetylcholinesterase butmore » failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson`s disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D- aspartate (NN4DA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival. however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deshpande, S.S.; Smith, C.D.; Filbert, M.G.

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 800/0 of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 ptN,concentration caused almost complete inhibition > 90% of acetylcholinesterase but failedmore » to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mNI). alone or in combination with soman. did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson`s disease, spasticity and other brain disorders. significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D- aspartate (NNIDA) excitotoxicity. In rats a single dose of memantine (18 mg kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival. however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.« less

Acetylcholinesterase inhibition and anti-Soman efficacy of homologs of physostigmine. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Anderson, D.R.; Pastelak, A.M.

1992-12-31

Inhibition of acetylcholinesterase (AChE) activity by physostigmine (PHY) is reversible due to spontaneous decarbamylation. Physostigmine has been shown to be effective as a pretreatment against potent anticholinesterase poisons (e.g., soman) in experimental animals, yet it is short acting and causes undesirable side effects in mammals. The two-fold purpose of this study was (1) to determine whether extension of the N-substituted alkyl chain (N-SAC) of PHY from N-methyl to N-ethyl (1), N-propyl (2), N-isopropyl (3), N-butyl (4) or N-heptyl (5) affects anti-AChE potency and spontaneous decarbamylation of inhibited AChE of guinea pig blood in vitro and in vivo and (2) tomore » see whether chain extension affects efficacy as pretreatment in poisoning by soman. The in vitro AChE inhibition studies were done using whole blood incubated at 37 deg C for 30 min. All 5 homologs possessed anti-AChE activity with I50s ranging from 1.1 to 27.6 x l0(-7)M; compound III was the least potent in vitro and in vivo. Lengthening of the N-SAC of PHY markedly extended the duration of anti-AChE activity when compared to PHY, but rendered the modified compounds ineffective as pretreatments against soman. These data support the premise that the decrease in decarbamylation rates observed upon extending the N-SAC of PHY is responsible for the loss of effectiveness of pretreatment regimens against soman. Perhaps, these homologs of PHY may have potential use in instances where sustained action of acetylcholine is required at cholinergic junctions because of disease conditions or drug overdosage.... Physostigmine, Nerve agent pretreatment, Soman, Acetylcholinesterase inhibition.« less

Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques.

PubMed

Hamilton, Lindsey R; Schachter, Steven C; Myers, Todd M

2017-07-01

Galantamine hydrobromide and (-)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID 50 ) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.

Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Testylier, Guy; Lahrech, Hana; Universite Joseph Fourier, Grenoble, F-38043

2007-04-15

Purpose: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. Methods: Three hours and 24 h after the intoxication with soman (172 {mu}g/kg), the mice were anesthetized with an isoflurane/N{sub 2}O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. Results: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication andmore » was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. Conclusions: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into Brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures.« less

Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

PubMed

Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

2010-12-01

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Published by Elsevier B.V.

Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates.

PubMed

Chambers, Janice E; Meek, Edward C; Chambers, Howard W

2016-06-01

Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood-brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood-brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain. © 2016 New York Academy of Sciences.

Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates

PubMed Central

Chambers, Janice E.; Meek, Edward C.; Chambers, Howard W.

2016-01-01

Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood–brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have invented novel substituted phenoxyalkyl pyridinium oximes (U.S. Patent 9,227,937 B2) that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, these novel oximes also showed an attenuation of seizure-like behavior compared to rats treated with 2-PAM, giving additional evidence of the ability of these oximes to penetrate the blood–brain barrier. Further, some of these oximes provided 24-hour survival superior to 2-PAM and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the concept of these life-saving oximes penetrating the brain. PMID:27153507

Anticonvulsant actions of anticholinergic drugs in soman poisoning. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Capacio, B.R.; Shih, T.M.

1991-12-31

The acute effects of the organophosphorus cholinesterase inhibitor soman include hypersecretions, convulsions, and death. The purpose of this study was to evaluate the anticholinergic compounds, aprophen, atropine sulfate, azaprophen, benactyzine, benztropine, biperiden, scopolamine HBr, and trihexyphenidyl for their efficacy in preventing soman-induced hypersecretions and convulsions. Male rats were injected with the oxime HI-6 (125 mg/kg, i.p.), to increase survival time, along with various intramuscular doses of the anticholinergics 30 min prior to a dose of soman that produced 100% convulsions. Signs of intoxication as well as the time-to-onset of convulsions were observed. The calculated anticonvulsant median effective dose values weremore » 0.18, 0.33, 0.36, 0.55, 2.17, 2.30, 2.45, and 31.09 micro mol per kilogram for scopolamine HBr, biperiden, trihexyphenidy, benactyzine, benztropine, azaprophen, aprophen, and atropine sulfate, respectively. The same rank order by potency for inhibition of hypersecretions among these compounds was observed.« less

Investigating the Hydrolysis Reactions of a Chemical Warfare Agent Surrogate. A Systematic Study using 1H, 13C, 17O, 19F, 31P, and 35Cl NMR Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alam, Todd M.; Wilson, Brendan W.

2015-07-24

During the summer of 2015, I participated in the DHS HS-STEM fellowship at Sandia National Laboratories (SNL, NM) under the supervision of Dr. Todd M. Alam in his Nuclear Magnetic Resonance (NMR) Spectroscopy research group. While with the group, my main project involved pursing various hydrolysis reactions with Diethyl Chlorophosphate (DECP), a surrogate for the agent Sarin (GB). Specifically, I performed different hydrolysis reactions, monitored and tracked the different phosphorous containing species using phosphorous ( 31P) NMR spectroscopy. With the data collected, I performed kinetics studies mapping the rates of DECP hydrolysis. I also used the NMR of different nucleimore » such as 1H, 13C, 17O, and 35Cl to help understand the complexity of the reactions that take place. Finally, my last task at SNL was to work with Insensitive Nuclei Enhanced by Polarization Transfer (INEPT) NMR Spectroscopy optimizing conditions for 19F- 31P filtering NMR experiments.« less

Evaluation of the efficacy of a portable LIBS system for detection of CWA on surfaces.

PubMed

L'Hermite, D; Vors, E; Vercouter, T; Moutiers, G

2016-05-01

Laser-induced breakdown spectroscopy (LIBS) is a laser-based optical technique particularly suited for in situ surface analysis. A portable LIBS instrument was tested to detect surface chemical contamination by chemical warfare agents (CWAs). Test of detection of surface contamination was carried out in a toxlab facility with four CWAs, sarin (GB), lewisite (L1), mustard gas (HD), and VX, which were deposited on different substrates, wood, concrete, military green paint, gloves, and ceramic. The CWAs were detected by means of the detection of atomic markers (As, P, F, Cl, and S). The LIBS instrument can give a direct response in terms of detection thanks to an integrated interface for non-expert users or so called end-users. We have evaluated the capability of automatic detection of the selected CWAs. The sensitivity of our portable LIBS instrument was confirmed for the detection of a CWA at surface concentrations above 15 μg/cm(2). The simultaneous detection of two markers may lead to a decrease of the number of false positive.

[The development of neurotoxic agents as chemical weapons during the National Socialist period in Germany].

PubMed

López-Muñoz, F; Alamo, C; Guerra, J A; García-García, P

The discovery and development of the so-called 'nerve agents' (neurotoxic substances to be used as weapons) took place in the Third Reich, largely thanks to the vast amount of progress being made in pharmacology in Germany at that time, both in academic and industrial terms. Furthermore, successive National Socialist governments set up a collaborative network made up of the academia, the chemical industry and military chiefs that also favoured this line of research. The first neurotoxic substance to be incorporated into the category of 'chemical warfare agent' did so almost wholly by chance. As part of the work being carried out on organophosphate-type pesticides and insecticides, Gerald Schrader, a chemist at the I.G. Farben company, synthesised tabun (ethyl N,N-dimethylphosphoramidocyanidate) and an incident involving accidental contamination of laboratory staff with this substance highlighted its potential toxicity. The same group of researchers later synthesised another substance with the same properties, sarin (isopropyl methylphosphonofluoridate). Both agents were studied for use as chemical weapons by Wolfgang Wirth. At the same time, a group led by Richard Kuhn, who won the Nobel Prize in Chemistry in 1938, synthesised pinacolyl methylphosphonofluoridate, otherwise known as soman. Pharmacological studies confirmed that the neurotoxic mechanism of action of these substances was the irreversible inhibition of the enzyme acetylcholinesterase, which is responsible for metabolising acetylcholine. Results also showed that an excess of this neurotransmitter led to a continuous over-stimulation of the cholinergic (nicotinic and muscarinic) receptors, which is what triggers the appearance of the wide range of symptoms of poisoning and their swift fatal effect.

Synthesis and in vitro reactivation study of isonicotinamide derivatives of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide as reactivators of Sarin and VX inhibited human acetylcholinesterase (hAChE).

PubMed

Karade, Hitendra N; Raviraju, G; Acharya, B N; Valiveti, Aditya Kapil; Bhalerao, Uma; Acharya, Jyotiranjan

2016-09-15

Previously (Karade et al., 2014), we have reported the synthesis and in vitro evaluation of bis-pyridinium derivatives of pyridine-3-yl-(2-hydroxyimino acetamide), as reactivators of sarin and VX inhibited hAChE. Few of the molecules showed superior in vivo protection efficacy (mice model) (Kumar et al., 2014; Swami et al., 2016) in comparison to 2-PAM against DFP and sarin poisoning. Encouraged by these results, herein we report the synthesis and in vitro evaluation of isonicotinamide derivatives of pyridine-3-yl-(2-hydroxyimino acetamide) (4a-4d) against sarin and VX inhibited erythrocyte ghost hAChE. Reactivation kinetics of these compounds was studied and the determined kinetic parameters were compared with that of commercial reactivators viz. 2-PAM and obidoxime. In comparison to 2-PAM and obidoxime, oxime 4a and 4b exhibited enhanced reactivation efficacy toward sarin inhibited hAChE while oxime 4c showed far greater reactivation efficacy toward VX inhibited hAChE. The acid dissociation constant and IC50 values of these oximes were determined and correlated with the observed reactivation potential. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sarin Exposures in A Cohort of British Military Participants in Human Experimental Research at Porton Down 1945-1987.

PubMed

Keegan, Thomas J; Carpenter, Lucy M; Brooks, Claire; Langdon, Toby; Venables, Katherine M

2017-12-15

The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30000 participants drawn from the UK armed services has been undertaken. Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Six principal nerve agents were tested on humans between 1945 and 1987. Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans. © The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Probing the reactivation process of sarin-inhibited acetylcholinesterase with α-nucleophiles: hydroxylamine anion is predicted to be a better antidote with DFT calculations.

PubMed

Khan, Md Abdul Shafeeuulla; Lo, Rabindranath; Bandyopadhyay, Tusar; Ganguly, Bishwajit

2011-08-01

Inactivation of acetylcholinesterase (AChE) due to inhibition by organophosphorus (OP) compounds is a major threat to human since AChE is a key enzyme in neurotransmission process. Oximes are used as potential reactivators of OP-inhibited AChE due to their α-effect nucleophilic reactivity. In search of more effective reactivating agents, model studies have shown that α-effect is not so important for dephosphylation reactions. We report the importance of α-effect of nucleophilic reactivity towards the reactivation of OP-inhibited AChE with hydroxylamine anion. We have demonstrated with DFT [B3LYP/6-311G(d,p)] calculations that the reactivation process of sarin-serine adduct 2 with hydroxylamine anion is more efficient than the other nucleophiles reported. The superiority of hydroxylamine anion to reactivate the sarin-inhibited AChE with sarin-serine adducts 3 and 4 compared to formoximate anion was observed in the presence and absence of hydrogen bonding interactions of Gly121 and Gly122. The calculated results show that the rates of reactivation process of adduct 4 with hydroxylamine anion are 261 and 223 times faster than the formoximate anion in the absence and presence of such hydrogen bonding interactions. The DFT calculated results shed light on the importance of the adjacent carbonyl group of Glu202 for the reactivation of sarin-serine adduct, in particular with formoximate anion. The reverse reactivation reaction between hydroxylamine anion and sarin-serine adduct was found to be higher in energy compared to the other nucleophiles, which suggests that this α-nucleophile can be a good antidote agent for the reactivation process. Copyright © 2011 Elsevier Inc. All rights reserved.

Unexpected nerve gas exposure in the city of Matsumoto: report of rescue activity in the first sarin gas terrorism.

PubMed

Okudera, H; Morita, H; Iwashita, T; Shibata, T; Otagiri, T; Kobayashi, S; Yanagisawa, N

1997-09-01

This report describes the rescue activities and the exposure of rescue and hospital personnel from the first unexpected nerve gas terrorist attack using sarin (isopropyl methylphophonofluoridate) in the city of Matsumoto at midnight on June 27, 1994. The details of the emergency activities in the disaster were studied based on the records from emergency departments of the affiliated hospitals and records from the firehouse. About 600 people, including residents and rescue staff, were exposed to sarin gas. Fifty-eight residents were admitted to hospitals, and 7 died. Among 95 rescuers and the duty doctor from the doctor car, 8 had mild symptoms of poisoning. All the rescue activity took place without gas masks or decontamination procedures. In this case of unexpected mass exposure to sarin gas, the emergency rescue system for a large disaster in Matsumoto city, which had been established for a conflagration or a local earthquake, was effective.

A Model of Medical Countermeasures for Organophosphates

DTIC Science & Technology

2015-10-01

Animal Data ................................................................. 51 6.2.1. Verifying AChE Activity ...17 Figure 4-3. Model Output for AChE Activity and Free/Stimulated Receptor Fraction with No OP Exposure...Figure 6-1. Sarin Model Output Compared to Individual AChE Activity in Acute Phase Following Tokyo Sarin Attack

Kinetics of degradation of sulfur mustard and sarin simulants on HKUST-1 metal organic framework.

PubMed

Roy, Anuradha; Srivastava, Avanish K; Singh, Beer; Shah, Dilip; Mahato, Timir Haran; Srivastava, Anchal

2012-10-28

The applicability of HKUST-1 for the degradation of sulfur mustard and sarin simulants was studied with and without coadsorbed water. Degradation was found to be via hydrolysis and dependent on the nucleophilic substitution reaction, vapour pressure and molecular diameter of the toxicants.

Effect of anticholinesterase agents on airway epithelial function. Annual report, 15 July 1888-14 August 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marin, M.G.

1989-09-15

Irreversible anticholinesterase compounds have potential serious health effects when employed as chemical warfare agents. Intoxication with these agents will cause an accumulation of acetylcholine at nerve muscle and nerve-gland junctions. Because tracheal glands have rich cholinergic innervation, we hypothesized that exposure to anticholinesterase agents, such as soman, would stimulate glandular secretion. This would cause pathological changes in the important lung defense mechanism of mucociliary clearance. Initial work on this contract revealed a dose-related increase in mucociliary transport in the ferret in response to soman. This effect could be inhibited by atropine but not by pralidoxime. The investigation described in thismore » report relates to the effects of soman and its antidotes on glycoconjugate secretion of ferret trachea in vitro.« less

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wymore, Troy W; Langan, Paul; Smith, Jeremy C

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ( bioscavengers ) is an emerging prophylactic approach to diminishing their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical (QM/MM) umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalentmore » intermediate. P F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily due to the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed -propeller folds for more efficient degradation of OP compounds.« less

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds along Two Different Reaction Pathways: Implications for Engineering Bioscavengers

PubMed Central

2015-01-01

Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (“bioscavengers”) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P–F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds. PMID:24720808

Therapeutic efficacy of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) against organophosphate intoxication.

PubMed

Bueters, Tjerk J H; Groen, Bas; Danhof, Meindert; IJzerman, Ad P; Van Helden, Herman P M

2002-11-01

The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun ( O-ethyl- N-dimethylphosphoramidocyanidate), sarin (isopropylmethylphosphonofluoridate), VX ( O-ethyl- S-2-diisopropylaminoethylmethylphosphonothiolate) and parathion ( O, O-diethyl- O-(4-nitrophenyl)phosphorothioate). The efficacy of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) against an OP intoxication was examined on the basis of the occurrence of clinical symptoms that are directly associated with such intoxication. CPA (1-2 mg/kg) effectively attenuated the cholinergic symptoms and prevented mortality in lethally tabun- or sarin-intoxicated rats. In contrast, CPA (2 mg/kg) proved to be ineffective against VX or parathion intoxication. Intracerebral microdialysis studies revealed that survival of sarin-poisoned and CPA-treated animals coincided with a minor elevation of extracellular ACh concentrations in the brain relative to the baseline value, whereas an 11-fold increase in transmitter levels was observed in animals not treated with CPA. In VX-intoxicated rats, however, the ACh amounts increased 18-fold, irrespective of treatment with CPA. The striatal acetylcholinesterase (AChE) activity following a lethal sarin intoxication was completely abolished in the vehicle-treated animals, whereas 10% and 60% AChE activity remained in animals treated with 2 mg/kg CPA 1 min after or 2 min prior to the poisoning, respectively. In VX-intoxicated animals the AChE activity in the brain was strongly reduced (striatum 10%, hippocampus 1%) regardless of the CPA treatment. These results demonstrate that CPA is highly effective against tabun or sarin poisoning, but fails to protect against VX or parathion. Survival and attenuation of clinical signs in tabun- or sarin-poisoned animals are associated with a reduction of ACh accumulation and with protection of AChE activity in the brain.

Blaptica dubia as sentinels for exposure to chemical warfare agents - a pilot study.

PubMed

Worek, Franz; Seeger, Thomas; Neumaier, Katharina; Wille, Timo; Thiermann, Horst

2016-11-16

The increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents a continuing threat to our societies. Early warning and detection is a key component for effective countermeasures against such deadly agents. Presently available and near term solutions have a number of major drawbacks, e.g. lack of automated, remote warning and detection of primarily low volatile chemical warfare agents. An alternative approach is the use of animals as sentinels for exposure to toxic chemicals. To overcome disadvantages of vertebrates the present pilot study was initiated to investigate the suitability of South American cockroaches (Blaptica dubia) as warning system for exposure to chemical warfare nerve and blister agents. Initial in vitro experiments with nerve agents showed an increasing inhibitory potency in the order tabun - cyclosarin - sarin - soman - VX of cockroach cholinesterase. Exposure of cockroaches to chemical warfare agents resulted in clearly visible and reproducible reactions, the onset being dependent on the agent and dose. With nerve agents the onset was related to the volatility of the agents. The blister agent lewisite induced signs largely comparable to those of nerve agents while sulfur mustard exposed animals exhibited a different sequence of events. In conclusion, this first pilot study indicates that Blaptica dubia could serve as a warning system to exposure of chemical warfare agents. A cockroach-based system will not detect or identify a particular chemical warfare agent but could trigger further actions, e.g. specific detection and increased protective status. By designing appropriate boxes with (IR) motion sensors and remote control (IR) camera automated off-site warning systems could be realized. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In vitro and in vivo genotoxicity assessment of HI-6 dimethanesulfonate/oxime.

PubMed

Nakab, Lauren; Bardot, Isabelle; Bardot, Sébastien; Simar, Sophie; Marzin, Daniel; Nesslany, Fabrice

2014-03-01

Organophosphate compounds, which induce organophosphate poisoning, were originally used as pesticides. But this type of product has also been used as warfare nerve agent like sarin, soman, Russian VX, or tabun. HI-6-dimethanesulfonate is a salt of the oxime HI-6 used in the treatment of nerve-agent poisoning. It is known to be the best re-activator component of inactivated acetyl cholinesterase. HI-6-dimethanesulfonate has shown a higher level of solubility with similar potency to reactivate acetyl cholinesterase and a similar pharmacokinetics profile compared with HI-6 dichloride. HI-6 dimethanesulfonate was tested for its mutagenic and genotoxic potential by use of the standard ICH S2R (1) battery for the evaluation of pharmaceuticals. HI-6-dimethanesulfonate was mutagenic in the Ames test only in the presence of metabolic activation. In the mutation assay at the Tk locus in L5178Y mouse-lymphoma cells, HI-6-dimethanesulfonate showed mutagenic activity both with and without metabolic activation, with a significant increase in small colonies. The effects were in favour of a clastogenic activity. It was concluded that the compound was mutagenic and possibly clastogenic in vitro. In contrast, the in vivo micronucleus test in rat bone-marrow did not demonstrate any genotoxic activity and the Comet assay performed in rat liver did not show any statistically or biologically significant increases in DNA strand-breaks. The results of both in vivo studies performed on two different organs with two endpoints are sufficient to conclude the absence of a genotoxic hazard in vivo and to consider that there is no genotoxic concern in humans for HI-6-dimethanesulfonate. Copyright © 2014 Elsevier B.V. All rights reserved.

Reactive chromophores for sensitive and selective detection of chemical warfare agents and toxic industrial chemicals

NASA Astrophysics Data System (ADS)

Frye-Mason, Greg; Leuschen, Martin; Wald, Lara; Paul, Kateri; Hancock, Lawrence F.

2005-05-01

A reactive chromophore developed at MIT exhibits sensitive and selective detection of surrogates for G-class nerve agents. This reporter acts by reacting with the agent to form an intermediate that goes through an internal cyclization reaction. The reaction locks the molecule into a form that provides a strong fluorescent signal. Using a fluorescent sensor platform, Nomadics has demonstrated rapid and sensitive detection of reactive simulants such as diethyl chloro-phosphate (simulant for sarin, soman, and related agents) and diethyl cyanophosphate (simulant for tabun). Since the unreacted chromophore does not fluoresce at the excitation wavelength used for the cyclized reporter, the onset of fluo-rescence can be easily detected. This fluorescence-based detection method provides very high sensitivity and could enable rapid detection at permissible exposure levels. Tests with potential interferents show that the reporter is very selective, with responses from only a few highly toxic, electrophilic chemicals such as phosgene, thionyl chloride, and strong acids such as HF, HCl, and nitric acid. Dimethyl methyl phosphonate (DMMP), a common and inactive simu-lant for other CW detectors, is not reactive enough to generate a signal. The unique selectivity to chemical reactivity means that a highly toxic and hazardous chemical is present when the reporter responds and illustrates that this sensor can provide very low false alarm rates. Current efforts focus on demonstrating the sensitivity and range of agents and toxic industrial chemicals detected with this reporter as well as developing additional fluorescent reporters for a range of chemical reactivity classes. The goal is to produce a hand-held sensor that can sensitively detect a broad range of chemical warfare agent and toxic industrial chemical threats.

Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation

DTIC Science & Technology

2005-05-01

nerve agents , soman is the great- terrorist acts. At the same time, OP pesticides , such as est challenge since both the rapid aging of the soman- paraoxon...also from enzyme very slowly (requiring hours, days, or weeks used as nerve warfare agents . Similar to pesticides , nerve for complete dissociation...TERMS acetylcholinesterase, nerve agent antidotes and propylaxis, organophosphate scavenging , oxime reactivation fluorescence spectroscopy, exposure

Alpha-Linolenic Acid Confers Neuroprotection and Improves Behavioral Deficits After Soman Exposure: Involvement of Neurogenesis Through an mTOR-Mediated Pathway

DTIC Science & Technology

2015-01-15

chemical warfare agent that irreversibly inhibits acetylcholinesterase in the periphery and central nervous system. Soman induces status epilepticus ...of signs and symptoms including status epilepticus and death. The neuropathology leads to severe cognitive performance, including long-term cognitive... status epilepticus and excessive synaptic accumulation of acetylcholine affects other organ systems beside the brain causing hypersecretions

Vapor Inhalation Exposure to Soman in Conscious Untreated Rats: Preliminary Assessment of Neurotoxicity

DTIC Science & Technology

2015-12-22

study, which did not survive until the 24 h post-exposure endpoint, experienced severe signs of cholin- ergic intoxication , resulting in mortality...following vapor inhalation exposure, to aid in the development of potential treatment strategies. Gross clinical signs of soman intoxication were...consistent with typical cholinergic-induced intoxication . The observed CWNA-induced cholinergic crises and clinical signs of toxicity such as straub tail

DOE Office of Scientific and Technical Information (OSTI.GOV)

Štengl, Václav, E-mail: stengl@iic.cas.cz; J.E. Purkyně University in Ústí nad Labem, Faculty of Environment, 400 96 Ústí nad Labem; Grygar, Tomáš Matys

Graphical abstract: Display Omitted Highlights: ► New nanodispersive materials based on Fe and Mn oxides for degradations of warfare agents. ► The best activities for the degradation of sulphur mustard (97.9% in 64 min) and soman (97.9% in 64 min). ► One pot synthesis with friendly transformed to industrial conditions. -- Abstract: Substituted iron(III)–manganese(III, IV) oxides, ammonio-jarosite and birnessite, were prepared by a homogeneous hydrolysis of potassium permanganate and iron(III) sulphate with 2-chloroacetamide and urea, respectively. Synthesised oxides were characterised using Brunauer–Emmett–Teller (BET) surface area and Barrett–Joiner–Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), Raman spectroscopy and scanning electronmore » microscopy (SEM). The oxides were taken for an experimental evaluation of their reactivity against sulphur mustard (HD) and soman (GD). When ammonio-jarosite formation is suppressed by adding urea to the reaction mixture, the reaction products are mixtures of goethite, schwertmannite and ferrihydrite, and their degradation activity against soman considerably increases. The best activities for the degradation of sulphur mustard (97.9% in 64 min) and soman (97.9% in 64 min) were observed for FeMn{sub 7}5 with 32.6 wt.% Fe (36.8 wt.% Mn) and FeMn{sub 3}7U with 60.8 wt.% Fe (10.1 wt.% Mn) samples, respectively.« less

Protection against both lethal and behavioral effects of soman.

PubMed

Harris, L W; McDonough, J H; Stitcher, D L; Lennox, W J

1984-01-01

This work developed two drug mixtures which alone had no effect on performance of a criterion behavior but when given as a pretreatment would protect against organophosphate-induced lethality and incapacitation. Candidate drugs (alone and together) were given to rats trained to respond on a two-component Fixed Ratio 10 - Extinction (FR10-EXT) schedule. After generating dose response curves for each cholinolytic drug, mixtures of atropine (A) + mecamylamine (M) + pyridostigmine (Py) or physostigmine (Ph) were prepared and a combination of doses that produced no effects on operant performance was determined (Mix I:A = .78, M = .78, Py = .056 mg/kg; Mix II:A = .78, M = .78, Ph = .026 mg/kg). Both pretreatment mixtures provided equivalent protection against the lethal effects of the organophosphate soman; however only Mix II was capable of reversing soman-induced physical incapacitation (PI) as assessed by performance on an accelerating rotarod or FR10 responding. Pretreatment of animals with Mix II resulted in significantly higher levels of brain acetylcholinesterase (AChE) than Mix I pretreated subjects 4 hrs after 1.3 LD50 soman, although peripheral AChE levels were not different. The results indicate organophosphate-induced PI can be attenuated by pretreatment with tertiary carbamates which protect significant amounts of brain AChE from irreversible inhibition.

Determination of Parameters for Development of a Physiologically Based Model for the Toxicokinetics of C(+)P(+)-Soman

DTIC Science & Technology

1993-06-01

In conducting research utilizing recombinant DNA technology , the investigator(s) adhered to current guidelines promulgated by the National...zur Rtickstandanalyse), saponin (BDH, Poole, UK), aluminium sulfate.16 H2 0 (BDH Analar, Ž 98%), sodium bicarbonate (Lamens en Indemans, ’s...isopropanol). The mixture was extracted with 3 ml ethyl acetate. Gas chromatographic analysis of the soman stereoisomers in the ethyl acetate phase was

Neuronal Death Following Soman Intoxication: Necrosis or Apoptosis?

DTIC Science & Technology

2006-05-01

post-treated with atropine methyl nitrate (AMN) (2.0 mg/kg, IM). HI-6 and AMN were used to decrease the mortality of soman-exposed animals (Shih et...and lithium- pilocarpine (Voutsinos-Porche et al., 2004; Kubova et al., 2002). Our results showed a strong association between the duration of...Fluoro-Jade labelling in the rat hippocampus following pilocarpine -induced status epilepticus. Neuroscience. 97:59-68. Posmantur RM, Kampfl A, Taft WC

Neuropharmacological Specificity of Brain Structures Involved in Soman-Induced Seizures

DTIC Science & Technology

2012-01-01

Bernabé Burckhart M-F, Lallement G. Efficacy of the ketamine-atropine combination in the delayed treatment of soman- induced status epilepticus ...The functional anatomy of limbic status epilepticus in the rat. I. Patterns of 14C-2-deoxyglucose uptake and fos immunochemistry. Journal of...Neuroscience 1993a;13(11):4787–801. White LE, Price JL. The functional anatomy of limbic status epilepticus in the rat. II. The effects of focal deactivation

Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman-Induced Seizures

DTIC Science & Technology

2008-01-01

23, 2008) Abstract: This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when...seizure activity that was detected in the electroencephalographic record. When given immediately after seizure onset, the anticonvulsant ED 50 of...that time. At the 40-min. treatment delay, the anticonvulsant ED 50 s of intramuscular or intranasal midazolam did not differ and both were

Effects of subacute pretreatment with carbamate together with acute adjunct pretreatment against nerve agent exposure. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, D.R.; Harris, L.W.; Lennox, W.J.

1991-12-31

Acute carbamate pretreatment, in conjunction with atropine pretreatment or followed by atropine and oxime therapy has been shown to protect rabbits, rats, guinea pigs and monkeys against multiple lethal doses of soman. In those experiments, pretreated animals were usually challenged with soman at the time of peak whole blood acetylcholinesterase (AChE) inhibition by the carbamate or when the concentration of carbamate in the blood was expected to be rapidly diminishing. However, soldiers in a chemical environment, having taken carbamate orally might well be exposed to nerve agent shortly thereafter. Thus, both active carbamate and nerve agent would be entering themore » blood simultaneously. In a recent study it was reported that subacute administration of physostigmine (Phy), via subcutaneously implanted 28 day osmotic minipump, afforded protection against an iv challenge of soman on the 27th day.« less

Development of pretreatment compounds against nerve-gas agents. Annual report (Final), 16 May 88-30 Sep 90

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carroll, F.I.; Abraham, P.

1990-09-30

The U. S. Army Medical Research and Development Command is interested in research directed toward the development of countermeasures to chemical warfare (CW) agents such as the nerve gas poison soman. Soman and other nerve gas poisons are extremely potent cholinesterase inhibitors. This inhibition leads to a buildup of excess acetylcholine resulting in over-stimulation of both the peripheral and central nervous system and can lead to death. Standard therapy for organophosphate nerve agent poisoning is based on co-administration of an anticholinergic agent such as atropine to antagonize the effects of accumulated acetylcholine and a cholinesterase reactivator such as 2-PAM tomore » dephosphorylate the inhibited enzyme. However, since many problems remain in the treatment of organophosphate nerve agent poisoning, there is considerable interest and need to develop new pretreatment and treatment drugs, particularly for soman poisoning.« less

Cholinesterase inhibitor soman increases inositol trisphosphate in rat brain. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mobley, P.L.

1990-12-31

Studies were conducted to determine the effect of the cholinesterase inhibitor soman on the amount of inositol trisphosphate in the neocortex, striatum, cerebellum, and medulla-pons regions of rat brain in vivo. The studies indicate that treatment with soman increase inositol trisphosphate in the neocortex and striatum, but not in the cerebellum or medulla-pons region. In the neocortex the most pronounced increases were observed in animals with severe poisoning symptoms; however, inositol trisphophate was also found to be elevated in animals with only mild poisoning symptoms. A variety of evidence suggests that the receptor-mediated hydrolysis of phosphatidyl inositol results in themore » formation of inositol trisphosphate (IP3) and diacylglycerol, both of which function as intracellular signal messengers, and that this mechanism represents a major signal transduction system through which extracellular signals can influence intracellular events.« less

Mechanisms of Organophosphorus (OP) Injury: Sarin-Induced Hippocampal Gene Expression Changes and Pathway Perturbation

DTIC Science & Technology

2012-01-01

components of the endomembrane system, including endoplasmic reticulum (ER) and Golgi apparatus were significantly down-regulated. As a result of...impairment in dopaminergic functions (Lucot JB, personal communication). Interestingly, data on sarin exposures have shown inhibition of new memory...quite unexpected that the endoplasmic reticulum (ER) and Golgi apparatus , the subcellular organelles essential for processing (e.g., folding, post

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Steven L., E-mail: stevenmiller17@gmail.com; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; Aroniadou-Anderjaska, Vassiliki, E-mail: vanderjaska@usuhs.edu

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS)more » at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after soman, blocked seizures. • With ATS at 0.5 mg/kg, LY293558 or UBP302 at 1 h after exposure terminated seizures. • LY293558 prevented brain pathology and behavioral deficits.« less

Younger rats are more susceptible to the lethal effects of sarin than adult rats: 24 h LC50 for whole-body (10 and 60 min) exposures.

PubMed

Wright, Linnzi K M; Lumley, Lucille A; Lee, Robyn B; Taylor, James T; Miller, Dennis B; Muse, William T; Emm, Edward J; Whalley, Christopher E

2017-04-01

Chemical warfare nerve agents (CWNA) inhibit acetylcholinesterase and are among the most lethal chemicals known to man. Children are predicted to be vulnerable to CWNA exposure because of their smaller body masses, higher ventilation rates and immature central nervous systems. While a handful of studies on the effects of CWNA in younger animals have been published, exposure routes relevant to battlefield or terrorist situations (i.e. inhalation for sarin) were not used. Thus, we estimated the 24 h LC 50 for whole-body (10 and 60 min) exposure to sarin using a stagewise, adaptive dose design. Specifically, male and female Sprague-Dawley rats were exposed to a range of sarin concentrations (6.2-44.0 or 1.6-12.5 mg/m³) for either 10 or 60 min, respectively, at six different times during their development (postnatal day [PND] 7, 14, 21, 28, 42 and 70). For male and female rats, the lowest LC 50 values were observed for PND 14 and the highest LC 50 values for PND 28. Sex differences were observed only for PND 42 for the 10 min exposures and PND 21 and 70 for the 60 min exposures. Thus, younger rats (PND 14) were more susceptible than older rats (PND 70) to the lethal effects of whole-body exposure to sarin, while adolescent (PND 28) rats were the least susceptible and sex differences were minimal. These results underscore the importance of controlling for the age of the animal in research on the toxic effects associated with CWNA exposure.

Nerve Agent Induced Status Epilepticus: From Seizure Onset to Long Lasting Pathology

DTIC Science & Technology

2014-01-31

of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev 25:297-323 168. Martin LF, Kem WR, Freedman R. 2004. Alpha-7...Pharmacol 82:931-42 220. Paxinos G, Watson C. 2005. The Rat Brain in Stereotaxic Coordinates. New York NY: Elsevier 221. Petras JM. 1981. Soman...neurotoxicity. Fundam Appl Toxicol 1 :242 222. Petras JM. 1994. Neurology and neuropathology of Soman-induced brain injury: an overview. J Exp Anal

The Anticholinergic and Antiglutamatergic Drug Caramiphen Reduces Seizure Duration in Soman-Exposed Rats: Synergism with the Benzodiazepine Diazepam

DTIC Science & Technology

2012-01-01

progress to self-sustained seizures ( status epilepticus , SE) and result in extensive neuropathology as seen in rats (de Araujo Furtado et al., 2009, 2010...physostigmineOP organophosphorus BuChE butyrylcholinesterase ChE cholinesterase SE status epilepticus ATR atropine sulfate 2-PAM 2-pralidoxime NMDA N...L.C., Lichtenstein, S., Yourick, D.L., 2010. Spontaneous recurrent seizures after status epilepticus induced by soman in Sprague-Dawley rats

Topographical distribution of decrements and recovery in muscarinic receptors from rat brains repeatedly exposed to sublethal doses of soman

DOE Office of Scientific and Technical Information (OSTI.GOV)

Churchill, L.; Pazdernik, T.L.; Jackson, J.L.

1984-08-01

(3H)Quinuclidinyl benzilate binding to rat brain muscarinic receptors decreased after repeated exposure to soman, a potent organophosphorus cholinesterase inhibitor. The topographical distribution of this decrement was analyzed by quantitative receptor autoradiography. After 4 weeks of soman, three times a week, quinuclidinyl benzilate binding decreased to 67 to 80% of control in frontal and parietal cortex, caudate-putamen, lateral septum, hippocampal body, dentate gyrus, superior colliculus, nucleus of the fifth nerve, and central grey. Minor or no decreases were observed in thalamic or hypothalamic nuclei, reticular formation, pontine nuclei, inferior colliculus, nucleus of the seventh nerve, and cerebellum. Scatchard analyses of saturationmore » curves using frontal cortex sections from soman-treated rats revealed a decrease in maximal quinuclidinyl benzilate binding from that in control rats and a return toward control levels by 24 days without any significant change in affinity. These brain areas showing significant decrements in muscarinic receptors recovered with a similar time course. An estimate of the time for 50% recovery for some of the brain areas was 14 days for superior colliculus, 16 days for cortex, and 19 days for hippocampal body. The application of quantitative receptor autoradiography to analyze receptor alterations has been valuable in localizing the telencephalon as a region more susceptible to change in receptor concentration.« less

[Comparison of the effects of BI-6, a new asymmetric bipyridine oxime, with HI-6 oxime and obidoxime in combination with atropine on soman and fosdrine toxicity in mice].

PubMed

Kassa, J

1999-01-01

The therapeutic efficacy of the new asymmetric bispyridinium oxime BI-6 against acute toxicity of the highly toxic organophosphate soman and the organophosphorus insecticide fosdrin by means of affecting the LD50 values of these noxiores substances was compared with the effect of the hitherto most perspective oxime HI-6 and the classic obidoxime always in combination with the identical dose of atropine. At the equimolar level the effect of oxime BI-6 against fosdrin completely equals the effects of both oximes HI-6 and obidoxime. The effect of oxime BI-6 against soman is even more marked than the effect of HI-6 but this difference is not statistically significant. On the other hand, at the equi-effective level, the effect of oxime BI-6 against soman is statistically significantly lower than the effect of HI-6, and against fosdrin it is even lower than the effect of both remaining oximes. The effects of the new oxime BI-6 equal, or slightly exceed the therapeutic effect of HI-6 but at the equimolar level only. At the equi-effective level which respects the toxicity of the oxime and is therefore more important for practical use, it is a therapeutically weaker reactivator of acetylcholinesterase than HI-6.

Generation and evaluation of Cryosat-2 SARIn L1b Interferometric elevation

NASA Astrophysics Data System (ADS)

DONG, Y.; Zhang, K.; Liu, Q.; MA, J.; WANG, J.

2016-12-01

CryoSat-2 radar altimeter data have successfully used in mapping surface elevations of ice caps and ice sheets, finding the change of surface height in polar area. The SARIn mode of Synthetic Aperture Interferometric Altimeter (SIRAL), which working similar with the traditional Interferometric Synthetic Aperture Radar (IFSAR) method, can improve the across- and along-track resolution by IFSAR processing algorithm. In this study, three L1b Baseline-C SARIn tracks over the Filchner ice shelf are used to generate the location and height of ground points in sloping glacial terrain. The elevation data is mapped and validated with IceBridge Airborne Topographic Mapper (ATM) data acquired at Nov. 2, 2012. The comparison with ATM data shows a mean difference of -1.91 m with a stand deviation of 4.04 m.

Circadian Rhythms of Heart Rate and Locomotion After Treatment With Low-Dose Acetylcholinesterase Inhibitors

DTIC Science & Technology

2006-01-01

with pyridostigmine bromide (PB), a carbamate AChE by air conditioned vans and air-freight to the Laboratory inhibitor that does not cross the blood ...15. SUBJECT TERMS Nerve agents, sarin, pyridostigmine bromide, cerebral glucose utilization, cerebrovascular circulation, low dose cholinesterase ...March 2006" Accepted 12 May 2006 ABSTRACT: This study tested the hypothesis that repeated exposure to low levels of sarin, pyridostigmine bromide (PB

Computational Simulation of Vibrational Overtone Spectral Regions: Sarin

DTIC Science & Technology

2006-12-01

level have been used to determine the vapour phase local mode parameters, [ and Dx, for each oscillator in the two spectrally significant conformers...approach to spectral simulation reported herein should be undertaken by acquiring the experimental spectral regions of several CWAs in the vapour and liquid...33 viii DRDC Suffield TR 2006-220 List of figures Figure 1: The vapour phase structures of the three lowest energy conformers of sarin, calculated

Natural Detoxification Capacity to Inactivate Nerve Agents Sarin and VX in the Rat Blood.

PubMed

Bajgar, Jiří; Cabal, Jiří; Kassa, Jiří; Pavlík, Michal

2015-01-01

The method of continual determination of the rat blood cholinesterase activity was developed to study the changes of the blood cholinesterases following different intervetions. The aim of this study is registration of cholinesterase activity in the rat blood and its changes to demonstrate detoxification capacity of rats to inactivate sarin or VX in vivo. The groups of female rats were premedicated (ketamine and xylazine) and cannulated to a. femoralis. Continual blood sampling (0.02 ml/min) and monitoring of the circulating blood cholinesterase activity were performed. Normal activity was monitored 1-2 min and then the nerve agent was administered i.m. (2×LD50). Using different time intervals of the leg compression and relaxation following the agent injection, cholinesterase activity was monitored and according to the inhibition obtained, detoxification capacity was assessed. Administration of sarin to the leg, then 1 and 5 min compression and 20 min later relaxation showed that further inhibition in the blood was not observed. On the other hand, VX was able to inhibit blood cholinesterases after this intervention. The results demonstrated that sarin can be naturally detoxified on the contrary to VX. Described method can be used as model for other studies dealing with changes of cholinesterases in the blood following different factors.

Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhote, Franck, E-mail: franck.dhote@irba.fr; Carpentier, Pierre; Barbier, Laure

2012-03-01

Epileptic seizures and status epilepticus (SE) induced by the poisoning with organophosphorus nerve agents (OP), like soman, are accompanied by neuroinflammation whose role in seizure-related brain damage (SRBD) is not clear. Antagonists of the NMDA glutamate ionotropic receptors are currently among the few compounds able to arrest seizures and provide neuroprotection even during refractory status epilepticus (RSE). Racemic ketamine (KET), in combination with atropine sulfate (AS), was previously shown to counteract seizures and SRBD in soman-poisoned guinea-pigs. In a mouse model of severe soman-induced SE, we assessed the potentials of KET/AS combinations as a treatment for SE/RSE-induced SRBD and neuroinflammation.more » When starting 30 min after soman challenge, a protocol involving six injections of a sub-anesthetic dose of KET (25 mg/kg) was evaluated on body weight loss, brain damage, and neuroinflammation whereas during RSE, anesthetic protocols were considered (KET 100 mg/kg). After confirming that during RSE, KET injection was to be repeated despite some iatrogenic deaths, we used these proof-of-concept protocols to study the changes in mRNA and related protein contents of some inflammatory cytokines, chemokines and adhesion molecules in cortex and hippocampus 48 h post-challenge. In both cases, the KET/AS combinations showed important neuroprotective effects, suppressed neutrophil granulocyte infiltration and partially suppressed glial activation. KET/AS could also reduce the increase in mRNA and related pro-inflammatory proteins provoked by the poisoning. In conclusion, the present study confirms that KET/AS treatment has a strong potential for SE/RSE management following OP poisoning. The mechanisms involved in the reduction of central neuroinflammation remain to be studied. -- Highlights: ► During soman-induced status epilepticus, ketamine-atropine limit brain damage. ► Molecular neuroinflammatory response is strongly decreased. ► Glial activation is not fully suppressed.« less

Diet Restriction and Fasting Exacerbate the Toxicity of Soman in Young and Old Guinea Pigs

DTIC Science & Technology

2012-09-01

1987;39:35-42. McDonough JH, Benjamin A, McMonagle JD, Rowland T, Shih TM. Effects of fosphenytoin on nerve agent-induced status epilepticus . Drug Chem...animals showed greater toxicity to soman than old animals. The notable exception was old DR-F animals. Guinea pigs of similar age and dietary status are...toxicity with overt toxicity. Alternatively, verifying the LD50 in a subset of animals with the same age, dietary restriction, and fasting status for

Subacute Low Dose Nerve Agent Exposure Causes DNA Fragmentation in Guinea Pig Leukocytes

DTIC Science & Technology

2005-10-01

1 SUBACUTE LOW DOSE NERVE AGENT EXPOSURE CAUSES DNA FRAGMENTATION IN GUINEA PIG LEUKOCYTES. Jitendra R. Dave1, John R. Moffett1, Sally M...DNA fragmentation in blood leukocytes from guinea pigs by ‘Comet’ assay after exposure to soman at doses ranging from 0.1LD50 to 0.4 LD50, once per...computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA treated guinea pigs as

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stengl, Vaclav, E-mail: stengl@iic.cas.cz; Bludska, Jana; Oplustil, Frantisek

Highlights: {yields} New nano-dispersive materials for warfare agents decontamination. {yields} 95% decontamination activities for sulphur mustard. {yields} New materials base on titanium and manganese oxides. -- Abstract: Titanium(IV)-manganese(IV) nano-dispersed oxides were prepared by a homogeneous hydrolysis of potassium permanganate and titanium(IV) oxo-sulphate with 2-chloroacetamide. Synthesised samples were characterised using Brunauer-Emmett-Teller (BET) surface area and Barrett-Joiner-Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), and scanning electron microscopy (SEM). These oxides were taken for an experimental evaluation of their reactivity with sulphur mustard (HD or bis(2-chloroethyl)sulphide) and soman (GD or (3,3'-dimethylbutan-2-yl)-methylphosphonofluoridate). Mn{sup 4+} content affects the decontamination activity; with increasing Mn{supmore » 4+} content the activity increases for sulphur mustard and decreases for soman. The best decontamination activities for sulphur mustard and soman were observed for samples TiMn{sub 3}7 with 18.6 wt.% Mn and TiMn{sub 5} with 2.1 wt.% Mn, respectively.« less

Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

NASA Astrophysics Data System (ADS)

Yang, Jun; Fan, Lixue; Wang, Feijian; Luo, Yuan; Sui, Xin; Li, Wanhua; Zhang, Xiaohong; Wang, Yongan

2016-05-01

The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06658a

In Vivo Microdialysis and Electroencephalographic Activity in Freely Moving Guinea Pigs Exposed to Organophosphorus Nerve Agents Sarin and VX: Analysis of Acetylcholine and Glutamate

DTIC Science & Technology

2011-01-01

3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs 5a...microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of...brain seizure activity . This robust double multi- variate design provides greater fidelity when comparing data while also reducing the required number

Seasonal sea surface and sea ice signal in the fjords of Eastern Greenland from CryoSat-2 SARin altimetry

NASA Astrophysics Data System (ADS)

Abulaitijiang, Adili; Baltazar Andersen, Ole; Stenseng, Lars

2014-05-01

Cryosat-2 offers the first ever possibility to perform coastal altimetric studies using SAR-Interferometry. This enabled qualified measurements of sea surface height (SST) in the fjords in Greenland. Scoresbysund fjord on the east coast of Greenland is the largest fjord in the world which is also covered by CryoSat-2 SAR-In mask making it a good test region. Also, the tide gauge operated by DTU Space is sitting in Scoresbysund bay, which provides solid ground-based sea level variation records throughout the year. We perform an investigation into sea surface height variation since the start of the Cryosat-2 mission using SAR-In L1B data processed with baseline B processing. We have employed a new develop method for projecting all SAR-In observations in the Fjord onto a centerline up the Fjord. Hereby we can make solid estimates of the annual and (semi-) annual signal in sea level/sea ice freeboard within the Fjord. These seasonal height variations enable us to derive sea ice freeboard changes in the fjord from satellite altimetry. Derived sea level and sea-ice freeboard can be validated by comparison with the tide gauge observations for sea level and output from the Microwave Radiometer derived observations of sea ice freeboard developed at the Danish Meteorological Institute.

Pathways for the Oxidation of Sarin in Urban Atmospheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerald E. Streit; James E. Bossert; Jeffrey S. Gaffney

1998-11-01

Terrorists have threatened and carried out chemicalhiological agent attacks on targets in major cities. The nerve agent sarin figured prominently in one well-publicized incident. Vapors disseminating from open containers in a Tokyo subway caused thousands of casualties. High-resolution tracer transport modeling of agent dispersion is at hand and will be enhanced by data on reactions with components of the urban atmosphere. As a sample of the level of complexity currently attainable, we elaborate the mechanisms by which sarin can decompose in polluted air. A release scenario is outlined involving the passage of a gas-phase agent through a city locale inmore » the daytime. The atmospheric chemistry database on related organophosphorus pesticides is mined for rate and product information. The hydroxyl,radical and fine-mode particles are identified as major reactants. A review of urban air chernistry/rnicrophysics generates concentration tables for major oxidant and aerosol types in both clean and dirty environments. Organic structure-reactivity relationships yield an upper limit of 10-1' cm3 molecule-' S-* for hydrogen abstraction by hydroxyl. The associated midday loss time scale could be as little as one hour. Product distributions are difficult to define but may include nontoxic organic oxygenates, inorganic phosphorus acids, sarin-like aldehydes, and nitrates preserving cholinergic capabilities. Agent molecules will contact aerosol surfaces in on the order of minutes, with hydrolysis and side-chain oxidation as likely reaction channels.« less

Infrared signature of micro-hydration in the organophosphate sarin: An ab initio study

DOE PAGES

Alam, Todd M.; Pearce, Charles Joseph

2015-06-28

The infrared (IR) spectra of micro-hydrated Sarin•(H 2O) n clusters containing between one and four explicit waters have been studied using ab initio density functional theory (DFT) methods. The phosphate group P=O bond vibration region (~1270 to 1290 cm –1) revealed the largest frequency variation with hydration, with a frequency red shift reflecting the direct hydrogen bond formation between the P=O of Sarin and water. Small variations to the P-F stretch (~810 to 815 cm –1) and the C-O-P vibrational modes (~995 to 1004 cm –1) showed that the water interactions with these functional groups were minor, and that themore » structures of Sarin were not extensively perturbed in the hydrated complexes. Increasing the number of explicit hydration waters produced only small vibrational changes in the lowest free energy complexes. These minor changes were consistent with a single water-phosphate hydrogen bond being the dominant structure, though a second water-phosphate hydrogen bond was observed in some complexes and was identified by an additional red shift of the P=O bond vibration. As a result, the H 2O•H 2O vibrational modes (~3450 to 3660 cm –1) increased in complexity with higher hydration levels and reflect the extended hydrogen bonding networks formed between the explicit waters in the hydrated Sarin clusters.« less

Protection by Tacrine and Some Adjuncts against the Depressant Effects of Soman in Guinea-Pig Atrium

DTIC Science & Technology

1993-01-01

and Szilagyi , 1992). It could also improve the efficacy readily available from commercial sources. of THA against soman by shifting the THA RESULTS...muscarinic 100 27.96+.47 subtypes (Lau and Szilagyi , 1992). The smaller 8 1518 WAI-MAN LAU ൳ 3- -6.5 -6.0 -5.5 -5.0 -4.5 LOG THA COCTTI N) Fig. 5. Effect...tacrine is the blockade of Ca2l channels in the atrium and Dua, 1989). The actual site of interaction has not (Lau and Szilagyi , 1992) although the

The Efficacy of LY293558 in Blocking Seizures and Associated Morphological, and Behavioral Alterations Induced by Soman in Immature Male Rats and the Role of the M1 Muscarinic Acetylcholine Receptor in Organophosphate Induced Seizures

DTIC Science & Technology

2015-01-30

Neurology 48:1363-7 140. Koliatsos VE, Martin LJ, Walker LC, Richardson RT, DeLong MR, Price DL. 1988. Topographic, non-collateralized basal...297-323 169. Martin LJ, Doebler JA, Shih TM, Anthony A. 1985. Protective effect of diazepam pretreatment on soman-induced brain lesion formation...G, Watson C. 2005. The rat brain in stereotaxic coordinates. Amsterdam ; Boston: Elsevier Academic Press 216. Petras JM. 1994. Neurology and

2010 Department of Defense (DoD) Chemical and Biological Defense Program (CBDP) Portfolio

DTIC Science & Technology

2010-03-01

a new oxime and (2) obtaining approval for use of pyridostigmine bromide , the component of Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) for...Pralidoxime Chloride Autoinjector N/A 6505-01-125-3248 11704-620-01 N/A DLA 8 Pyridostigmine Bromide Tabs USP 30 mg I.S. (SNAPP) N/A 6505-01-178-7903 N...Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) N/A 6505-01-483-7162 N/A N/A N/A N/A Vaccines Anthrax Vaccine Adsorbed (AVA) N/A 6505-01-399

Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

DTIC Science & Technology

2013-01-01

status epilepticus (SE)], which are due to elevated acetylcholine levels in the peripheral and central nervous system (for reviews see Bajgar, 2005... status epilepticus . 133 at W alter R eed A rm y Institute of R esearch on January 10, 2013 jpet.aspetjournals.org D ow nloaded from an unexpected...induced generalized seizures and reduces the total duration of status epilepticus (SE) in the 24- hour period after soman exposure. (A) Administration of

Soman Induces Ictogenesis in the Amygdala and Interictal Activity in the Hippocampus That Are Blocked by a GluR5 Kainate Receptor Antagonist In Vitro

DTIC Science & Technology

2009-01-01

to organophosphorus nerve agents in- uces brain seizures, which can cause profound brain dam- ge resulting in death or long-term cognitive deficits...The mygdala and the hippocampus are two of the most seizure- rone brain structures, but their relative contribution to the eneration of seizures after...nerve agent exposure is unclear. ere, we report that application of 1 M soman for 30 min, in at coronal brain slices containing both the hippocampus

Evaluation of CryoSat-2 SARIn vs. SAR Arctic Sea Ice Freeboard

NASA Astrophysics Data System (ADS)

Di Bella, A.; Skourup, H.; Forsberg, R.

2017-12-01

Earth climate is a complex system which behaviour is dictated by the interaction among many components. Sea ice, one of these fundamental components, interacts directly with the oceans and the atmosphere playing an important role in defining heat exchange processes and, thus, impacting weather patterns on a global scale. Sea ice thickness estimates have notably improved in the last couple of decades, however, the uncertainty of such estimates is still significant. For the past 7 years, the ESA CryoSat-2 (CS2) mission has provided a unique opportunity to observe polar regions due to its extended coverage up to 88° N/S. The SIRAL radar altimeter on board CS2 enables the sea ice community to estimate sea ice thickness by measuring the sea ice freeboard. Studies by Armitage and Davidson [2014] and Di Bella et al. [submitted] showed that the interferometric capabilities of SIRAL can be used to retrieve an increased number of valid sea surface heights in sea ice covered regions and thus reduce the random uncertainty of the estimated freeboards, especially in areas with a sparse lead distribution. This study focuses on the comparison between sea ice freeboard estimates obtained by processing L1B SARIn data inside the Wingham box - an area in the Arctic Ocean where SIRAL has acquired SARIn data for 4 years - and those obtained by processing L1B SAR data in the area surrounding the box. This comparison evaluates CS2 performance on Arctic sea ice from a statistical perspective by analysing the continuity of freeboard estimates in areas where SIRAL switches between SAR and SARIn acquisition modes. Data collected during the Operation IceBridge and CryoVEx field campaigns are included in the study as an additional validation. Besides investigating the possibility of including the phase information from SIRAL in currently available freeboard estimates, this results provide valuable information for a possible SARIn CryoSat follow-on mission.

Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

DTIC Science & Technology

2013-08-01

GFAP,IL6,CCL2, TNF, L118, Lif, IL10 Hip, Ctx Ctx Ctx CORT=corticosterone;(200mg/L) for days 7-14 P8= pyridostigmine bromide ;P8(2.5 mg/kg/day, s.c...reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB), the insect repellent DEET and, potentially, the nerve agent, sarin. These...acetylcholinesterase (AChE) inhibitor, pyridostigmine bromide (PB), the insect repellent, DEET, and, potentially, acutely to the nerve agent sarin. Previously, we

Manned Gaming and Simulation Relating to Terrorism and Weapons of Mass Destruction: A Review of the Literature

DTIC Science & Technology

2004-04-17

Israel’s Blood group and the 1995 use of sarin on the Tokyo subway by the Japanese Aum Shinrikyo cult. However, in the former case, the number of...Center Ft. Irwin, CA Civilian information: (760) 380-3369 http://www.irwin.army.mil/default.htm U.S. Army Red Franchise Organization TRADOC...examination of the 1995 Aum Shinrikyo sarin attack in the Tokyo subway system. From there, Ataxia inventories the various federal response assets and

Huperzine a as a pretreatment candidate drug against nerve agent toxicity. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grunwald, J.; Raveh, L.; Doctor, B.P.

1994-12-31

Huperzine A (HUP) is a naturally-occurring, potent, reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. To examine its ability to protect against nerve agent poisoning, HUP was administered i.p. to mice, and the s.c. LD50 of soman was determined at various time intervals after pretreatment. Results were compared to those obtained for animals treated with physostigmine. A protective ratio of approximately 2 was maintained for at least 6 hr after a single injection of HUP, without the need for any post-challenge drug therapy. By contrast, pretreatment with physostigmine increased the LD50 of soman by 1.4- to 1.5-fold formore » only up to 90 min. The long-lasting antidotal efficacy displayed by HUP correlated with the time course of the blood-AChE inhibition. The results suggest that the protection of animals by HUP from soman poisoning was achieved by temporarily sequestering the active site region of the physiologically important AChE.« less

Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Gennings, C.; Carter, W.H.

1994-12-31

Diazepam (DZ) and scopolamine (SCP) are known to be beneficial when each is used in combination with atropine (AT) + oxime therapy against intoxication by soman, but the efficacy of each might be expected to vary with the dosage of AT. Thus, the therapeutic efficacy of SCP (5 doses; 0 - 0.86 mg/kg) versus DZ (5 doses; 0 - 5 mg/kg), when used in conjunction with AT (3 doses; 0.5 - S mg/kg) + 2-PAM (25 mg/kg) therapy, was tested in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5 or 3.2 LD5Os of soman. Response surface methodologymore » was employed to describe the relationship between lethality and the AT/DZ or AT/SCP dosages. Results show that within the indicated dose ranges used, the efficacy of SCP is not dependent on the presence of AT, whereas AT is needed for DZ to maintain the lowest probability of death. These findings suggest that in guinea pigs SCP could supplement AT or replace DZ as therapy against nerve agent intoxication.« less

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

PubMed Central

Antonijevic, Biljana; Stojiljkovic, Milos P.

2007-01-01

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX. TMB-4 and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of controlled clinical trials on the use of TMB-4 in human organophosphate pesticide poisoning, LüH-6 may be a better option. PMID:17456837

Enhanced efficacy of anticonvulsants when combined with levetiracetam in soman-exposed rats.

PubMed

Myhrer, Trond; Enger, Siri; Jonassen, Morten; Aas, Pål

2011-12-01

Results from studies based on microinfusions into seizure controlling brain sites (area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have shown that procyclidine, muscimol, caramiphen, and NBQX, but not ketamine, exert anticonvulsant effects against soman-induced seizures. The purpose of the present study was to examine whether levetiracetam (Keppra(®)) may enhance the anticonvulsant potency of the above drugs to become optimally effective when used systemically. Levetiracetam has a unique profile in preclinical models of epilepsy and has been shown to increase the potency of other antiepileptic drugs. The rats were pretreated with pyridostigmine (0.1mg/kg) to enhance survival and received anticonvulsants 20 min after onset of seizures evoked by soman (1.15 × LD(50)). The results showed that no single drug was able to terminate seizure activity. However, when levetiracetam (LEV; 50mg/kg) was combined with either procyclidine (PCD; 10mg/kg) or caramiphen (CMP; 10mg/kg) complete cessation of seizures was achieved, but the nicotinic antagonist mecamylamine was needed to induce full motor rest in some rats. In a subsequent experiment, rats were pretreated with HI-6 (125 mg/kg) to enhance survival and treatment started 40 min following seizure onset of a soman dose of 1.6 × LD(50). LEV (50mg/kg) combined with either PCD (20mg/kg) or CMP (20mg/kg) terminated seizure activity, but the survival rate was considerably higher for LEV+PCD than LEV+CMP. Both therapies could also save the lives of rats that were about to die 5-10 min after seizure onset. Thus, the combination of LEV and PCD or CMP may make up a model of a future autoinjector being effective regardless of the time of application. Copyright © 2011 Elsevier Inc. All rights reserved.

Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices

PubMed Central

Alkondon, Manickavasagom; Albuquerque, Edson X.; Pereira, Edna F.R.

2013-01-01

The involvement of brain nicotinic acetylcholine receptors (nAChRs) in the neurotoxicological effects of soman, a potent acetylcholinesterase (AChE) inhibitor and a chemical warfare agent, is not clear. This is partly due to a poor understanding of the role of AChE in brain nAChR-mediated functions. To test the hypothesis that AChE inhibition builds sufficient acetylcholine (ACh) in the brain and facilitates nAChR-dependent glutamate transmission, we used whole-cell patch-clamp technique to record spontaneous glutamate excitatory postsynaptic currents (EPSCs) from CA1 stratum radiatum interneurons (SRI) in hippocampal slices. First, the frequency, amplitude and kinetics of EPSCs recorded from slices of control guinea pigs were compared to those recorded from slices of guinea pigs after a single injection of the irreversible AChE inhibitor soman (25.2 μg/kg, s.c.). Second, EPSCs were recorded from rat hippocampal slices before and after their superfusion with the reversible AChE inhibitor donepezil (100 nM). The frequency of EPSCs was significantly higher in slices taken from guinea pigs 24 h but not 7 days after the soman injection than in slices from control animals. In 52% of the rat hippocampal slices tested, bath application of donepezil increased the frequency of EPSCs. Further, exposure to donepezil increased both burst-like and large-amplitude EPSCs, and increased the proportion of short (20–100 ms) inter-event intervals. Donepezil’s effects were suppressed significantly in presence of 10 μM mecamylamine or 10 nM methyllycaconitine. These results support the concept that AChE inhibition is able to recruit nAChR-dependent glutamate transmission in the hippocampus and such a mechanism can contribute to the acute neurotoxicological actions of soman. PMID:23511125

Analysis of chemical weapons decontamination waste from old ton containers from Johnston Atoll using multiple analytical methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Creasy, W.R.; Brickhouse, M.D.; Morrisse, K.M.

1999-07-01

Decontamination waste from chemical weapons (CW) agents has been stored in ton containers on Johnston Atoll since 1971. The waste was recently sampled and analyzed to determine its chemical composition in preparation for future cleanups. Due to the range of products and analytical requirements, multiple chromatographic and spectroscopic methods were necessary, including gas chromatography/mass spectrometry (GC/MS), gas chromatography/atomic emission detection (GC/AED), liquid chromatography/mass spectrometry (LC/MS), capillary electrophoresis (CE), and nuclear magnetic resonance spectroscopy (NMR). The samples were screened for residual agents. No residual sarin (GB) or VX was found to detection limits of 20 ng/mL, but 3% of the samplesmore » contained residual sulfur mustard (HD) at < 140 ng/mL. Decontamination products of agents were identified. The majority (74%) of the ton containers were documented correctly, in that the observed decontamination products were in agreement with the labeled agent type, but for a number of the containers, the contents were not in agreement with the labels. In addition, arsenic compounds that are decontamination products of the agent lewisite (L) were observed in a few ton containers, suggesting that lewisite was originally present but not documented. This study was a prototype to demonstrate the level of effort required to characterize old bulk CW-related waste.« less

Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lazar, Shlomi; Egoz, Inbal; Brandeis, Rachel

Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80 μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48 h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6 h post exposure while TSPO receptor density increased only at 24 h. Inmore » all brain regions tested, bax mRNA decreased 1 h post exposure followed by an increase 24 h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous “first response” mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention. - Highlights: • The severity of brain damage post 1LD50 sarin exposure is time dependent. • Sarin induce differential progression of early processes in the rat brain. • Potential treatments should be timed according to early events following exposure. • The biphasic astrocytes activity suggests a delay in anti-inflammatory intervention.« less

Stable-carbon isotope ratios for sourcing the nerve-agent precursor methylphosphonic dichloride and its products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. It is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ13C analysis to be used as a fingerprinting toolmore » in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. We demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a measureable isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Stable-Carbon Isotope Ratios for Sourcing the Nerve-Agent Precursor Methylphosphonic Dichloride and Its Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13C analysis to be used as a fingerprintingmore » tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. Here, we demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Stable-Carbon Isotope Ratios for Sourcing the Nerve-Agent Precursor Methylphosphonic Dichloride and Its Products

DOE PAGES

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

2018-04-01

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13C analysis to be used as a fingerprintingmore » tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. Here, we demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Stable-carbon isotope ratios for sourcing the nerve-agent precursor methylphosphonic dichloride and its products.

PubMed

Moran, James J; Fraga, Carlos G; Nims, Megan K

2018-08-15

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13 C analysis to be used as a fingerprinting tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. We demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool. Copyright © 2018. Published by Elsevier B.V.

Synthesis and in-vitro reactivation screening of imidazolium aldoximes as reactivators of sarin and VX-inhibited human acetylcholinesterase (hAChE).

PubMed

Sharma, Rahul; Gupta, Bhanushree; Sahu, Arvind Kumar; Acharya, Jyotiranjan; Satnami, Manmohan L; Ghosh, Kallol K

2016-11-25

Post-treatment of organophosphate (OP) poisoning involves the application of oxime reactivator as an antidote. Structurally different oximes are widely studied to examine their kinetic and mechanistic behavior against OP-inhibited cholinesterase enzyme. A series of structurally related 1,3-disubstituted-2-[(hydroxyiminomethyl)alkyl]imidazolium halides (5a-5e, 9a-9c) were synthesized and further evaluated for their in-vitro reactivation ability to reactivate sarin- and VX-inhibited human acetylcholinesterase (hAChE). The observed results were compared with the reactivation efficacy of standard reactivators; 2-PAM, obidoxime and HI-6. Amongst the synthesized oximes, 5a, 9a and 9b were found to be most potent reactivators against sarin-inhibited hAChE while in case of VX only 9a exhibited comparable reactivity with 2-PAM. Incorporation of pyridinium ring to the imidazole ring resulted in substantial increase in the reactivation strength of prepared reactivator. Physicochemical properties of synthesized reactivators have also been evaluated. Copyright © 2016. Published by Elsevier Ireland Ltd.

Quantum-Chemical Study of the Adsorption of DMMP and Sarin on gamma-Al2O3

DTIC Science & Technology

2007-02-01

In this and in the following section, ∆Eads is not corrected for zero-point vibrational energy ( ZPE ); however, a counterpoise correction for basis set...Ångstroms and the bond angle is in degrees. Values in parentheses are BSSE-corrected (∆Eads C ) results. ∆Eads has not been corrected for ZPE . b 6-31G...sets. The ∆ Eads C values are given in parentheses. No ZPE corrections have been applied. e The basis sets used were 6-311G(df) for Sarin and for the Al

Cerebral acetylcholine and choline contents and turnover following low-dose acetylcholinesterase inhibitors treatment in rats.

PubMed

Shih, Tsung-Ming; Scremin, Oscar U; Roch, Margareth; Huynh, Ly; Sun, Wei; Jenden, Donald J

2006-11-01

Male Sprague-Dawley rats were treated for 3 weeks with (1) regular tap drinking water plus subcutaneous (s.c.) saline (0.5 ml/kg) injections three times/week, (2) pyridostigmine bromide (PB) in drinking water (80 mg/L) plus s.c. saline injections three times/week, (3) regular tap drinking water plus s.c. sarin (0.5 x LD(50)) injections three times/week, or (4) PB in drinking water plus s.c. sarin injections three times/week. Repeated doses of sarin, in the presence or absence of PB, were devoid of acute toxicity during the three-week treatment period. Two, 4, and 16 weeks post-treatment, animals were given an intravenous pulse injection of choline labeled with 4 deuterium atoms (D4Ch) followed, after 1 min, by microwave fixation of the brain in vivo. Tissue levels of endogenous acetylcholine (D0ACh), endogenous choline (D0Ch), D4Ch, and ACh synthesized from D4Ch (D4ACh) were measured by gas-chromatography mass-spectrometry in hippocampus, infundibulum, mesencephalon, neocortex, piriform cortex, and striatum. Ch uptake from blood and ACh turnover were estimated from D4Ch and D4ACh concentrations in brain tissue, respectively. Statistically significant differences among brain regions were found for D0Ch, D4Ch, D0ACh and D4ACh at 2, 4 and 16 weeks post-treatment. However, differences in the values of these parameters between control and drug treatments were found only for D0ACh and D0Ch at 2 and 4 weeks, but not at 16 weeks post-treatment. In conclusion, the results from these experiments do not support a delayed or persistent alteration in cholinergic function after exposure to low doses of PB and/or sarin.

Acute effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate, on cardiovascular parameters in anaesthetized, artificially ventilated rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Yoshimasa; Itoh, Takeo, E-mail: titoh@med.nagoya-cu.ac.jp; Shiraishi, Hiroaki

The organophosphorus compound sarin irreversibly inhibits acetylcholinesterase. We examined the acute cardiovascular effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate (BIMP), in anaesthetized, artificially ventilated rats. Intravenous administration of BIMP (0.8 mg/kg; the LD50 value) induced a long-lasting increase in blood pressure and tended to increase heart rate. In rats pretreated with the non-selective muscarinic-receptor antagonist atropine, BIMP significantly increased both heart rate and blood pressure. In atropine-treated rats, hexamethonium (antagonist of ganglionic nicotinic receptors) greatly attenuated the BIMP-induced increase in blood pressure without changing the BIMP-induced increase in heart rate. In rats treated with atropine plus hexamethonium, intravenous phentolaminemore » (non-selective α-adrenergic receptor antagonist) plus propranolol (non-selective β-adrenergic receptor antagonist) completely blocked the BIMP-induced increases in blood pressure and heart rate. In atropine-treated rats, the reversible acetylcholinesterase inhibitor neostigmine (1 mg/kg) induced a transient increase in blood pressure, but had no effect on heart rate. These results suggest that in anaesthetized rats, BIMP induces powerful stimulation of sympathetic as well as parasympathetic nerves and thereby modulates heart rate and blood pressure. They may also indicate that an action independent of acetylcholinesterase inhibition contributes to the acute cardiovascular responses induced by BIMP. - Highlights: • A sarin-like agent BIMP markedly increased blood pressure in anaesthetized rats. • Muscarinic receptor blockade enhanced the BIMP-induced increase in blood pressure. • Ganglionic nicotinic receptor blockade attenuated the BIMP-induced response. • Blockade of α- as well as β-receptors attenuated the BIMP-induced response.« less

CryoSat-2 SAR and SARin Inland Water Heights from the CRUCIAL project

NASA Astrophysics Data System (ADS)

Benveniste, J.; Restano, M.; Ambrózio, A.; Moore, P.; Birkinshaw, S.

2017-12-01

CRUCIAL was an ESA/STSE funded project investigating innovative land and inland water applications from CryoSat-2 with a forward-look component to the Sentinel-3 and Jason-CS/Sentinel-6 missions. The high along-track sampling of CryoSat-2 in its SAR and SARin modes offers the opportunity to recover high frequency signals over inland waters. A methodology was developed to process the FBR L1A Doppler beams to form a waveform product using ground cell gridding, beam steering and beam stacking. Inland water heights from CryoSat-2 are derived by using a set of empirical retrackers formulated for inland water applications. Results of the processing strategy include a comparison of waveforms and heights from the burst echoes (80 m along-track) and from multi-look waveforms (320 m along-track). SAR and SARin FBR data are available for the Amazon, Brahmaputra and Mekong for 2011-2015. FBR SAR results are compared against stage data from the nearest gauge. Heights from Tonlé Sap are also compared against Jason-2 data from the United States Department of Agriculture. A strategy to select the number of multi-looks over rivers was designed based on the rms of heights across Tonlé Sap. Comparisons include results from the empirical retrackers and from waveforms and heights obtained via ESA's Grid Processing on Demand (G-POD/SARvatore) using the SAMOSA2 retracker. Results of FBR SARin processing for the Amazon and Brahmaputra are presented including comparison of heights from the two antennae, extraction of slope of the ground surface and validation against ground data where appropriate.

Engineering Bacteria to Catabolize the Carbonaceous Component of Sarin: Teaching E. coli to Eat Isopropanol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Margaret E.; Mukhopadhyay, Aindrila; Keasling, Jay D.

In this paper, we report an engineered strain of Escherichia coli that catabolizes the carbonaceous component of the extremely toxic chemical warfare agent sarin. Enzymatic decomposition of sarin generates isopropanol waste that, with this engineered strain, is then transformed into acetyl-CoA by enzymatic conversion with a key reaction performed by the acetone carboxylase complex (ACX). We engineered the heterologous expression of the ACX complex from Xanthobacter autotrophicus PY2 to match the naturally occurring subunit stoichiometry and purified the recombinant complex from E. coli for biochemical analysis. Incorporating this ACX complex and enzymes from diverse organisms, we introduced an isopropanol degradationmore » pathway in E. coli, optimized induction conditions, and decoupled enzyme expression to probe pathway bottlenecks. Our engineered E. coli consumed 65% of isopropanol compared to no-cell controls and was able to grow on isopropanol as a sole carbon source. Finally, in the process, reconstitution of this large ACX complex (370 kDa) in a system naïve to its structural and mechanistic requirements allowed us to study this otherwise cryptic enzyme in more detail than would have been possible in the less genetically tractable native Xanthobacter system.« less

Extending injury prevention methodology to chemical terrorism preparedness: the Haddon Matrix and sarin.

PubMed

Varney, Shawn; Hirshon, Jon Mark; Dischinger, Patricia; Mackenzie, Colin

2006-01-01

The Haddon Matrix offers a classic epidemiological model for studying injury prevention. This methodology places the public health concepts of agent, host, and environment within the three sequential phases of an injury-producing incident-pre-event, event, and postevent. This study uses this methodology to illustrate how it could be applied in systematically preparing for a mass casualty disaster such as an unconventional sarin attack in a major urban setting. Nineteen city, state, federal, and military agencies responded to the Haddon Matrix chemical terrorism preparedness exercise and offered feedback in the data review session. Four injury prevention strategies (education, engineering, enforcement, and economics) were applied to the individual factors and event phases of the Haddon Matrix. The majority of factors identified in all phases were modifiable, primarily through educational interventions focused on individual healthcare providers and first responders. The Haddon Matrix provides a viable means of studying an unconventional problem, allowing for the identification of modifiable factors to decrease the type and severity of injuries following a mass casualty disaster such as a sarin release. This strategy could be successfully incorporated into disaster planning for other weapons attacks that could potentially cause mass casualties.

A Review Of CryoSat-2/SIRAL Applications For The Monitoring Of River Water Levels

NASA Astrophysics Data System (ADS)

Bercher, Nicolas; Dinardo, Salvatore; Lucas, Bruno Manuel; Fleury, Sara; Calmant, Stephane; Femenias, Pierre; Boy, Francois; Picot, Nicolas; Benveniste, Jerome

2013-12-01

Regarding hydrology applications and particularly the monitoring of river water levels from space, the CryoSat- 2 ice mission has two main valuable characteristics: (1) its geodetic orbit and (2) the altimeter's SAR and SARin modes. The benefits of the geodetic orbit of the satellite have been illustrated in the frame of the ”20 years of progress in radar altimetry” symposium (Venice, 2012) [2]. It has been shown that, with such an orbit, the way river water level was monitored using conventional altimeters had to be revisited. In particular, using LRM mode only, CryoSat-2 allowed us to build spatio-temporal time series of the river water level, to map river's topography and eventually derive pseudo-time series and pseudo-profiles of the river. This paper focuses on the new ways to use altimetry for the monitoring of river water levels. SIRAL's (CryoSat-2 altimeter) SAR and SARin modes have the ability to deliver surface heights with an unprecedented along-track resolution of about 300 m. Moreover, using the SARin mode (involving the satellite's two antennas), the cross- track angle of the retracked echo is also available in routine. These two aspects of the SARin mode (high resolution and cross-track angle) make it a new tool to distinguish whether the retracked echo came from the sur- face of interest (e.g., a river) or any other reflective object nearby the surface of interest (e.g., another river section, lakes or temporary lake after flooding events or any other specular surfaces). We introduce the multiple benefits of using the intermediate multi-look matrix (also known as stack matrix), among them: (1) to refine and select among the multiple Doppler-beam waveforms before averaging and retracking them, and (2) to be able to study the surfaces response according to their view angle. Custom products processed at ESA (ESRIN) by Dinardo et al. [7], in the perspective of Sentinel-3, as well as official CryoSat-2 L1b and L2 products were used to illustrate these perspectives. The paper mainly introduces the potential new applications brought by SIRAL's SAR and SARin modes. Finally, combined with its really dense geodetic orbit, CryoSat-2 can be seen as a topography mission that paves the way toward the SWOT mission.

CryoSat Level1b SAR/SARin BaselineC: Product Format and Algorithm Improvements

NASA Astrophysics Data System (ADS)

Scagliola, Michele; Fornari, Marco; Di Giacinto, Andrea; Bouffard, Jerome; Féménias, Pierre; Parrinello, Tommaso

2015-04-01

CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. Cryosat carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. This allows to reach a significantly improved along track resolution with respect to traditional pulse-width limited altimeters. CryoSat is the first altimetry mission operating in SAR mode and continuous improvements in the Level1 Instrument Processing Facility (IPF1) are being identified, tested and validated in order to improve the quality of the Level1b products. The current IPF, Baseline B, was released in operation in February 2012. A reprocessing campaign followed, in order to reprocess the data since July 2010. After more than 2 years of development, the release in operations of Baseline C is expected in the first half of 2015. BaselineC Level1b products will be distributed in an updated format, including for example the attitude information (roll, pitch and yaw) and, for SAR/SARIN, the waveform length doubled with respect to Baseline B. Moreveor, various algorithm improvements have been identified: • a datation bias of about -0.5195 ms will be corrected (SAR/SARIn) • a range bias of about 0.6730 m will be corrected (SAR/SARIn) • a roll bias of 0.1062 deg and a pitch bias of 0.0520 deg • Surface sample stack weighting to filter out the single look echoes acquired at highest look angle, that results in a sharpening of the 20Hz waveforms With the operational release of BaselineC, the second CryoSat reprocessing campaign will be initiated, taking benefit of the upgrade implemented in the IPF1 processing chain but also at IPF2 level. The reprocessing campaign will cover the full Cryosat mission starting on 16th July 2010. This poster details the new information that will be added in the CryoSat BaselineC Level1b SAR/SARin products and the main quality improvements will be described.

The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE.

PubMed

Chao, Chih-Kai; Balasubramanian, Narayanaganesh; Gerdes, John M; Thompson, Charles M

2018-06-16

In this study, the mechanisms of HuAChE and HuBChE inhibition by Me-P(O) (OPNP) (OR) [PNP = p-nitrophenyl; R = CH 2 CH 3 , CH 2 CH 2 F, OCH(CH 3 ) 2 , OCH(CH 3 ) (CH 2 F)] representing surrogates and fluoro-surrogates of VX and sarin were studied by in vitro kinetics and mass spectrometry. The in vitro measures showed that the VX- and fluoro-VX surrogates were relatively strong inhibitors of HuAChE and HuBChE (k i  ∼ 10 5 -10 6  M -1 min -1 ) and underwent spontaneous and 2-PAM-mediated reactivation within 30 min. The sarin surrogates were weaker inhibitors of HuAChE and HuBChE (k i  ∼ 10 4 -10 5  M -1 min -1 ), and in general did not undergo spontaneous reactivation, although HuAChE adducts were partially reactivatable at 18 h using 2-PAM. The mechanism of HuAChE and HuBChE inhibition by the surrogates was determined by Q-TOF and MALDI-TOF mass spectral analyses. The surrogate-adducted proteins were trypsin digested and the active site-containing peptide bearing the OP-modified serine identified by Q-TOF as triply- and quadruply-charged ions representing the respective increase in mass of the attached OP moiety. Correspondingly, monoisotopic ions of the tryptic peptides representing the mass increase of the OP-adducted peptide was identified by MALDI-TOF. The mass spectrometry analyses validated the identity of the OP moiety attached to HuAChE or HuBChE as MeP(O) (OR)-O-serine peptides (loss of the PNP leaving group) via mechanisms consistent with those found with chemical warfare agents. MALDI-TOF MS analyses of the VX-modified peptides versus time showed a steady reduction in adduct versus parent peptide (reactivation), whereas the sarin-surrogate-modified peptides remained largely intact over the course of the experiment (24 h). Overall, the presence of a fluorine atom on the surrogate modestly altered the rate constants of inhibition and reactivation, however, the mechanism of inhibition (ejection of PNP group) did not change. Copyright © 2018. Published by Elsevier B.V.

Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koplovitz, I.; Menton, R.; Matthews, C.

1995-12-31

H1-6 (1-2-hydrnxyiminomethyl-1 pyridino-3-(4-carbameyl- 1--pyddino)-2- oxaprnpane dichioride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OPmore » and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman.« less

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population

PubMed Central

Apland, James P.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Pidoplichko, Volodymyr I.; Rossetti, Katia

2018-01-01

The currently Food and Drug Administration–approved anticonvulsant for the treatment of status epilepticus (SE) induced by nerve agents is the benzodiazepine diazepam; however, diazepam does not appear to offer neuroprotective benefits. This is of particular concern with respect to the protection of children because, in the developing brain, synaptic transmission mediated via GABAA receptors, the target of diazepam, is weak. In the present study, we exposed 21-day-old male rats to 1.2 × LD50 soman and compared the antiseizure, antilethality, and neuroprotective efficacy of diazepam (10 mg/kg), LY293558 (an AMPA/GluK1 receptor antagonist; 15 mg/kg), caramiphen (CRM, an antimuscarinic with NMDA receptor-antagonistic properties; 50 mg/kg), and LY293558 (15 mg/kg) + CRM (50 mg/kg), administered 1 hour after exposure. Diazepam, LY293558, and LY293558 + CRM, but not CRM alone, terminated SE; LY293558 + CRM treatment acted significantly faster and produced a survival rate greater than 85%. Thirty days after soman exposure, neurodegeneration in limbic regions was most severe in the CRM-treated group, minimal to severe—depending on the region—in the diazepam group, absent to moderate in the LY293558-treated group, and totally absent in the LY293558 + CRM group. Amygdala and hippocampal atrophy, a severe reduction in spontaneous inhibitory activity in the basolateral amygdala, and increased anxiety-like behavior in the open-field and acoustic startle response tests were present in the diazepam and CRM groups, whereas the LY293558 and LY293558 + CRM groups did not differ from controls. The combined administration of LY293558 and CRM, by blocking mainly AMPA, GluK1, and NMDA receptors, is a very effective anticonvulsant and neuroprotective therapy against soman in young rats. PMID:29467308

Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support.

PubMed

Lallement, G; Clarençon, D; Galonnier, M; Baubichon, D; Burckhart, M F; Peoc'h, M

1999-03-01

Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.

Protection by pyridostigmine bromide of marmoset hemi-diaphragm acetylcholinesterase activity after soman exposure.

PubMed

Haigh, Julian R; Adler, Michael; Apland, James P; Deshpande, Sharad S; Barham, Charles B; Desmond, Patrick; Koplovitz, Irwin; Lenz, David E; Gordon, Richard K

2010-09-06

Pyridostigmine bromide (PB) was approved by the U.S. Food and Drug Administration (FDA) in 2003 as a pretreatment in humans against the lethal effects of the irreversible nerve agent soman (GD). Organophosphate (OP) chemical warfare agents such as GD exert their toxic effects by inhibiting acetylcholinesterase (AChE) from terminating the action of acetylcholine at postsynaptic sites in cholinergic nerve terminals (including crucial peripheral muscle such as diaphragm). As part of the post-marketing approval of PB, the FDA required (under 21CFR314, the "two animal rule") the study of a non-human primate model (the common marmoset Callithrix jacchus jacchus) to demonstrate increased survival against lethal GD poisoning, and protection of physiological hemi-diaphragm function after PB pretreatment and subsequent GD exposure. Marmosets (male and female) were placed in the following experimental groups: (i) control (saline pretreatment only), (ii) low dose PB (12.5 microg/kg), or (iii) high dose (39.5 microg/kg) PB. Thirty minutes after the PB dose, animals were challenged with either saline (control) or soman (GD, 45 microg/kg), followed 1 min later by atropine (2mg/kg) and 2-PAM (25mg/kg). After a further 16 min, animals were euthanized and the complete diaphragm removed; the right hemi-diaphragm was frozen immediately at -80 degrees C, and the left hemi-diaphragm was placed in a tissue bath for 4h (to allow for decarbamylation to occur), then frozen. AChE activities were determined using the automated WRAIR cholinesterase assay. Blood samples were collected for AChE activities prior to PB, before GD challenge, and after sacrifice. RBC-AChE was inhibited by approximately 18% and 50% at the low and high doses of PB, respectively, compared to control (baseline) activity. In the absence of PB pretreatment, the inhibition of RBC-AChE by GD was 98%. The recovery of hemi-diaphragm AChE activity after the 4h wash period (decarbamylation) was approximately 8% and 17%, at the low and high PB doses, respectively, compared with the baseline (control) AChE activity prior to PB pretreatment or soman exposure. The results suggest that PB pretreatment protects a critical fraction of AChE activity in the marmoset diaphragm, which is sufficient to allow the animal to breathe despite exposure to a dose of soman that is lethal in unprotected animals. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: a mini review.

PubMed

Lenz, David E; Yeung, David; Smith, J Richard; Sweeney, Richard E; Lumley, Lucille A; Cerasoli, Douglas M

2007-04-20

Currently fielded treatments for nerve agent intoxication promote survival, but do not afford complete protection against either nerve agent-induced motor and cognitive deficits or neuronal pathology. The use of human plasma-derived butyrylcholinesterase (HuBuChE) to neutralize the toxic effects of nerve agents in vivo has been shown to both aid survival and protect against decreased cognitive function after nerve agent exposure. Recently, a commercially produced recombinant form of human butyrylcholinesterase (r-HuBuChE; PharmAthene Inc.) expressed in the milk of transgenic goats has become available. This material is biochemically similar to plasma-derived HuBuChE in in vitro assays. The pharmacokinetic characteristics of a polyethylene glycol coated (pegylated) form of r-HuBuChE were determined in guinea pigs; the enzyme was rapidly bioavailable with a half-life (t(1/2)) and pharmacokinetic profile that resembled that of plasma-derived huBuChE. Guinea pigs were injected with 140mg/kg (i.m.) of pegylated r-HuBuChE 18h prior to exposure (sc) to 5.5xLD(50) VX or soman. VX and soman were administered in a series of three injections of 1.5xLD(50), 2.0xLD(50), and 2.0xLD(50), respectively, with injections separated by 2h. Pretreatment with pegylated r-HuBuChE provided 100% survival against multiple lethal doses of VX and soman. Guinea pigs displayed no signs of nerve agent toxicity following exposure. Assessments of motor activity, coordination, and acquisition of spatial memory were performed for 2 weeks following nerve agent exposure. There were no measurable decreases in motor or cognitive function during this period. In contrast, animals receiving 1.5xLD(50) challenges of soman or VX and treated with standard atropine, 2-PAM, and diazepam therapy showed 50 and 100% survival, respectively, but exhibited marked decrements in motor function and, in the case of GD, impaired spatial memory acquisition. The advances in this field have resulted in the decision to select both the plasma-derived and the recombinant form of BuChE for advanced development and transition to clinical trials. Efforts have now been expanded to identify a catalytic protein capable of not only binding, but also rapidly hydrolyzing the standard threat nerve agents. Recent work has focused on paraoxonase-1 (PON1), a naturally occurring human serum enzyme with the capacity to catalyze the hydrolysis of nerve agents, albeit too slowly to afford dramatic protection. Using rational design, several amino acids involved in substrate binding have been identified and site-directed mutations have revealed that residue H115 plays an important role in binding. In addition, the stereospecificity of PON1 for the catalytic hydrolysis of soman has been examined. The enzyme exhibits a slight stereospecificity for the C+P+ isomer of soman, which is due more to preferential binding than to selective hydrolysis of this isomer. The results suggest that it may be possible to engineer a mutant form of PON1 with enhanced activity and stereospecificity for the most toxic nerve agent isoforms.

Soman

MedlinePlus

... Cyanogen chloride (CK) Digitalis Case Definition: Digitalis Poisoning Ethylene glycol Fentanyls and other opioids Case Definition: Opioids ( ... Thallium Toxic alcohols Case Definition: Toxic Alcohol Poisoning Ethylene glycol Trichothecene Case Definition: Trichothecene Mycotoxin Poisoning Unidentified ...

Fine Ice Sheet margins topography from swath processing of CryoSat SARIn mode data

NASA Astrophysics Data System (ADS)

Gourmelen, N.; Escorihuela, M. J.; Shepherd, A.; Foresta, L.; Muir, A.; Briggs, K.; Hogg, A. E.; Roca, M.; Baker, S.; Drinkwater, M. R.

2014-12-01

Reference and repeat-observations of Glacier and Ice Sheet Margin (GISM) topography are critical to identify changes in ice thickness, provide estimates of mass gain or loss and thus quantify the contribution of the cryosphere to sea level change. The lack of such sustained observations was identified in the Integrated Global Observing Strategy (IGOS) Cryosphere Theme Report as a major shortcoming. Conventional altimetry measurements over GISMs exist, but coverage has been sparse and characterized by coarse ground resolution. Additionally, and more importantly, they proved ineffective in the presence of steep slopes, a typical feature of GISM areas. Since the majority of Antarctic and Greenland ice sheet mass loss is estimated to lie within 100 km from the coast, but only about 10% is surveyed, there is the need for more robust and dense observations of GISMs, in both time and space. The ESA Altimetry mission CryoSat aims at gaining better insight into the evolution of the Cryosphere. CryoSat's revolutionary design features a Synthetic Interferometric Radar Altimeter (SIRAL), with two antennas for interferometry. The corresponding SAR Interferometer (SARIn) mode of operation increases spatial resolution while resolving the angular origin of off-nadir echoes occurring over sloping terrain. The SARIn mode is activated over GISMs and the elevation for the Point Of Closest Approach (POCA) is a standard product of the CryoSat mission. Here we present an approach for more comprehensively exploiting the SARIn mode of CryoSat and produce an ice elevation product with enhanced spatial resolution compared to standard CryoSat-2 height products. In this so called L2-swath processing approach, the full CryoSat waveform is exploited under specific conditions of signal and surface characteristics. We will present the rationale, validation exercises and preliminary results from the Eurpean Space Agency's STSE CryoTop study over selected test regions of the margins of the Greenland and Antarctic Ice Sheets.

Ion mobility spectrometric analysis of vaporous chemical warfare agents by the instrument with corona discharge ionization ammonia dopant ambient temperature operation.

PubMed

Satoh, Takafumi; Kishi, Shintaro; Nagashima, Hisayuki; Tachikawa, Masumi; Kanamori-Kataoka, Mieko; Nakagawa, Takao; Kitagawa, Nobuyoshi; Tokita, Kenichi; Yamamoto, Soichiro; Seto, Yasuo

2015-03-20

The ion mobility behavior of nineteen chemical warfare agents (7 nerve gases, 5 blister agents, 2 lachrymators, 2 blood agents, 3 choking agents) and related compounds including simulants (8 agents) and organic solvents (39) was comparably investigated by the ion mobility spectrometry instrument utilizing weak electric field linear drift tube with corona discharge ionization, ammonia doping, purified inner air drift flow circulation operated at ambient temperature and pressure. Three alkyl methylphosphonofluoridates, tabun, and four organophosphorus simulants gave the intense characteristic positive monomer-derived ion peaks and small dimer-derived ion peaks, and the later ion peaks were increased with the vapor concentrations. VX, RVX and tabun gave both characteristic positive monomer-derived ions and degradation product ions. Nitrogen mustards gave the intense characteristic positive ion peaks, and in addition distinctive negative ion peak appeared from HN3. Mustard gas, lewisite 1, o-chlorobenzylidenemalononitrile and 2-mercaptoethanol gave the characteristic negative ion peaks. Methylphosphonyl difluoride, 2-chloroacetophenone and 1,4-thioxane gave the characteristic ion peaks both in the positive and negative ion mode. 2-Chloroethylethylsulfide and allylisothiocyanate gave weak ion peaks. The marker ion peaks derived from two blood agents and three choking agents were very close to the reactant ion peak in negative ion mode and the respective reduced ion mobility was fluctuated. The reduced ion mobility of the CWA monomer-derived peaks were positively correlated with molecular masses among structurally similar agents such as G-type nerve gases and organophosphorus simulants; V-type nerve gases and nitrogen mustards. The slope values of the calibration plots of the peak heights of the characteristic marker ions versus the vapor concentrations are related to the detection sensitivity, and within chemical warfare agents examined the slope values for sarin, soman, tabun and nitrogen mustards were higher. Some CWA simulants and organic solvents gave the ion peaks eluting at the similar positions of the CWAs, resulting in false positive alarms. Copyright © 2015 Elsevier B.V. All rights reserved.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for detection and identification of albumin phosphylation by organophosphorus pesticides and G- and V-type nerve agents.

PubMed

John, Harald; Breyer, Felicitas; Thumfart, Jörg Oliver; Höchstetter, Hans; Thiermann, Horst

2010-11-01

Toxic organophosphorus compounds (OPC), e.g., pesticides and nerve agents (NA), are known to phosphylate distinct endogenous proteins in vivo and in vitro. OPC adducts of butyrylcholinesterase and albumin are considered to be valuable biomarkers for retrospective verification of OPC exposure. Therefore, we have detected and identified novel adducts of human serum albumin (HSA) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Pure albumin and plasma were incubated with numerous pesticides and NA of the V- and G-type in different molar ratios. Samples were prepared either by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by in-gel enzymatic cleavage using endoproteinase Glu-C (Glu-C) or by combining highly albumin-selective affinity extraction with ultrafiltration followed by reduction, carbamidomethylation, and enzymatic cleavage (Glu-C) prior to MALDI-TOF MS analysis. Characteristic mass shifts for phosphylation revealed tyrosine adducts at Y(411) (Y(401)KFQNALLVRY(411)TKKVPQVSTPTLVE(425)), Y(148) and Y(150) (I(142)ARRHPY(148)FY(150)APE(153), single and double labeled), and Y(161) (L(154)LFFAKRY(161)KAAFTE(167)) produced by original NA (tabun, sarin, soman, cyclosarin, VX, Chinese VX, and Russian VX) as well as by chlorpyrifos-oxon, diisopropyl fluorophosphate (DFP), paraoxon-ethyl (POE), and profenofos. MALDI-MS/MS of the single-labeled I(142)-E(153) peptide demonstrated that Y(150) was phosphylated with preference to Y(148). Aged albumin adducts were not detected. The procedure described was reproducible and feasible for detection of adducts at the most reactive Y(411)-residue (S/N ≥ 3) when at least 1% of total albumin was labeled. This was achieved by incubating plasma with molar HSA/OPC ratios ranging from approximately 1:0.03 (all G-type NA, DFP, and POE) to 1:3 (V-type NA, profenofos). Relative signal intensity of the Y(411) adduct correlated well with the spotted relative molar amount underlining the usefulness for quantitative adduct determination. In conclusion, the current analytical design exhibits potential as a verification tool for high-dose exposure.

Dual Role of Water in Heterogeneous Catalytic Hydrolysis of Sarin by Zirconium-Based Metal-Organic Frameworks.

PubMed

Momeni, Mohammad R; Cramer, Christopher J

2018-05-22

Recent experimental studies on Zr IV -based metal-organic frameworks (MOFs) have shown the extraordinary effectiveness of these porous materials for the detoxification of phosphorus-based chemical warfare agents (CWAs). However, pressing challenges remain with respect to characterizing these catalytic processes both at the molecular and crystalline levels. We here use theory to compare the reactivity of different zirconium-based MOFs for the catalytic hydrolysis of the CWA sarin, using both periodic and cluster modeling. We consider both hydrated and dehydrated secondary building units, as well as linker functionalized MOFs, to more fully understand and rationalize available experimental findings as well as to enable concrete predictions for achieving higher activities for the decomposition of CWAs.

Molecular targets for organophosphates in the central nervous system. Midterm report, 18 May 1995-17 November 1996

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albuquerque, E.X.

1996-11-01

In this study, the patch-clamp technique was used as an approach to evaluate the pre- and postsynaptic effects of VX and soman on synaptic currents of cultured hippocampal neurons. Compared to control, the frequency of the currents mediated by the activation of GABA or glutamate receptors was increased in a concentration-dependent manner from 200% to 550%, when exposed to VX from 10 nM to 1 pM. The effect of VX was observed in the presence of TTX and atropine, indicating that it was a presynaptic effect unrelated to the activation of muscarinic receptors. In addition, it was found that themore » dlhydron-B-erythroldine did not prevent or abolished the effects of VX. Because, either soman or acetylcholine at high concentrations, applied for 5 to 10 min to the cultured neurons did not mimic the potentiation of transmitter release induced by VX, it was concluded that the presynaptic effect of VX was unrelated to the inhibition of cholinesterase enzyme. At the concentrations studied, VX and soman did not change the post-synaptic properties of GABAA, NMDA, and AMPA receptors. The effect of VX was markedly reduced when the extracellular calcium was removed, but was unaffected when the calcium channel blocker verapamil was added to the preparation. The present findings shows that VX exerts a presynaptic effect unrelated to cholinesterase enzyme that is unaffected by the common antidote atropine used for treating intoxication with VX.« less

Effects of subacute pyridostigmine administration on mammalian skeletal muscle function. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adler, M.; Deshpande, S.S.; Foster, R.E.

1992-12-31

The subacute effects of pyridostigmine bromide were investigated on the contractile properties of rat extensor digitorum longus (EDL) and diaphragm muscles. The cholinesterase inhibitor was delivered via subcutaneously implanted osmotic minipumps (Alzet) at 9 microns g h-1 (low dose) or 60 micro g h-1 (high dose). Animals receiving high-dose pyridostigmine pumps exhibited marked alterations in muscle properties within the first day of exposure that persisted for the remaining 13 days. With 0.1 Hz stimulation, EDL twitch tensions of treated animals were elevated relative to control. Repetitive stimulation at frequencies > 1 Hz led a use-dependent depression in the amplitude ofmore » successive twitches during the train. Recovery from pyridostigmine was essentially complete by 1 day of withdrawal. Rats implanted with low-dose pyridostigmine pumps showed little or no alteration of in vivo twitch tensions during the entire 14 days of treatment. Diaphragm and EDL muscles excised from pyridostigmine-treated rats and tested in vitro showed no significant alterations in twitch and tetanic tensions and displayed the same sensitivity as muscles of control animals to subsequent pyridostigmine exposures. In the presence of atropine, subacutely administered pyridostigmine protected rats from two LD5O doses of the irreversible cholinesterase inhibitor, soman. In the absence of atropine, the LD50 of soman was not altered by subacute pyridostigmine treatment. Extensor digitorum longus; diaphragm; twitch tension; ACh release; subacute; Alzet pumps; tolerance; anticholinesterase; pyridostigmine; soman.« less

A novel approach to multihazard modeling and simulation.

PubMed

Smith, Silas W; Portelli, Ian; Narzisi, Giuseppe; Nelson, Lewis S; Menges, Fabian; Rekow, E Dianne; Mincer, Joshua S; Mishra, Bhubaneswar; Goldfrank, Lewis R

2009-06-01

To develop and apply a novel modeling approach to support medical and public health disaster planning and response using a sarin release scenario in a metropolitan environment. An agent-based disaster simulation model was developed incorporating the principles of dose response, surge response, and psychosocial characteristics superimposed on topographically accurate geographic information system architecture. The modeling scenarios involved passive and active releases of sarin in multiple transportation hubs in a metropolitan city. Parameters evaluated included emergency medical services, hospital surge capacity (including implementation of disaster plan), and behavioral and psychosocial characteristics of the victims. In passive sarin release scenarios of 5 to 15 L, mortality increased nonlinearly from 0.13% to 8.69%, reaching 55.4% with active dispersion, reflecting higher initial doses. Cumulative mortality rates from releases in 1 to 3 major transportation hubs similarly increased nonlinearly as a function of dose and systemic stress. The increase in mortality rate was most pronounced in the 80% to 100% emergency department occupancy range, analogous to the previously observed queuing phenomenon. Effective implementation of hospital disaster plans decreased mortality and injury severity. Decreasing ambulance response time and increasing available responding units reduced mortality among potentially salvageable patients. Adverse psychosocial characteristics (excess worry and low compliance) increased demands on health care resources. Transfer to alternative urban sites was possible. An agent-based modeling approach provides a mechanism to assess complex individual and systemwide effects in rare events.

Sarin

MedlinePlus

... Cyanogen chloride (CK) Digitalis Case Definition: Digitalis Poisoning Ethylene glycol Fentanyls and other opioids Case Definition: Opioids ( ... Thallium Toxic alcohols Case Definition: Toxic Alcohol Poisoning Ethylene glycol Trichothecene Case Definition: Trichothecene Mycotoxin Poisoning Unidentified ...

Structure-dependent Pseudoreceptor Intracellular Traffic of Adamantyl Globotriaosyl Ceramide Mimics*

PubMed Central

Saito, Mitsumasa; Mylvaganum, Murugespillai; Tam, Patty; Novak, Anton; Binnington, Beth; Lingwood, Clifford

2012-01-01

The verotoxin (VT) (Shiga toxin) receptor globotriaosyl ceramide (Gb3), mediates VT1/VT2 retrograde transport to the endoplasmic reticulum (ER) for cytosolic A subunit access to inhibit protein synthesis. Adamantyl Gb3 is an amphipathic competitive inhibitor of VT1/VT2 Gb3 binding. However, Gb3-negative VT-resistant CHO/Jurkat cells incorporate adaGb3 to become VT1/VT2-sensitive. CarboxyadaGb3, urea-adaGb3, and hydroxyethyl adaGb3, preferentially bound by VT2, also mediate VT1/VT2 cytotoxicity. VT1/VT2 internalize to early endosomes but not to Golgi/ER. AdabisGb3 (two deacyl Gb3s linked to adamantane) protects against VT1/VT2 more effectively than adaGb3 without incorporating into Gb3-negative cells. AdaGb3 (but not hydroxyethyl adaGb3) incorporation into Gb3-positive Vero cells rendered punctate cell surface VT1/VT2 binding uniform and subverted subsequent Gb3-dependent retrograde transport to Golgi/ER to render cytotoxicity (reduced for VT1 but not VT2) brefeldin A-resistant. VT2-induced vacuolation was maintained in adaGb3-treated Vero cells, but vacuolar membrane VT2 was lost. AdaGb3 destabilized membrane cholesterol and reduced Gb3 cholesterol stabilization in phospholipid liposomes. Cholera toxin GM1-mediated Golgi/ER targeting was unaffected by adaGb3. We demonstrate the novel, lipid-dependent, pseudoreceptor function of Gb3 mimics and their structure-dependent modulation of endogenous intracellular Gb3 vesicular traffic. PMID:22418442

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilat, E.; Kadar, T.; Levy, A.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 {+-} 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsantmore » effect (53 {+-} 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.« less

Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Carl D., E-mail: carl.d.smith179.mil@mail.mil; Wright, Linnzi K.M.; Garcia, Gregory E.

Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was tomore » determine the 24-hour median lethal dose (LD{sub 50}) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD{sub 50} of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD{sub 50}s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity. - Highlights: • The LD{sub 50} of sarin was determined in female rats throughout the stages of the estrous cycle. • Females in proestrus had a significantly higher LD{sub 50} compared to estrous or ovariectomized females. • No sex differences were observed between male and female rats. • It is unlikely that plasma esterase activity underlies the observed differences in LD{sub 50}s.« less

78 FR 26669 - Self-Regulatory Organizations; EDGX Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-07

... gigabyte Copper circuit; $750 per physical port that connects to the System via a 1 gigabyte Fiber circuit; and $1,000 per physical port that connects to the System via a 10 gigabyte Fiber circuit. The Exchange... physical port that connects to the System via a 1 gigabyte Fiber circuit from $750 to $1,000; (ii) increase...

Analyzing large data sets acquired through telemetry from rats exposed to organophosphorous compounds: an EEG study.

PubMed

de Araujo Furtado, Marcio; Zheng, Andy; Sedigh-Sarvestani, Madineh; Lumley, Lucille; Lichtenstein, Spencer; Yourick, Debra

2009-10-30

The organophosphorous compound soman is an acetylcholinesterase inhibitor that causes damage to the brain. Exposure to soman causes neuropathology as a result of prolonged and recurrent seizures. In the present study, long-term recordings of cortical EEG were used to develop an unbiased means to quantify measures of seizure activity in a large data set while excluding other signal types. Rats were implanted with telemetry transmitters and exposed to soman followed by treatment with therapeutics similar to those administered in the field after nerve agent exposure. EEG, activity and temperature were recorded continuously for a minimum of 2 days pre-exposure and 15 days post-exposure. A set of automatic MATLAB algorithms have been developed to remove artifacts and measure the characteristics of long-term EEG recordings. The algorithms use short-time Fourier transforms to compute the power spectrum of the signal for 2-s intervals. The spectrum is then divided into the delta, theta, alpha, and beta frequency bands. A linear fit to the power spectrum is used to distinguish normal EEG activity from artifacts and high amplitude spike wave activity. Changes in time spent in seizure over a prolonged period are a powerful indicator of the effects of novel therapeutics against seizures. A graphical user interface has been created that simultaneously plots the raw EEG in the time domain, the power spectrum, and the wavelet transform. Motor activity and temperature are associated with EEG changes. The accuracy of this algorithm is also verified against visual inspection of video recordings up to 3 days after exposure.

Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX.

PubMed

Saxena, Ashima; Sun, Wei; Fedorko, James M; Koplovitz, Irwin; Doctor, Bhupendra P

2011-01-01

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2×LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ∼24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5×LD(50) of soman or 8×LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents. Published by Elsevier Inc.

The clock gene cycle plays an important role in the circadian clock of the cricket Gryllus bimaculatus.

PubMed

Uryu, Outa; Karpova, Svetlana G; Tomioka, Kenji

2013-07-01

To dissect the molecular oscillatory mechanism of the circadian clock in the cricket Gryllus bimaculatus, we have cloned a cDNA of the clock gene cycle (Gb'cyc) and analyzed its structure and function. Gb'cyc contains four functional domains, i.e. bHLH, PAS-A, PAS-B and BCTR domains, and is expressed rhythmically in light dark cycles, peaking at mid night. The RNA interference (RNAi) of Clock (Gb'Clk) and period (Gb'per) reduced the Gb'cyc mRNA levels and abolished the rhythmic expression, suggesting that the rhythmic expression of Gb'cyc is regulated by a mechanism including Gb'Clk and Gb'per. These features are more similar to those of mammalian orthologue of cyc (Bmal1) than those of Drosophila cyc. A single treatment with double-stranded RNA (dsRNA) of Gb'cyc effectively knocked down the Gb'cyc mRNA level and abolished its rhythmic expression. The cyc RNAi failed to disrupt the locomotor rhythm, but lengthened its free-running period in constant darkness (DD). It is thus likely that Gb'cyc is involved in the circadian clock machinery of the cricket. The cyc RNAi crickets showed a rhythmic expression of Gb'per and timeless (Gb'tim) in the optic lobe in DD, explaining the persistence of the locomotor rhythm. Surprisingly, cyc RNAi revealed a rhythmic expression of Gb'Clk in DD which is otherwise rather constitutively expressed in the optic lobe. These facts suggest that the cricket might have a unique clock oscillatory mechanism in which both Gb'cyc and Gb'Clk are rhythmically controlled and that under abundant expression of Gb'cyc the rhythmic expression of Gb'Clk may be concealed. Copyright © 2013 Elsevier Ltd. All rights reserved.

How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

PubMed

Auray-Blais, Christiane; Ntwari, Aimé; Clarke, Joe T R; Warnock, David G; Oliveira, João Paulo; Young, Sarah P; Millington, David S; Bichet, Daniel G; Sirrs, Sandra; West, Michael L; Casey, Robin; Hwu, Wuh-Liang; Keutzer, Joan M; Zhang, X Kate; Gagnon, René

2010-12-14

Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb(3)), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb(3)), is increased in patients with the disease. Until now, lyso-Gb(3) was not detectable in urine, possibly because of the presence of interfering compounds. We undertook to: 1) characterize lyso-Gb(3) in urine; 2) develop a method to quantitate urinary lyso-Gb(3) by mass spectrometry; 3) evaluate urinary lyso-Gb(3) as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb(3) is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb(3) from 83 Fabry patients and 77 healthy age-matched controls. The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb(3)/creatinine correlated with the concentrations of Gb(3) (r(2)=0.43), type of mutations (p=0.0006), gender (p<0.0001) and enzyme replacement therapy status (p=0.0012). Urine from healthy controls contained no detectable lyso-Gb(3). Lyso-Gb(3) did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb(3) of Fabry patients correlated well with a number of indicators of disease severity. Lyso-Gb(3) is a reliable independent biomarker for clinically important characteristics of Fabry disease. Copyright © 2010 Elsevier B.V. All rights reserved.

Information, Information, Information

ERIC Educational Resources Information Center

Pratt, John

2013-01-01

According to researchers at the University of Southern California (Washington Post, 2011), the world's storage capacity for digital data increased from 0.2 billion gigabytes in 1986 to 276 billion gigabytes by 2007 (at the same time analogue storage capacity increased from 2.6 to 18.9 billion gigabytes). This huge growth is often seen in…

Expression of Selected Ginkgo biloba Heat Shock Protein Genes After Cold Treatment Could Be Induced by Other Abiotic Stress

PubMed Central

Cao, Fuliang; Cheng, Hua; Cheng, Shuiyuan; Li, Linling; Xu, Feng; Yu, Wanwen; Yuan, Honghui

2012-01-01

Heat shock proteins (HSPs) play various stress-protective roles in plants. In this study, three HSP genes were isolated from a suppression subtractive hybridization (SSH) cDNA library of Ginkgo biloba leaves treated with cold stress. Based on the molecular weight, the three genes were designated GbHSP16.8, GbHSP17 and GbHSP70. The full length of the three genes were predicted to encode three polypeptide chains containing 149 amino acids (Aa), 152 Aa, and 657 Aa, and their corresponding molecular weights were predicted as follows: 16.67 kDa, 17.39 kDa, and 71.81 kDa respectively. The three genes exhibited distinctive expression patterns in different organs or development stages. GbHSP16.8 and GbHSP70 showed high expression levels in leaves and a low level in gynoecia, GbHSP17 showed a higher transcription in stamens and lower level in fruit. This result indicates that GbHSP16.8 and GbHSP70 may play important roles in Ginkgo leaf development and photosynthesis, and GbHSP17 may play a positive role in pollen maturation. All three GbHSPs were up-regulated under cold stress, whereas extreme heat stress only caused up-regulation of GbHSP70, UV-B treatment resulted in up-regulation of GbHSP16.8 and GbHSP17, wounding treatment resulted in up-regulation of GbHSP16.8 and GbHSP70, and abscisic acid (ABA) treatment caused up-regulation of GbHSP70 primarily. PMID:22754330

Cytoplasmic tail domain of glycoprotein B is essential for HHV-6 infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mahmoud, Nora F.; Faculty of Pharmacy, Suez Canal University, Ismailia; Jasirwan, Chyntia

2016-03-15

Human herpesvirus 6 (HHV-6) glycoprotein B (gB) is an abundantly expressed viral glycoprotein required for viral entry and cell fusion, and is highly conserved among herpesviruses. The present study examined the function of HHV-6 gB cytoplasmic tail domain (CTD). A gB CTD deletion mutant was constructed which, in contrast to its revertant, could not be reconstituted. Moreover, deletion of gB cytoplasmic tail impaired the intracellular transport of gB protein to the trans-Golgi network (TGN). Taken together, these results suggest that gB CTD is critical for HHV-6 propagation and important for intracellular transportation. - Highlights: • Glycoprotein B (gB) is highlymore » conserved among herpesviruses. • HHV-6 gB is also abundantly expressed in virions. • In the present study, we showed the function of HHV-6 gB cytoplasmic tail domain (CTD). • We found that deletion of gB CTD impairs the intracellular transport of gB protein to the trans-Golgi network (TGN), and CTD of gB is critical for HHV-6 propagation.« less

Dynamics of Helium-Loaded Grain Boundaries under Shear Deformation in α-Fe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Fei; Yang, Li; Heinisch, Howard L.

2014-03-30

The defects produced in collision cascades will interact with microstructural features in materials, such as GBs and dislocations. The coupled motion of GBs under stress has been widely observed in simulations and experiments. Two symmetric tilt GBs with a common <110> tilt axis (Σ3 and Σ11) in bcc iron are used to investigate the coupled motion of GBs under shear deformation. Also, we have explored the effect of self-interstitial atoms (SIAs) loading on the GB motion, with different concentrations of interstitials randomly inserted around the GB plane. The simulation results show that the interstitial loading reduces the critical stress ofmore » the GB coupled motion for the Σ3 GB. Furthermore, the interstitials and vacancies are inserted randomly at the GB plane and at a distance of 1 nm away from the GB plane, respectively, to understand the self-healing mechanism of GBs under stress. The behavior of the defect-loaded GBs depends on the GB structure. The loaded interstitials in the Σ3 GB easily form <111> interstitial clusters that do not move along with the GB. The vacancies in the Σ3 GB impede the GB motion. However, the interstitials move along with the Σ11 GB and annihilate with vacancies when the GB moves into the vacancy-rich region, leading to the self-healing and damage recovery of the Σ11 GB.« less

Symptoms of Gulf War veterans possibly exposed to organophosphate chemical warfare agents at Khamisiyah, Iraq.

PubMed

McCauley, L A; Rischitelli, G; Lambert, W E; Lasarev, M; Sticker, D L; Spencer, P S

2001-01-01

During the 1991 Gulf War, some Allied troops were potentially exposed to sarin/cyclosarin as the result of the destruction of Iraqi munitions at Khamisiyah. To evaluate the prevalence of past and current symptoms known to be associated with exposure to these chemical warfare agents, the authors conducted a computer-assisted telephone survey of 2,918 U.S. Gulf War veterans. Veterans who had participated in or witnessed the demolition in 1991 were more likely to report historical or extant symptoms than were veterans from other military units. These results should be viewed cautiously because they are based on symptoms recalled nine years after the event without precise characterization of exposure. Nonetheless, the findings suggest that symptoms consistent with low-level sarin exposure may have initially occurred, and health effects may have persisted in the veterans who were nearest to the demolition activity. Further research is warranted.

Health effects in Army Gulf War veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq: Part I. Morbidity associated with potential exposure.

PubMed

Mahan, Clare M; Page, William F; Bullman, Tim A; Kang, Han K

2005-11-01

In March 1991, U.S. troops detonated the Khamisiyah, Iraq, ammunition depot, possibly releasing two chemical warfare agents, sarin and cyclosarin. The long-term health effects associated with possible exposure to these chemical warfare agents are unknown. This study was undertaken to investigate whether possible exposure was associated with morbidity among Army Gulf War veterans using morbidity data for 5,555 Army veterans who were deployed to the Gulf region. Responses to 86 self-assessed health measures, as reported in the 1995 Department of Veterans Affairs National Health Survey of Gulf War Era Veterans, were evaluated. We found little association between potential exposure and health, after adjustment for demographic variables, and conclude that potential exposure to sarin or cyclosarin at Khamisiyah does not seem to have adversely affected self-perceived health status, as evidenced by a wide range of health measures.

Nerve-gas destruction with metal organic frameworks

EPA Science Inventory

Chemical warfare agents (CWAs) such as saran, soman, and tabun have been developed since World War I. Their mode of action involves the rapid formation of phosphate ester bonds with acetylcholinesterase to attenuate activity. The cumulative result of this activity loss leads to a...

The diagnostic accuracy of transabdominal ultrasonography needs to be considered when managing gallbladder polyps.

PubMed

French, Daniel G; Allen, Philippe D; Ellsmere, James C

2013-11-01

Transabdominal ultrasonography (TAUS) is the most commonly used modality to diagnose gallbladder (GB) disease. GB polyps are reported in 1-5.6 % of TAUS studies. Histopathologic studies suggest that there is a relationship between GB polyps and GB cancer. Previous literature suggests GB polyps reported on TAUS do not correlate well with histological findings. There have been recent advances in TAUS technology. We hypothesize the recent advances in TAUS technology have improved the accuracy of TAUS for diagnosing GB polyps. Radiology and pathology databases at our tertiary care center were retrospectively searched between January 1, 2000, and December 31, 2010. Ultrasound reports that suggested a GB polyp was present on TAUS were correlated to histopathology in cases where a cholecystectomy was performed. The pathology reports where a GB polyp was found were correlated with preoperative TAUS reports. There were 102,740 TAUS reports referring to the GB, of which 6,612 (6.4 %) contained search terms suggesting a GB polyp was present. There were 13,278 cholecystectomy pathology reports, of which 159 (1.2 %) included a diagnosis of GB polyp. TAUS detected only 50 % of the polyps identified on histopathology. The sensitivity and specificity of TAUS for diagnosing GB polyps were 50.0 and 98.3 %, respectively. The positive and negative predictive values were 10.5 and 99.8 %. Despite improvement in TAUS technology, the accuracy for GB polyps remains poor. This needs to be considered when managing patients with TAUS-detected GB polyps. We recommend that the decision to operate on TAUS-detected GB polyps be largely based on symptoms, and following GB polyps with TAUS should be discouraged.

Molecular Cloning, Characterization, and Functional Analysis of Acetyl-CoA C-Acetyltransferase and Mevalonate Kinase Genes Involved in Terpene Trilactone Biosynthesis from Ginkgo biloba.

PubMed

Chen, Qiangwen; Yan, Jiaping; Meng, Xiangxiang; Xu, Feng; Zhang, Weiwei; Liao, Yongling; Qu, Jinwang

2017-01-02

Ginkgolides and bilobalide, collectively termed terpene trilactones (TTLs), are terpenoids that form the main active substance of Ginkgo biloba . Terpenoids in the mevalonate (MVA) biosynthetic pathway include acetyl-CoA C -acetyltransferase (AACT) and mevalonate kinase (MVK) as core enzymes. In this study, two full-length (cDNAs) encoding AACT ( GbAACT , GenBank Accession No. KX904942) and MVK ( GbMVK , GenBank Accession No. KX904944) were cloned from G. biloba . The deduced GbAACT and GbMVK proteins contain 404 and 396 amino acids with the corresponding open-reading frame (ORF) sizes of 1215 bp and 1194 bp, respectively. Tissue expression pattern analysis revealed that GbAACT was highly expressed in ginkgo fruits and leaves, and GbMVK was highly expressed in leaves and roots. The functional complementation of GbAACT in AACT-deficient Saccharomyces cerevisiae strain Δerg10 and GbMVK in MVK-deficient strain Δerg12 confirmed that GbAACT mediated the conversion of mevalonate acetyl-CoA to acetoacetyl-CoA and GbMVK mediated the conversion of mevalonate to mevalonate phosphate. This observation indicated that GbAACT and GbMVK are functional genes in the cytosolic mevalonate (MVA) biosynthesis pathway. After G. biloba seedlings were treated with methyl jasmonate and salicylic acid, the expression levels of GbAACT and GbMVK increased, and TTL production was enhanced. The cloning, characterization, expression and functional analysis of GbAACT and GbMVK will be helpful to understand more about the role of these two genes involved in TTL biosynthesis.

Capacities of metabotropic glutamate modulators in counteracting soman-induced seizures in rats.

PubMed

Myhrer, Trond; Mariussen, Espen; Enger, Siri; Aas, Pål

2013-10-15

Current treatment of nerve agent poisoning with ionotropic drugs proves inadequate, and alternative treatment strategies are searched for. Based on positive findings with metabotropic glutamate modulators in microinfusion studies, the present study was initiated to examine anticonvulsant effects of MPEP (2-Methyl-6-(phenylethynyl)pyridine hydrochloride), a metabotropic glutamate receptor 5 antagonist, and DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine), a metabotropic glutamate receptor 2/3 agonist, when administered systemically in combinations with HI-6 (1-[([4-(aminocarbonyl)pyridino]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium) and procyclidine or HI-6 and levetiracetam relative to the combination of HI-6, procyclidine, and levetiracetam. The results showed that MPEP or DCG-IV combined with HI-6 and procyclidine resulted in substantial antidotal efficacy when administered 20 min after onset of seizures elicited by soman. MPEP or DCG-IV combined with HI-6 and levetiracetam did not terminate seizures and preserve lives. When given 20 min before challenge with soman, DCG-IV in combination with HI-6 and procyclidine provided protection, whereas MPEP combined with HI-6 and procyclidine did not. Combinations with metabotropic glutamate receptor modulators did not achieve the same high level of antidotal efficacy as the combination of HI-6, procyclidine, and levetiracetam. MPEP alone inhibited pseudocholinesterase activity in the brain markedly. A positive correlation was found between latency to seizure onset or full protection and level of pseudocholinesterase activity in brain. MPEP and DCG-IV can serve as effective anticonvulsants against nerve agent poisoning when combined with HI-6 and procyclidine. Metabotropic glutamate receptor modulators may represent an alternative or supplement to treatment with ionotropic drugs. © 2013 Elsevier B.V. All rights reserved.

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

PubMed Central

Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.; Braga, Maria F.M.

2015-01-01

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2XLD50), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. PMID:25689173

78 FR 26667 - Self-Regulatory Organizations; EDGA Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-07

... per physical port that connects to the System via a 1 gigabyte Fiber circuit; and $1,000 per physical port that connects to the System via a 10 gigabyte Fiber circuit. The Exchange proposes to amend its... that connects to the System via a 1 gigabyte Fiber circuit from $750 to $1,000; (ii) increase the...

Analysis of RNA-Seq data reveals involvement of JAK/STAT signalling during leg regeneration in the cricket Gryllus bimaculatus.

PubMed

Bando, Tetsuya; Ishimaru, Yoshiyasu; Kida, Takuro; Hamada, Yoshimasa; Matsuoka, Yuji; Nakamura, Taro; Ohuchi, Hideyo; Noji, Sumihare; Mito, Taro

2013-03-01

In the cricket Gryllus bimaculatus, missing distal parts of the amputated leg are regenerated from the blastema, a population of dedifferentiated proliferating cells that forms at the distal tip of the leg stump. To identify molecules involved in blastema formation, comparative transcriptome analysis was performed between regenerating and normal unamputated legs. Components of JAK/STAT signalling were upregulated more than twofold in regenerating legs. To verify their involvement, Gryllus homologues of the interleukin receptor Domeless (Gb'dome), the Janus kinase Hopscotch (Gb'hop) and the transcription factor STAT (Gb'Stat) were cloned, and RNAi was performed against these genes. Gb'dome(RNAi), Gb'hop(RNAi) and Gb'Stat(RNAi) crickets showed defects in leg regeneration. Blastema expression of Gb'cyclinE was decreased in the Gb'Stat(RNAi) cricket compared with that in the control. Hyperproliferation of blastema cells caused by Gb'fat(RNAi) or Gb'warts(RNAi) was suppressed by RNAi against Gb'Stat. The results suggest that JAK/STAT signalling regulates blastema cell proliferation during leg regeneration.

Ice elevation change from Swath Processing of CryoSat SARIn Mode Data

NASA Astrophysics Data System (ADS)

Foresta, Luca; Gourmelen, Noel; Shepherd, Andrew; Muir, Alan; Nienow, Pete

2015-04-01

Reference and repeat-observations of Glacier and Ice Sheet Margin (GISM) topography are critical to identify changes in ice elevation, provide estimates of mass gain or loss and thus quantify the contribution of the cryosphere to sea level rise (e.g. McMillan et al., 2014). The Synthetic Interferometric Radar Altimeter (SIRAL) onboard the ESA radar altimetry CryoSat (CS) mission has collected ice elevation measurements since 2010. The corresponding SARIn mode of operation, activated over GISM areas, provides high spatial resolution in the along-track direction while resolving the angular origin of echoes (i.e. across-track). The current ESA SARIn processor calculates the elevation of the Point Of Closest Approach (POCA) within each waveform and maps of elevation change in Antarctica and Greenland have been produced using the regular CS height product (McMillan et al., 2014; Helm et al., 2014). Data from the CS-SARIn mode has also been used to produce measurements of ice elevation beyond the POCA, also known as swath elevation (Hawley et al. 2009; Gray et al., 2013; ESA-STSE CryoTop project). Here we use the swath processing approach to generate maps of ice elevation change from selected regions around the margins of the Greenland and Antarctic Ice Sheets. We discuss the impact of the swath processing on the spatial resolution and precision of the resulting ice elevation field and compare our results to current dh/dt estimates. References: ESA STSE CryoTop project - http://www.stse-cryotop.org/ Gray L., Burgess D., Copland L., Cullen R., Galin N., Hawley R. and Helm V. Interferometric swath processing of Cryosat data for glacial ice topography. The Cryosphere, 7(6):1857-1867, December 2013. Hawley R.L., Shepherd A., Cullen R., Helm V. and WIngham D.J. Ice-sheet elevations from across-track processing of airborne interferometric radar altimetry. Geophysical Research Letters, 36(22):L22501, November 2009. Helm V., Humbert A. and Miller H. Elevation and elevation change of Greenland and Antarctica derived from CryoSat-2. The Cryosphere, 8(4):1539-1559, August 2014. McMillan M., Shepherd A., Sundal A., Briggs K., Muir A., Ridout A., Hogg A. and Wingham D. Increased ice losses from Antarctica detected by CryoSat-2. Geophysical Research Letters, pages 3899-3905, 2014.

The performance of the Hydromorphological Index of Diversity (HMID) in a hydropower affected meandering river

NASA Astrophysics Data System (ADS)

Stähly, Severin; Bourqui, Pierre; Franca, Mario J.; Robinson, Christopher; Schleiss, Anton J.

2016-04-01

More than half of the Swiss electricity is produced by hydropower. Large price fluctuations cause severe hydropeaking flow regimes due to corresponding production fluctuations, which undisputedly have a negative impact on aquatic biota. Water diversion due to dams on the other hand imposes downstream residual flow regimes. The absence of flood events and regular sediment supply disrupts sediment dynamics and disconnects floodplains, which are habitats of high value, from its main channel. The residual-flow controlled reach at the Sarine river in western Switzerland is the subject of the present study. The Sarine meanders strongly and the river reach under analysis has a bed incision of locally more than 100 m. Its incision provokes the isolation of the river which is consequently minimally touched by human structures and shows a natural geomorphology. Since the construction of a dam upstream this reach in 1948, aiming at the water abstraction to hydropower, vegetation could establish and the active floodplain decreased its area, as airborne images show. Nevertheless, it is classified as a floodplain of national importance and it has been under protection since 1992. It is supposed to be a valuable habitat for a wide range of organisms. The Hydromorphological Index of Diversity (HMID) is a simple tool for quantifying the habitat richness in a river reach, taking into account the mean values and the variation of water depth and flow velocity. For channelized rivers, HMID values from up to 5 are expected, while morphological pristine sites with a high spatial variability of water depth and velocity show values of 9 or higher. For the residual flow of the Sarine River, flow depth and velocity were measured using ADCP and ADV. The results are compared with a nearby natural reference river and the outcome of a 2D numerical simulation. Finally, the behaviour and limitations of the HMID, in a hydropower affected river, are discussed. In the close future an artificial flood is expected in the Sarine in order to reactivate the sediment dynamics. Using 2D numerical simulations in combination with a well understanding of the HMID an optimal planning of this event will be implemented. The present study is financed by the Swiss National Foundation (SNF), National Research Project 70, Energy Turnaround.

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

DTIC Science & Technology

1989-07-30

i.e., oxotremorine, pilocarpine, carbachol , physostigmine [Olney et al., 1983]). These are some of the same regions affected by soman-induced...Diehl et al., 1984). Carbachol kindling also has been reported (Wasterlain, 1989), linking the cholinergic system to an increase in the sensitivity to

Protective effects of aerosolized scopolamine against soman-induced acute respiratory toxicity in guinea pigs.

PubMed

Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Song, Jian; Oguntayo, Samuel; Morthole, Venee; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2011-12-01

The protective efficacy of the antimuscarinic agent scopolamine was evaluated against soman (o-pinacolyl methylphosphonofluoridate [GD])-induced respiratory toxicity in guinea pigs. Anesthetized animals were exposed to GD (841 mg/m(3)) by microinstillation inhalation exposure and treated 30 seconds later with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 hours. Treatment with scopolamine significantly increased survival and reduced clinical signs of toxicity and body weight loss in GD-exposed animals. Analysis of bronchoalveolar lavage (BAL) fluid showed normalization of GD-induced increased cell death, total cell count, and protein following scopolamine treatment. The BAL fluid acetylcholinesterase and butyrylcholinesterase levels were also increased by scopolamine treatment. Respiratory dynamics parameters were normalized at 4 and 24 hours post-GD exposure in scopolamine-treated animals. Lung histology showed that scopolamine treatment reduced bronchial epithelial and subepithelial inflammation and multifocal alveolar septal edema. These results suggest that aerosolized scopolamine considerably protects against GD-induced respiratory toxicity.

Percutaneous toxicity and decontamination of soman, VX, and paraoxon in rats using detergents.

PubMed

Misík, Jan; Pavliková, Růžena; Kuča, Kamil

2013-06-01

Highly toxic organophosphorus compounds (OPs) were originally developed for warfare or as agricultural pesticides. Today, OPs represent a serious threat to military personnel and civilians. This study investigates the in vivo decontamination of male Wistar rats percutaneously exposed to paraoxon and two potent nerve agents--soman (GD) and VX. Four commercial detergents were tested as decontaminants--Neodekont(TM), Argos(TM), Dermogel(TM), and FloraFree(TM). Decontamination performed 2 min after exposure resulted in a higher survival rate in comparison with non-decontaminated controls. The decontamination effectiveness was expressed as protective ratio (PR, median lethal dose of agent in decontaminated animals divided by the median lethal dose of agent in untreated animals). The highest decontamination effectiveness was consistently achieved with Argos(TM) (PR=2.3 to 64.8), followed by Dermogel(TM) (PR=2.4 to 46.1). Neodekont(TM) and FloraFree(TM) provided the lowest decontamination effectiveness, equivalent to distilled water (PR=1.0 to 43.2).

Species differences in the negative inotropic effect of acetylcholine and soman in rat, guinea pig, and rabbit hearts. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maxwell, D.M.; Thomsen, R.H.; Baskin, S.I.

1991-12-31

Acetylcholine reduced atrial contractions by 82.5% in guinea pig, 50.8% in rat, and 41.5% in rabbit. 2. The EC50, values for the negative inotropic effect of acetylcholine were 3.3 x 10(-7) M in rat and guinea pig atria and 4.1 x 10(-6) M in rabbit atria. 3. There was no correlation between the species differences in the negative inotropic effect of acetylcholine in atria and the density or affinity of acetylcholinesterase or muscarinic receptors. 4. Inhibition of atrial acetylcholinesterase with soman reduced the EC50 of acetylcholine three-fold in all species, but did not change the maximal inotropic effect of acetylcholine.more » 5. Species differences in the negative inotropic effect of acetylcholine may be caused by differences in the coupling between myocardial muscarinic receptors and the ion channels that mediate negative inotropy. Acetylcholine, cardiovascular response, species variation negative inotropic response.« less

Role of glutamate-199 in the aging of cholinesterase. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saxena, A.; Doctor, B.P.; Maxwell, D.M.

1993-11-30

Aging of organophosphate-conjugated acetylcholinesterase results from the loss of an alkoxy group with concomitant stabilization of the conjugate to spontaneous or nucleophile-induced deacylation. We have examined the kinetics of aging in a pinacolylmethylphosphonofluoridate (soman)-inhibited mutant enzyme in which the glutamate (E199) located at the amino-terminal to the active-site sense (S200) was converted to glutamine (Q). For wild type enzyme, the soman-acetylcholinesterase conjugate aged immediately, giving rise to a form of enzyme resistant to reactivation by oximes. In contrast, the E199Q mutant enzyme was largely resistant to aging and could be reactivated by oximes. Since the pH dependence for aging wasmore » not altered appreciably, the primary influence of the loss of charge appears to be on the intrinsic rate of aging. The negative charge on E199 likely imparts an inductive effect on the conjugated organophosphate to facilitate removal of the alkoxy group. Cholinesterases, Aging, Organophosphate.« less

Genome Information Broker (GIB): data retrieval and comparative analysis system for completed microbial genomes and more

PubMed Central

Fumoto, Masaki; Miyazaki, Satoru; Sugawara, Hideaki

2002-01-01

Genome Information Broker (GIB) is a powerful tool for the study of comparative genomics. GIB allows users to retrieve and display partial and/or whole genome sequences together with the relevant biological annotation. GIB has accumulated all the completed microbial genome and has recently been expanded to include Arabidopsis thaliana genome data from DDBJ/EMBL/GenBank. In the near future, hundreds of genome sequences will be determined. In order to handle such huge data, we have enhanced the GIB architecture by using XML, CORBA and distributed RDBs. We introduce the new GIB here. GIB is freely accessible at http://gib.genes.nig.ac.jp/. PMID:11752256

Mapping regions of Epstein-Barr virus (EBV) glycoprotein B (gB) important for fusion function with gH/gL

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plate, Aileen E.; Reimer, Jessica J.; Jardetzky, Theodore S.

Glycoproteins gB and gH/gL are required for entry of Epstein-Barr virus (EBV) into cells, but the role of each glycoprotein and how they function together to mediate fusion is unclear. Analysis of the functional homology of gB from the closely related primate gammaherpesvirus, rhesus lymphocryptovirus (Rh-LCV), showed that EBV gB could not complement Rh gB due to a species-specific dependence between gB and gL. To map domains of gB required for this interaction, we constructed a panel of EBV/Rh gB chimeric proteins. Analysis showed that insertion of Rh gB from residues 456 to 807 restored fusion function of EBV gBmore » with Rh gH/gL, suggesting this region of gB is important for interaction with gH/gL. Split YFP bimolecular complementation (BiFC) provided evidence of an interaction between EBV gB and gH/gL. Together, our results suggest the importance of a gB-gH/gL interaction in EBV-mediated fusion with B cells requiring the region of EBV gB from 456 to 807.« less

Molecular cloning and characterization of three genes encoding dihydroflavonol-4-reductase from Ginkgo biloba in anthocyanin biosynthetic pathway.

PubMed

Hua, Cheng; Linling, Li; Shuiyuan, Cheng; Fuliang, Cao; Feng, Xu; Honghui, Yuan; Conghua, Wu

2013-01-01

Dihydroflavonol-4-reductase (DFR, EC1.1.1.219) catalyzes a key step late in the biosynthesis of anthocyanins, condensed tannins (proanthocyanidins), and other flavonoids important to plant survival and human nutrition. Three DFR cDNA clones (designated GbDFRs) were isolated from the gymnosperm Ginkgo biloba. The deduced GbDFR proteins showed high identities to other plant DFRs, which form three distinct DFR families. Southern blot analysis showed that the three GbDFRs each belong to a different DFR family. Phylogenetic tree analysis revealed that the GbDFRs share the same ancestor as other DFRs. The expression of the three recombinant GbDFRs in Escherichia coli showed that their actual protein sizes were in agreement with predictions from the cDNA sequences. The recombinant proteins were purified and their activity was analyzed; both GbDFR1 and GbDFR3 could catalyze dihydroquercetin conversion to leucocyanidin, while GbDFR2 catalyzed dihydrokaempferol conversion to leucopelargonidin. qRT-PCR showed that the GbDFRs were expressed in a tissue-specific manner, and transcript accumulation for the three genes was highest in young leaves and stamens. These transcription patterns were in good agreement with the pattern of anthocyanin accumulation in G.biloba. The expression profiles suggested that GbDFR1 and GbDFR2 are mainly involved in responses to plant hormones, environmental stress and damage. During the annual growth cycle, the GbDFRs were significantly correlated with anthocyanin accumulation in leaves. A fitted linear curve showed the best model for relating GbDFR2 and GbDFR3 with anthocyanin accumulation in leaves. GbDFR1 appears to be involved in environmental stress response, while GbDFR3 likely has primary functions in the synthesis of anthocyanins. These data revealed unexpected properties and differences in three DFR proteins from a single species.

Molecular Cloning and Characterization of Three Genes Encoding Dihydroflavonol-4-Reductase from Ginkgo biloba in Anthocyanin Biosynthetic Pathway

PubMed Central

Hua, Cheng; Linling, Li; Shuiyuan, Cheng; Fuliang, Cao; Feng, Xu; Honghui, Yuan; Conghua, Wu

2013-01-01

Dihydroflavonol-4-reductase (DFR, EC1.1.1.219) catalyzes a key step late in the biosynthesis of anthocyanins, condensed tannins (proanthocyanidins), and other flavonoids important to plant survival and human nutrition. Three DFR cDNA clones (designated GbDFRs) were isolated from the gymnosperm Ginkgo biloba. The deduced GbDFR proteins showed high identities to other plant DFRs, which form three distinct DFR families. Southern blot analysis showed that the three GbDFRs each belong to a different DFR family. Phylogenetic tree analysis revealed that the GbDFRs share the same ancestor as other DFRs. The expression of the three recombinant GbDFRs in Escherichia coli showed that their actual protein sizes were in agreement with predictions from the cDNA sequences. The recombinant proteins were purified and their activity was analyzed; both GbDFR1 and GbDFR3 could catalyze dihydroquercetin conversion to leucocyanidin, while GbDFR2 catalyzed dihydrokaempferol conversion to leucopelargonidin. qRT-PCR showed that the GbDFRs were expressed in a tissue-specific manner, and transcript accumulation for the three genes was highest in young leaves and stamens. These transcription patterns were in good agreement with the pattern of anthocyanin accumulation in G.biloba. The expression profiles suggested that GbDFR1 and GbDFR2 are mainly involved in responses to plant hormones, environmental stress and damage. During the annual growth cycle, the GbDFRs were significantly correlated with anthocyanin accumulation in leaves. A fitted linear curve showed the best model for relating GbDFR2 and GbDFR3 with anthocyanin accumulation in leaves. GbDFR1 appears to be involved in environmental stress response, while GbDFR3 likely has primary functions in the synthesis of anthocyanins. These data revealed unexpected properties and differences in three DFR proteins from a single species. PMID:23991027

Homeostasis and catabolism of choline and glycine betaine: lessons from Pseudomonas aeruginosa.

PubMed

Wargo, Matthew J

2013-04-01

Most sequenced bacteria possess mechanisms to import choline and glycine betaine (GB) into the cytoplasm. The primary role of choline in bacteria appears to be as the precursor to GB, and GB is thought to primarily act as a potent osmoprotectant. Choline and GB may play accessory roles in shaping microbial communities, based on their limited availability and ability to enhance survival under stress conditions. Choline and GB enrichment near eukaryotes suggests a role in the chemical relationships between these two kingdoms, and some of these interactions have been experimentally demonstrated. While many bacteria can convert choline to GB for osmoprotection, a variety of soil- and water-dwelling bacteria have catabolic pathways for the multistep conversion of choline, via GB, to glycine and can thereby use choline and GB as sole sources of carbon and nitrogen. In these choline catabolizers, the GB intermediate represents a metabolic decision point to determine whether GB is catabolized or stored as an osmo- and stress protectant. This minireview focuses on this decision point in Pseudomonas aeruginosa, which aerobically catabolizes choline and can use GB as an osmoprotectant and a nutrient source. P. aeruginosa is an experimentally tractable and ecologically relevant model to study the regulatory pathways controlling choline and GB homeostasis in choline-catabolizing bacteria. The study of P. aeruginosa associations with eukaryotes and other bacteria also makes this a powerful model to study the impact of choline and GB, and their associated regulatory and catabolic pathways, on host-microbe and microbe-microbe relationships.

Shear response of grain boundaries with metastable structures by molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Zhang, Liang; Lu, Cheng; Shibuta, Yasushi

2018-04-01

Grain boundaries (GBs) can play a role as the favored locations to annihilate point defects, such as interstitial atoms and vacancies. It is thus highly probable that different boundary structures can be simultaneously present in equilibrium with each other in the same GB, and thus the GB achieves a metastable state. However, the structural transition and deformation mechanism of such GBs are currently not well understood. In this work, molecular dynamics simulations were carried out to study the multiple structures of a Σ5(310)/[001] GB in bicrystal Al and to investigate the effect of structural multiplicity on the mechanical and kinetic properties of such a GB. Different GB structures were obtained by changing the starting atomic configuration of the bicrystal model, and the GB structures had significantly different atomic density. For the Σ5(310) GB with metastable structures, GB sliding was the dominant mechanism at a low temperature (T = 10 K) under shear stress. The sliding mechanism resulted from the uncoordinated transformation of the inhomogeneous structural units. The nucleation of voids was observed during GB sliding at the low temperature, and the voids subsequently evolved to a nanocrack at the boundary plane. Increasing the temperature can induce the structural transition of local GB structures and can change their overall kinetic properties. GB migration with occasional GB sliding dominated the deformation mechanism at elevated temperatures (T = 300 and 600 K), and the migration process of the metastable GB structures is closely related to the thermally assisted diffusion mechanism.

Analysis of globotriaosylceramide (Gb3) isoforms/analogs in unfractionated leukocytes, B lymphocytes and monocytes from Fabry patients using ultra-high performance liquid chromatography/tandem mass spectrometry.

PubMed

Toupin, Amanda; Lavoie, Pamela; Arthus, Marie-Françoise; Abaoui, Mona; Boutin, Michel; Fortier, Carole; Ménard, Claudia; Bichet, Daniel G; Auray-Blais, Christiane

2018-07-26

Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb 3 ) isoforms/analogs, globotriaosylsphingosine (lyso-Gb 3 ) and analogs, and galabiosylceramide (Ga 2 ) isoforms/analogs may accumulate in biological fluids and different organs. The aims of this study were to: 1) develop/validate a novel UHPLC-MS/MS method for relative quantitation of Gb 3 in leukocytes (unfractionated white blood cells), B lymphocytes and monocytes; 2) evaluate these biomarkers in a cohort of Fabry patients and healthy controls; and 3) assess correlations between these biomarkers, treatment and genotype. Whole blood, plasma and urine samples from 21 Fabry patients and 20 healthy controls were analyzed. Samples were purified by liquid-liquid extraction and analyzed by UHPLC-MS/MS in positive electrospray ionization. Methylated Gb 3 isoforms were detected, showing that a methylation process occurs at the cellular level. Our results show that there were no significant differences in the distribution of the different Gb 3 isoforms/analogs in blood cells between Fabry patients and healthy controls. In leukocyte, Gb 3 [(d18:1)(C14:0)], Gb 3 [(d18:1)(C16:0)], Gb 3 [(d18:1)(C16:0)]Me, Gb 3 [(d18:1)(C16:1)], Gb 3 [(d18:1)(C18:0)], Gb 3 [(d18:1)(C18:1)], Gb 3 [(d18:1)(C20:1)], Gb 3 [(d18:1)(C24:2)], Gb 3 [(d18:1)(C26:1)] and total Gb 3 allowed good discrimination between male Fabry patients and male controls, patients having higher biomarker levels than controls. Regarding B lymphocytes and monocytes, the same tendency was observed without reaching statistical significance. A positive concordance between mutation types and biomarker levels in white blood cells was established. Our results might provide a deeper mechanistic comprehension of the underlying biochemical processes of Gb 3 biomarkers in white blood cells of Fabry patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional Fluorescent Protein Insertions in Herpes Simplex Virus gB Report on gB Conformation before and after Execution of Membrane Fusion

PubMed Central

Gallagher, John R.; Atanasiu, Doina; Saw, Wan Ting; Paradisgarten, Matthew J.; Whitbeck, J. Charles; Eisenberg, Roselyn J.; Cohen, Gary H.

2014-01-01

Entry of herpes simplex virus (HSV) into a target cell requires complex interactions and conformational changes by viral glycoproteins gD, gH/gL, and gB. During viral entry, gB transitions from a prefusion to a postfusion conformation, driving fusion of the viral envelope with the host cell membrane. While the structure of postfusion gB is known, the prefusion conformation of gB remains elusive. As the prefusion conformation of gB is a critical target for neutralizing antibodies, we set out to describe its structure by making genetic insertions of fluorescent proteins (FP) throughout the gB ectodomain. We created gB constructs with FP insertions in each of the three globular domains of gB. Among 21 FP insertion constructs, we found 8 that allowed gB to remain membrane fusion competent. Due to the size of an FP, regions in gB that tolerate FP insertion must be solvent exposed. Two FP insertion mutants were cell-surface expressed but non-functional, while FP insertions located in the crown were not surface expressed. This is the first report of placing a fluorescent protein insertion within a structural domain of a functional viral fusion protein, and our results are consistent with a model of prefusion HSV gB constructed from the prefusion VSV G crystal structure. Additionally, we found that functional FP insertions from two different structural domains could be combined to create a functional form of gB labeled with both CFP and YFP. FRET was measured with this construct, and we found that when co-expressed with gH/gL, the FRET signal from gB was significantly different from the construct containing CFP alone, as well as gB found in syncytia, indicating that this construct and others of similar design are likely to be powerful tools to monitor the conformation of gB in any model system accessible to light microscopy. PMID:25233449

The Effects of Repeated Low-Dose Sarin Exposure

DTIC Science & Technology

2006-01-01

Scientific (Pittsburgh, PA). Neostig- negative for the presence of agitation, chewing, tremors, facial dysmorphia , and mine bromide, acetylcholine chloride...no Chewing -- yes -no Facial Dysmorphia .--. yes -no Tremors ._...yes -no Vocalizations ... yes -no Animal handling Ease of removal from cage: (R

Human Serum Butyrylcholinesterase: A Bioscavenger for the Protection of Humans from Organophosphorus Exposure

DTIC Science & Technology

2009-10-01

Current medical countermeasures against OP nerve agent poisoning include a combination of pretreatment with a carbamate, pyridostigmine bromide , to...The protection of primates against soman poisoning by pretreatment with pyridostigmine , J. Pharm. Pharmacol. 31 (1979) 295-299. [2] C.G. McLeod

Risk score to predict gastrointestinal bleeding after acute ischemic stroke.

PubMed

Ji, Ruijun; Shen, Haipeng; Pan, Yuesong; Wang, Penglian; Liu, Gaifen; Wang, Yilong; Li, Hao; Singhal, Aneesh B; Wang, Yongjun

2014-07-25

Gastrointestinal bleeding (GIB) is a common and often serious complication after stroke. Although several risk factors for post-stroke GIB have been identified, no reliable or validated scoring system is currently available to predict GIB after acute stroke in routine clinical practice or clinical trials. In the present study, we aimed to develop and validate a risk model (acute ischemic stroke associated gastrointestinal bleeding score, the AIS-GIB score) to predict in-hospital GIB after acute ischemic stroke. The AIS-GIB score was developed from data in the China National Stroke Registry (CNSR). Eligible patients in the CNSR were randomly divided into derivation (60%) and internal validation (40%) cohorts. External validation was performed using data from the prospective Chinese Intracranial Atherosclerosis Study (CICAS). Independent predictors of in-hospital GIB were obtained using multivariable logistic regression in the derivation cohort, and β-coefficients were used to generate point scoring system for the AIS-GIB. The area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration, respectively. A total of 8,820, 5,882, and 2,938 patients were enrolled in the derivation, internal validation and external validation cohorts. The overall in-hospital GIB after AIS was 2.6%, 2.3%, and 1.5% in the derivation, internal, and external validation cohort, respectively. An 18-point AIS-GIB score was developed from the set of independent predictors of GIB including age, gender, history of hypertension, hepatic cirrhosis, peptic ulcer or previous GIB, pre-stroke dependence, admission National Institutes of Health stroke scale score, Glasgow Coma Scale score and stroke subtype (Oxfordshire). The AIS-GIB score showed good discrimination in the derivation (0.79; 95% CI, 0.764-0.825), internal (0.78; 95% CI, 0.74-0.82) and external (0.76; 95% CI, 0.71-0.82) validation cohorts. The AIS-GIB score was well calibrated in the derivation (P = 0.42), internal (P = 0.45) and external (P = 0.86) validation cohorts. The AIS-GIB score is a valid clinical grading scale to predict in-hospital GIB after AIS. Further studies on the effect of the AIS-GIB score on reducing GIB and improving outcome after AIS are warranted.

Comparative Analysis of Glycoprotein B (gB) of Equine Herpesvirus Type 1 and Type 4 (EHV-1 and EHV-4) in Cellular Tropism and Cell-to-Cell Transmission

PubMed Central

Spiesschaert, Bart; Osterrieder, Nikolaus; Azab, Walid

2015-01-01

Glycoprotein B (gB) plays an important role in alphaherpesvirus cellular entry and acts in concert with gD and the gH/gL complex. To evaluate whether functional differences exist between gB1 and gB4, the corresponding genes were exchanged between the two viruses. The gB4-containing-EHV-1 (EHV-1_gB4) recombinant virus was analyzed for growth in culture, cell tropism, and cell entry rivaling no significant differences when compared to parental virus. We also disrupted a potential integrin-binding motif, which did not affect the function of gB in culture. In contrast, a significant reduction of plaque sizes and growth kinetics of gB1-containing-EHV-4 (EHV-4_gB1) was evident when compared to parental EHV-4 and revertant viruses. The reduction in virus growth may be attributable to the loss of functional interaction between gB and the other envelope proteins involved in virus entry, including gD and gH/gL. Alternatively, gB4 might have an additional function, required for EHV-4 replication, which is not fulfilled by gB1. In conclusion, our results show that the exchange of gB between EHV-1 and EHV-4 is possible, but results in a significant attenuation of virus growth in the case of EHV-4_gB1. The generation of stable recombinant viruses is a valuable tool to address viral entry in a comparative fashion and investigate this aspect of virus replication further. PMID:25654240

Characterization of gastrointestinal hemorrhage and prediction of mortality in Asian patients with alcoholic hepatitis.

PubMed

Kim, Su Hwan; Kim, Byeong Gwan; Kim, Won; Oh, Sohee; Kim, Hwi Young; Jung, Yong Jin; Jeong, Ji Bong; Kim, Ji Won; Lee, Kook Lae

2016-04-01

Gastrointestinal bleeding (GIB) often accompanies alcoholic hepatitis (AH). The study aimed to investigate clinical characteristics of GIB in AH patients and to identify risk factors for mortality in AH patients with GIB. Data from 329 patients hospitalized with AH in a single center during 1999-2014 were retrospectively analyzed. Patients with AH were dichotomized into GIB and non-GIB groups. The GIB group was further divided into portal hypertensive bleeding (PHB) and non-PHB groups. Clinical characteristics and survival outcomes were compared between the groups. Risk factors for mortality were analyzed using Cox regression. Among the 329 AH patients, 132 experienced GIB at admission or during hospitalization. The most common cause of GIB was an esophageal varix. The GIB group had worse survival outcomes than the non-GIB group (log-rank test, P = 0.034). The PHB group had worse survival outcomes than the non-PHB group (log-rank test, P = 0.001). On multivariate analysis, alcohol consumption, ascites, encephalopathy, infection, Maddrey's discriminant function, and the model for end-stage liver disease (MELD) score independently predicted mortality in the entire AH cohort. The MELD score (hazard ratio, 1.085; 95% confidence interval, 1.052-1.120; P < 0.001) and PHB (hazard ratio, 2.162; 95% confidence interval, 1.021-4.577; P = 0.044) were significant prognosticators for patients with AH and GIB. The presence of PHB and a higher MELD score adversely affected survival in AH patients with GIB. Accordingly, prompt endoscopic examination for exploring the etiologies of GIB may alert physicians to predict the risk of death in AH patients with GIB. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Shear-coupled grain-boundary migration dependence on normal strain/stress

NASA Astrophysics Data System (ADS)

Combe, N.; Mompiou, F.; Legros, M.

2017-08-01

In specific conditions, grain-boundary (GB) migration occurs in polycrystalline materials as an alternative vector of plasticity compared to the usual dislocation activity. The shear-coupled GB migration, the expected most efficient GB based mechanism, couples the GB motion to an applied shear stress. Stresses on GB in polycrystalline materials seldom have, however, a unique pure shear component. This work investigates the influence of a normal strain on the shear coupled migration of a Σ 13 (320 )[001 ] GB in a copper bicrystal using atomistic simulations. We show that the yield shear stress inducing the GB migration strongly depends on the applied normal stress. Beyond, the application of a normal stress on this GB qualitatively modifies the GB migration: while the Σ 13 (320 )[001 ] GB shear couples following the 〈110 〉 migration mode without normal stress, we report the observation of the 〈010 〉 mode under a sufficiently high tensile normal stress. Using the nudge elastic band method, we uncover the atomistic mechanism of this 〈010 〉 migration mode and energetically characterize it.

Dynamics of defect-loaded grain boundary under shear deformation in alpha iron

NASA Astrophysics Data System (ADS)

Yang, L.; Zhou, H. L.; Liu, H.; Gao, F.; Zu, X. T.; Peng, S. M.; Long, X. G.; Zhou, X. S.

2018-02-01

Two symmetric tilt grain boundaries (GBs) (Σ3〈110〉{112} and Σ11〈110〉{332}) in alpha iron were performed to investigate the dynamics of defect-loaded GBs under shear deformation. The results show that the loaded self-interstitial atoms (SIAs) reduce the critical stress of the coupled GB motion in the Σ3 GB, but increase the critical stress in the Σ11 GB. The loaded SIAs in the Σ3 GB easily form 〈111〉 clusters and remain in the bulk when the GB moves away. However, the SIAs move along with the Σ11 GB and combine with the vacancies in the bulk, leading to the defect self-healing. The helium (He) atoms loaded into the GBs significantly affect the coupled GB motion. Once He clusters emit interstitials, the Σ11 GB carries those interstitials away but the Σ3 does not. The loaded He atoms reduce the critical stress of the Σ3 GB, but increase the critical stress of the Σ11 GB.

Homeostasis and Catabolism of Choline and Glycine Betaine: Lessons from Pseudomonas aeruginosa

PubMed Central

2013-01-01

Most sequenced bacteria possess mechanisms to import choline and glycine betaine (GB) into the cytoplasm. The primary role of choline in bacteria appears to be as the precursor to GB, and GB is thought to primarily act as a potent osmoprotectant. Choline and GB may play accessory roles in shaping microbial communities, based on their limited availability and ability to enhance survival under stress conditions. Choline and GB enrichment near eukaryotes suggests a role in the chemical relationships between these two kingdoms, and some of these interactions have been experimentally demonstrated. While many bacteria can convert choline to GB for osmoprotection, a variety of soil- and water-dwelling bacteria have catabolic pathways for the multistep conversion of choline, via GB, to glycine and can thereby use choline and GB as sole sources of carbon and nitrogen. In these choline catabolizers, the GB intermediate represents a metabolic decision point to determine whether GB is catabolized or stored as an osmo- and stress protectant. This minireview focuses on this decision point in Pseudomonas aeruginosa, which aerobically catabolizes choline and can use GB as an osmoprotectant and a nutrient source. P. aeruginosa is an experimentally tractable and ecologically relevant model to study the regulatory pathways controlling choline and GB homeostasis in choline-catabolizing bacteria. The study of P. aeruginosa associations with eukaryotes and other bacteria also makes this a powerful model to study the impact of choline and GB, and their associated regulatory and catabolic pathways, on host-microbe and microbe-microbe relationships. PMID:23354714

Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

DTIC Science & Technology

2011-08-01

evaluated alone and in combination (i.e. pyridostigmine bromide (PB), diethyl-m-toluamide (DEET), 5 lipopolysaccharide (LPS), corticosterone (CORT) and...acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB), the insect repellent DEET and, potentially, the nerve agent, sarin. These combined

Preventing Terrorism Using Information Sharing Networks

DTIC Science & Technology

2006-09-01

in fusing information and providing valuable intelligence that thwarted a terrorist attack at Disneyland . A videotape was received that contained a...creditable threat of a Sarin gas attack at Disneyland . The LA TEW conducted the initial analysis of the tape and the initial investigation that

Effects of Sarin on the Operant Behavior of Guinea Pigs

DTIC Science & Technology

2005-07-19

a after behavioral sessions had ended. The first collection time modified autoshaping procedure (concurrent variable-time was after the final saline...after behavioral sessions had ended. The first collection time modified autoshaping procedure (concurrent variable-time was after the final saline

Autonomic Cholinergic Neurotransmission in the Respiratory System: Effect of Organophosphate Poisoning and Its Treatment

DTIC Science & Technology

1992-05-01

NORWEGIAN: IN ENGLISH: a) Soman Al) Som b) Airways b) Luftveier c) Acetylcholine c) Acetylkolin d) Neuromodulation d Neuromodulering e) Reactivators...and augmented CAMP levels can enhance neurcitransmitter release in brain slices.’-"I Adenosine (ADO) is a neuromodulator both in the Methyixanthines

Treatment Strategies fir the NMDA Component of Organophosphorous Convulsions

DTIC Science & Technology

2005-04-01

Prophylactic and agents induce seizures and brain damage in lithium-treated rats. therapeutic efficacy of memantine against seizures produced by Science 1983;220...Gupta, R.C., Dettbarn, W.D., Wamil, A.W. (1992) Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat

Crystal structure of Gib2, a signal-transducing protein scaffold associated with ribosomes in Cryptococcus neoformans

NASA Astrophysics Data System (ADS)

Ero, Rya; Dimitrova, Valya Tenusheva; Chen, Yun; Bu, Wenting; Feng, Shu; Liu, Tongbao; Wang, Ping; Xue, Chaoyang; Tan, Suet Mien; Gao, Yong-Gui

2015-03-01

The atypical Gβ-like/RACK1 Gib2 protein promotes cAMP signalling that plays a central role in regulating the virulence of Cryptococcus neoformans. Gib2 contains a seven-bladed β transducin structure and is emerging as a scaffold protein interconnecting signalling pathways through interactions with various protein partners. Here, we present the crystal structure of Gib2 at a 2.2-Å resolution. The structure allows us to analyse the association between Gib2 and the ribosome, as well as to identify the Gib2 amino acid residues involved in ribosome binding. Our studies not only suggest that Gib2 has a role in protein translation but also present Gib2 as a physical link at the crossroads of various regulatory pathways important for the growth and virulence of C. neoformans.

Single-Organ Gallbladder Vasculitis

PubMed Central

Hernández-Rodríguez, José; Tan, Carmela D.; Rodríguez, E. René; Hoffman, Gary S.

2014-01-01

Abstract Systemic vasculitis (SV) involving abdominal structures usually has a poor prognosis. Gallbladder vasculitis (GV) has been reported as part of SV (GB-SV) and focal single-organ vasculitis (GB-SOV). We analyzed clinical and histologic characteristics of patients with GV to identify features that differentiate GB-SOV from the systemic forms of GV. To identify affected patients with GV we used pathology databases from our institution and an English-language PubMed search. Clinical manifestations, laboratory and histologic features, treatment administered, and outcomes were recorded. Patients were divided in 2 groups, GB-SOV and GB-SV. As in previous studies of single-organ vasculitis, GB-SOV was only considered to be a sustainable diagnosis if disease beyond the gallbladder was not apparent after a follow-up period of at least 6 months. Sixty-one well-characterized patients with GV were included (6 from our institution). There was no significant sex bias (32 female patients, 29 male). Median age was 52 years (range, 18–94 yr). GB-SOV was found in 20 (33%) and GB-SV in 41 (67%) patients. No differences were observed in age, sex frequency, or duration of gallbladder symptoms between groups. Past episodes of recurrent right-upper quadrant or abdominal pain and lithiasic cholecystitis were more frequent in GB-SOV patients, whereas acalculous cholecystitis occurred more often in GB-SV. In GB-SV, gallbladder-related symptoms occurred more often concomitantly with or after the systemic features, but they sometimes appeared before SV was fully developed (13.5%). Constitutional and musculoskeletal symptoms were reported only in GB-SV patients. Compared to GB-SOV, GB-SV patients presented more often with fever (62.5% vs 20%; p = 0.003) and exhibited higher erythrocyte sedimentation rate levels (80 ± 28 vs 37 ± 25 mm/h, respectively; p = 0.006). All GB-SV patients required glucocorticoids and 50% of them also received cytotoxic agents. Mortality in GB-SV was higher than in GB-SOV (35.5% vs 10%; p = 0.05). Nongranulomatous inflammation with fibrinoid necrosis of medium-sized vessels occurred equally in both groups (>90%). Forms of SV affecting the gallbladder included polyarteritis nodosa (n = 10), hepatitis B virus-associated vasculitis (n = 8), cryoglobulinemic (essential or hepatitis C virus-associated) vasculitis (n = 6), vasculitis associated with autoimmune diseases (n = 6), microscopic polyangiitis (n = 4), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (n = 4), IgA vasculitis (Henoch-Schönlein) (n = 2), and giant cell arteritis (n = 1). GV is uncommon. Its histology most often consists of a nongranulomatous necrotizing vasculitis affecting medium-sized vessels. GB-SOV is usually discovered after routine cholecystectomy performed because of the presence of local symptoms, gallstone-associated cholecystitis, and contrary to GB-SV, GB-SOV is usually not associated with systemic symptoms. Acute phase reactants and surrogate markers of autoimmunity are usually normal or negative in GB-SOV. GB-SOV does not require systemic antiinflammatory or immunosuppressive therapy; surgery is adequate to achieve cure. GB-SV always warrants immunosuppressant therapy and is associated with high mortality. The finding of GV may precede the generalized manifestations of SV. Therefore, once GV is discovered, studies to determine disease extent and a vigilant follow-up are mandatory. PMID:25500710

Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX.

PubMed

Chambers, Janice E; Chambers, Howard W; Funck, Kristen E; Meek, Edward C; Pringle, Ronald B; Ross, Matthew K

2016-11-25

Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2 h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Synergistic behavior of glycine betaine-urea mixture: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Kumar, Narendra; Kishore, Nand

2013-09-01

Glycine betaine (GB) is one of the most important osmolyte which is known to stabilize proteins as well as counteract the denaturing effect of urea. There have been many studies indicating protein stabilization and counteraction of the effect of urea by GB. However, the exact mechanism of counteraction is still debated and is of important research interest. In this study, distribution functions, hydrogen bonds, and energetics were analysed to understand different interactions between GB and urea, and their solvation properties in presence of each other. The results show that in the GB-urea mixture, GB acted as a stronger osmolyte and urea became a weaker denaturing agent than its individual counterparts. The increase in the solvation of urea and GB in GB-urea mixture and their mutual interactions through hydrogen bonding and coulombic energy resulted in more involvement of GB and urea with solvent as well as with themselves. This might result in the increase of the exclusion of GB from protein surface and decrease in the protein-urea interactions in the mixture. This synergistic behavior might be the prime reason for the counteraction of denaturing effect of urea by GB.

Mechanistic insights into osmolyte action in protein stabilization under harsh conditions: N-methylacetamide in glycine betaine-urea mixture

NASA Astrophysics Data System (ADS)

Kumar, Narendra; Kishore, Nand

2014-10-01

Glycine betaine (GB), a small naturally occurring osmolyte, stabilizes proteins and counteracts harsh denaturing conditions such as extremes of temperature, cellular dehydration, and presence of high concentration of urea. In spite of several studies on understanding mechanism of protein stabilization and counteraction of these harsh conditions by osmolytes, studies centred on GB, one of the most important osmolyte, are scarce, hence, there is need for more investigations. To explore mechanism of protein stabilization and counteraction of denaturing property of urea by GB, molecular dynamics studies of N-methylacetamide (NMA), a model peptide representing denatured state of a protein, in the presence of GB, urea, and GB-urea mixture were carried out. The results show that GB and urea work such that the strength of GB as a protecting osmolyte is increased and the denaturing ability of urea is decreased in the GB-urea mixture. It can be inferred that GB counteracts urea by decreasing its hydrophobic interactions with proteins. The mutual interactions between GB and urea also play an important role in protein stabilization. This study provides insights on osmolyte induced counteraction of denaturing property of urea.

Risk of gastrointestinal bleeding during anticoagulant treatment.

PubMed

Lanas-Gimeno, Aitor; Lanas, Angel

2017-06-01

Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009. Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, focusing on randomized controlled trials, meta-analyses, and post-marketing observational studies. Dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily increase the risk of GIB compared to warfarin. The risk increase with edoxaban is dose-dependent, while apixaban shows apparently, no increased risk. We summarize what is known about GIB risk factors for individual anticoagulants, the location of GIB in patients taking these compounds, and prevention strategies that lower the risk of GIB. Expert opinion: Recently there has been an important shift in the clinical presentation of GIB. Specifically, upper GIB has decreased with the decreased incidence of peptic ulcers due to the broad use of proton pump inhibitors and the decreased prevalence of H. pylori infections. In contrast, the incidence of lower GIB has increased, due in part to colonic diverticular bleeding and angiodysplasia in the elderly. In this population, the addition of oral anticoagulation therapy, especially DOACs, seems to increase the risk of lower GIB.

Characterization, Function, and Transcriptional Profiling Analysis of 3-Hydroxy-3-methylglutaryl-CoA Synthase Gene (GbHMGS1) towards Stresses and Exogenous Hormone Treatments in Ginkgo biloba.

PubMed

Meng, Xiangxiang; Song, Qiling; Ye, Jiabao; Wang, Lanlan; Xu, Feng

2017-10-12

3-Hydroxy-3-methylglutaryl-CoA synthase (HMGS) is one of the rate-limiting enzymes in the mevalonate pathway as it catalyzes the condensation of acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA. In this study, A HMGS gene (designated as GbHMGS1 ) was cloned from Ginkgo biloba for the first time. GbHMGS1 contained a 1422-bp open-reading frame encoding 474 amino acids. Comparative and bioinformatics analysis revealed that GbHMGS1 was extensively homologous to HMGSs from other plant species. Phylogenetic analysis indicated that the GbHMGS1 belonged to the plant HMGS superfamily, sharing a common evolutionary ancestor with other HMGSs, and had a further relationship with other gymnosperm species. The yeast complement assay of GbHMGS1 in HMGS -deficient Saccharomyces cerevisiae strain YSC6274 demonstrated that GbHMGS1 gene encodes a functional HMGS enzyme. The recombinant protein of GbHMGS1 was successfully expressed in E. coli . The in vitro enzyme activity assay showed that the k cat and K m values of GbHMGS1 were 195.4 min -1 and 689 μM, respectively. GbHMGS1 was constitutively expressed in all tested tissues, including the roots, stems, leaves, female flowers, male flowers and fruits. The transcript accumulation for GbHMGS1 was highest in the leaves. Expression profiling analyses revealed that GbHMGS1 expression was induced by abiotic stresses (ultraviolet B and cold) and hormone treatments (salicylic acid, methyl jasmonate, and ethephon) in G. biloba , indicating that GbHMGS1 gene was involved in the response to environmental stresses and plant hormones.

Study of grain boundary transparency in (Y b1 -xC ax) B a2C u3O bicrystal thin films over a wide temperature, field, and field orientation range

NASA Astrophysics Data System (ADS)

Li, Pei; Abraimov, Dmytro; Polyanskii, Anatolii; Kametani, Fumitake; Larbalestier, David

2015-03-01

The residual low-angle grain boundary (GB) network is still the most important current-limiting mechanism operating in biaxially textured rare-earth barium-copper-oxide (REBCO) coated conductors. While Ca doping is well established to improve supercurrent flow across low-angle GBs in weak fields at high temperatures, Ca doping also depresses Tc, making it so far impractical for high-temperature applications of REBCO coated conductors. On the other hand, high-field-magnet applications of REBCO require low temperatures. Here we systematically evaluate the effectiveness of Ca doping in improving the GB transparency, rGB=JcGB/ Jcgrain , of low-angle Y b1 -xC axBaCuO [001] tilt bicrystal films down to 10 K and with magnetic fields perpendicular and parallel to the film surfaces, while varying the Ca and oxygen doping level. Using low-temperature scanning laser microscopy and magneto-optical imaging, we found rGB to strongly depend on the angle between magnetic field and the GB plane and clearly identified regimes in which JcGB can exceed Jcgrain(rGB>1 ) where the GB pinning is optimized by the field being parallel to the GB dislocations. However, even in this favorable situation, we found that rGB became much smaller at lower temperatures. Calculations of the GB Ca segregation profile predict that the high-Jc channels between the GB dislocation cores are almost Ca free. It may be therefore that the positive effects of Ca doping seen by many authors near Tc are partly a consequence of the higher Tc of these Ca-free channels.

Prevalence of and risk factors for gallbladder polyps detected by ultrasonography among healthy Chinese: analysis of 34 669 cases.

PubMed

Lin, Wey-Ran; Lin, Deng-Yn; Tai, Dar-In; Hsieh, Sen-Yung; Lin, Chun-Yen; Sheen, I-Shyan; Chiu, Cheng-Tang

2008-06-01

Gallbladder (GB) polyps are tumor or tumor-like projections arising from GB mucosa. Although most polyps are benign, some early GB carcinomas present as polypoid lesions. The diagnosis of GB polyps is relatively easy by ultrasonography. Although numerous studies have investigated GB polyps, few studies have addressed the prevalence of and factors associated with GB polyps for specific ethnic populations. This study analyzes the prevalence and factors associated with GB polyps in a Chinese population who can afford a paid general checkup. The prevalence of and risk factors for GB polyps diagnosed by ultrasonography were retrospectively investigated in 34 669 Chinese patients who underwent a general checkup at Chang Gung Memorial Hospital (Taipei, Taiwan) between 2000 and 2003. Demographic, hemogram, serum biochemistry, hepatitis B surface antigen, hepatitis C antibody, and ultrasonography study data was available for all the patients. The correlations between the prevalence of GB polyps and age, sex, body height, body weight, body mass index, hemogram, serum biochemistry, and viral markers were examined for all the patients. Excluding the patients who underwent cholecystectomy, the overall prevalence of GB polyps was 9.5% and highest for middle-aged males. The analyzed risk factors with increased odds ratios (OR) for the development of GB polyps were male sex (OR 0.646, P < 0.0005) and hepatitis B virus surface antigen positivity (OR 1.113, P < 0.0005). Other demographic characteristics and biochemical parameters, including body height, body weight, body mass index, lipid profile, chronic hepatitis C virus infection, and liver function did not correlate with the presence of GB polyps. The prevalence of GB polyps among the Chinese in this study is higher than that reported for other populations. Chinese males and other patients with chronic hepatitis B viral infections have a high risk for developing GB polyps.

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

PubMed Central

Ferreira, Susana; Auray-Blais, Christiane; Boutin, Michel; Lavoie, Pamela; Nunes, José Pedro; Martins, Elisabete; Garman, Scott; Oliveira, João Paulo

2016-01-01

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study. PMID:26070511

Germinated barley as a functional ingredient in chicken sausages: effect on physicochemical and technological properties at different levels.

PubMed

Kim, Hyun-Wook; Hwang, Ko-Eun; Song, Dong-Heon; Kim, Yong-Jae; Ham, Youn-Kyung; Jeong, Tae-Jun; Choi, Yun-Sang; Kim, Cheon-Jei

2016-01-01

The objective of this study was to evaluate the effect of germinated barley (GB) levels on physicochemical and technological properties of cooked chicken sausages. The chicken sausages were formulated with 0-4 % GB. Addition of GB increased pH and yellowness but decreased lightness of the cooked chicken sausages. However, there was no difference in redness among treatments (P > 0.05). Based on the positive effects of GB on measurements related to water and/or fat retention ability, such as emulsion stability, cooking loss, and thawing loss, such results depended upon the added amount of GB. In addition, apparent viscosity increased with increasing levels of GB, resulting in hardness, springiness, and chewiness (P < 0.05). These results could be associated with polysaccharides contained in GB, such as insoluble fiber, β-glucan, and starch. Therefore, our results suggests that GB could be a functional ingredient to improve physicochemical and technological properties of chicken sausages and optimal level of GB was determined as minimum 2 %.

Treecode-based generalized Born method

NASA Astrophysics Data System (ADS)

Xu, Zhenli; Cheng, Xiaolin; Yang, Haizhao

2011-02-01

We have developed a treecode-based O(Nlog N) algorithm for the generalized Born (GB) implicit solvation model. Our treecode-based GB (tGB) is based on the GBr6 [J. Phys. Chem. B 111, 3055 (2007)], an analytical GB method with a pairwise descreening approximation for the R6 volume integral expression. The algorithm is composed of a cutoff scheme for the effective Born radii calculation, and a treecode implementation of the GB charge-charge pair interactions. Test results demonstrate that the tGB algorithm can reproduce the vdW surface based Poisson solvation energy with an average relative error less than 0.6% while providing an almost linear-scaling calculation for a representative set of 25 proteins with different sizes (from 2815 atoms to 65456 atoms). For a typical system of 10k atoms, the tGB calculation is three times faster than the direct summation as implemented in the original GBr6 model. Thus, our tGB method provides an efficient way for performing implicit solvent GB simulations of larger biomolecular systems at longer time scales.

Elementary Mechanisms of Shear-Coupled Grain Boundary Migration

NASA Astrophysics Data System (ADS)

Rajabzadeh, A.; Mompiou, F.; Legros, M.; Combe, N.

2013-06-01

A detailed theoretical study of the elementary mechanisms occurring during the shear-coupled grain boundary (GB) migration at low temperature is performed focusing on both the energetic and structural characteristics. The migration of a Σ13(320) GB in a copper bicrystal in response to external shear displacements is simulated using a semiempirical potential. The minimum energy path of the shear-coupled GB migration is computed using the nudge elastic band method. The GB migration occurs through the nucleation and motion of GB steps identified as disconnections. Energy barriers for the GB and disconnection migrations are evaluated.

Interaction between glycogen body cell and neuron: examination in co-culture system.

PubMed

Imagawa, Tomohiro; Shogaki, Kyoko; Uehara, Masato

2006-10-01

The glycogen body (GB) is in the dorsal area of the lumbosacral spinal cord in birds and is composed of uniform cells characterized by high glycogen storage. The glycogen of GB cells remains unchanged in vivo by the effects of a variety of hormones such as insulin, glucagon, adrenocorticotropic hormone and by physiological conditions such as starvation. In order to investigate the latent functionability of GB cells, we observed morphological changes of glycogen body cells in a co-culture system with cerebellar neurons by light and transmission electron microscopy. Cultured GB cells were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). The cultured neurons derived from cerebellum were co-cultured with the labeled GB cells. Under the co-culture with neurons, 2 types of GB cells were detected. One was conventional with numerous glycogen deposits in the cytoplasm and tended to make clusters. The other type of GB cells singly extended the processes attaching to the neuronal body and axons. In the axons in contact with GB cell processes, small vesicles appearing as synaptic vesicles were observed. These observations suggested that some GB cells can differentiate to an average astrocyte. The GB cells were assumed to involve the synapse formation or maturing as astrocytes in the CNS.

Effects of anticonvulsants on soman-induced epileptiform activity in the guinea-pig in vitro hippocampus.

PubMed

Harrison, Patrick K; Sheridan, Robert D; Green, A Chris; Tattersall, John E H

2005-08-22

Seizures arising from acetylcholinesterase inhibition are a feature of organophosphate anticholinesterase intoxication. Although benzodiazepines are effective against these seizures, alternative anticonvulsant drugs may possess greater efficacy and fewer side-effects. We have investigated in the guinea-pig hippocampal slice preparation the ability of a series of anticonvulsants to suppress epileptiform bursting induced by the irreversible organophosphate anticholinesterase, soman (100 nM). Carbamazepine (300 microM), phenytoin (100 microM), topiramate (100-300 microM) and retigabine (1-30 microM) reduced the frequency of bursting but only carbamazepine and phenytoin induced a concurrent reduction in burst duration. Felbamate (100-500 microM) and clomethiazole (100-300 microM) had no effect on burst frequency but decreased burst duration. Clozapine (3-30 microM) reduced the frequency but did not influence burst duration. Levetiracetam (100-300 microM) and gabapentin (100-300 microM) were without effect. These data suggest that several compounds, in particular clomethiazole, clozapine, felbamate, topiramate and retigabine, merit further evaluation as possible treatments for organophosphate poisoning.

Inhibitory activities of the heterotrimers formed from two α-type phospholipase A2 inhibitory proteins with different enzyme affinities and importance of the intersubunit electrostatic interaction in trimer formation.

PubMed

Nishida, Masanori; Okamoto, Masataka; Ohno, Ai; Okumura, Kohji; Hayashi, Kyozo; Ikeda, Kiyoshi; Inoue, Seiji

2010-11-01

α-type phospholipase A2 inhibitory protein (PLIα) isolated from the serum of the venomous snake Glyoidius brevicaudus, GbPLIα, is a homotrimer of subunits having a C-type lectin-like domain. The serum protein from nonvenomous snake Elaphe quadrivirgata, EqPLIα-LP, is homologous to GbPLIα, but it does not show any inhibitory activity against PLA2s. When a mixture of denaturant-treated monomeric forms of GbPLIα and EqPLIα-LP was used to reconstitute their trimers, no significant amounts of heterotrimers composed of GbPLIα and EqPLIα-LP subunits could be formed. On the other hand, when a mixture of denaturant-treated monomeric forms of GbPLIα and the recombinant chimeric EqPLIα-LP, Eq13Gb37Eq, in which the residues 13-36 were replaced by those of GbPLIα, was used to reconstitute their trimers, significant amounts of their heterotrimers were observed. Furthermore, when a mixture of denaturant-treated monomeric forms of EqPLIα-LP and the recombinant chimeric GbPLIα, Gb13Eq37Gb, in which the residues 13-36 were replaced by those of EqPLIα-LP, was used, significant amounts of their heterotrimers were observed. By comparison of the respective inhibitory activities of the heterotrimeric subspecies, it was suggested that the inhibitory activity of the trimer was governed by one subunit with the highest activity, and not affected by the number of these subunits. The intermolecular electrostatic interactions between Glu23 and Lys28 of GbPLIα were also suggested to be important in stabilizing the trimeric structure. The importance of the electrostatic interaction was supported by the less stability of the homotrimeric structure of a mutant GbPLIα with a single amino acid substitution, GbPLIα(K28E). Copyright © 2010 Elsevier B.V. All rights reserved.

Molecular cloning of two novel peroxidases and their response to salt stress and salicylic acid in the living fossil Ginkgo biloba.

PubMed

Novo-Uzal, Esther; Gutiérrez, Jorge; Martínez-Cortés, Teresa; Pomar, Federico

2014-10-01

Peroxidase isoenzymes play diverse roles in plant physiology, such as lignification and defence against pathogens. The actions and regulation of many peroxidases are not known with much accuracy. A number of studies have reported direct involvement of peroxidase isoenzymes in the oxidation of monolignols, which constitutes the last step in the lignin biosynthesis pathway. However, most of the available data concern only peroxidases and lignins from angiosperms. This study describes the molecular cloning of two novel peroxidases from the 'living fossil' Ginkgo biloba and their regulation by salt stress and salicylic acid. Suspension cell cultures were used to purify peroxidases and to obtain the cDNAs. Treatments with salicylic acid and sodium chloride were performed and peroxidase activity and gene expression were monitored. A novel peroxidase was purified, which preferentially used p-hydroxycinnamyl alcohols as substrates and was able to form dehydrogenation polymers in vitro from coniferyl and sinapyl alcohols. Two peroxidase full-length cDNAs, GbPrx09 and GbPrx10, were cloned. Both peroxidases showed high similarity to other basic peroxidases with a putative role in cell wall lignification. Both GbPrx09 and GbPrx10 were expressed in leaves and stems of the plant. Sodium chloride enhanced the gene expression of GbPrx09 but repressed GbPrx10, whereas salicylic acid strongly repressed both GbPrx09 and GbPrx10. Taken together, the data suggest the participation of GbPrx09 and GbPrx10 in the developmental lignification programme of the cell wall. Both peroxidases possess the structural characteristics necessary for sinapyl alcohol oxidation. Moreover, GbPrx09 is also involved in lignification induced by salt stress, while salicylic acid-mediated lignification is not a result of GbPrx09 and GbPrx10 enzymatic activity. © The Author 2014. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Newly identified allatostatin Bs and their receptor in the two-spotted cricket, Gryllus bimaculatus.

PubMed

Tsukamoto, Yusuke; Nagata, Shinji

2016-06-01

A cDNA encoding allatostatin Bs (ASTBs) containing the W(X)6W motif was identified using a database generated by a next generation sequencer (NGS) in the two-spotted cricket, Gryllus bimaculatus. The contig sequence revealed the presence of five novel putative ASTBs (GbASTBs) in addition to GbASTBs previously identified in G. bimaculatus. MALDI-TOF MS analyses revealed the presence of these novel and previously identified GbASTBs with three missing GbASTBs. We also identified a cDNA encoding G. bimaculatus GbASTB receptor (GbASTBR) in the NGS data. Phylogenetic analysis demonstrated that this receptor was highly conserved with other insect ASTBRs, including the sex peptide receptor of Drosophila melanogaster. Calcium imaging analyses indicated that the GbASTBR heterologously expressed in HEK293 cells exhibited responses to all identified GbASTBs at a concentration range of 10(-10)-10(-5)M. Copyright © 2016 Elsevier Inc. All rights reserved.

Can 100Gb/s wavelengths be deployed using 10Gb/s engineering rules?

NASA Astrophysics Data System (ADS)

Saunders, Ross; Nicholl, Gary; Wollenweber, Kevin; Schmidt, Ted

2007-09-01

A key challenge set by carriers for 40Gb/s deployments was that the 40Gb/s wavelengths should be deployable over existing 10Gb/s DWDM systems, using 10Gb/s link engineering design rules. Typical 10Gb/s link engineering rules are: 1. Polarization Mode Dispersion (PMD) tolerance of 10ps (mean); 2. Chromatic Dispersion (CD) tolerance of +/-700ps/nm 3. Operation at 50GHz channel spacing, including transit through multiple cascaded [R]OADMs; 4. Optical reach up to 2,000km. By using a combination of advanced modulation formats and adaptive dispersion compensation (technologies rarely seen at 10Gb/s outside of the submarine systems space), vendors did respond to the challenge and broadly met this requirement. As we now start to explore feasible technologies for 100Gb/s optical transport, driven by 100GE port availability on core IP routers, the carrier challenge remains the same. 100Gb/s links should be deployable over existing 10Gb/s DWDM systems using 10Gb/s link engineering rules (as listed above). To meet this challenge, optical transport technology must evolve to yet another level of complexity/maturity in both modulation formats and adaptive compensation techniques. Many clues as to how this might be achieved can be gained by first studying sister telecommunications industries, e.g. satellite (QPSK, QAM, LDCP FEC codes), wireless (advanced DSP, MSK), HDTV (TCM), etc. The optical industry is not a pioneer of new ideas in modulation schemes and coding theory, we will always be followers. However, we do have the responsibility of developing the highest capacity "modems" on the planet to carry the core backbone traffic of the Internet. As such, the key to our success will be to analyze the pros and cons of advanced modulation/coding techniques and balance this with the practical limitations of high speed electronics processing speed and the challenges of real world optical layer impairments. This invited paper will present a view on what advanced technologies are likely candidates to support 100GE optical IP transport over existing 10Gb/s DWDM systems, using 10Gb/s link engineering rules.

Nano-LC-MS/MS for Quantification of Lyso-Gb3 and Its Analogues Reveals a Useful Biomarker for Fabry Disease

PubMed Central

Sueoka, Hideaki; Ichihara, Junji; Tsukimura, Takahiro; Togawa, Tadayasu; Sakuraba, Hitoshi

2015-01-01

Biomarkers useful for diagnosis and evaluation of treatment for patients with Fabry disease are urgently needed. Recently, plasma globotriaosylsphingosine (lyso-Gb3) and lyso-Gb3-related analogues have attracted attention as promising biomarkers of Fabry disease. However, the plasma concentrations of lyso-Gb3 and its analogues are extremely low or below the detection limits in some Fabry patients as well as in healthy subjects. In this paper, we introduce the novel application of a nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) system to the measurement of lyso-Gb3 and its analogues in plasma. Nano-LC-MS/MS requires smaller amounts of samples and is more sensitive than conventional techniques. Using this method, we measured the plasma concentrations of lyso-Gb3 and its analogues in 40 healthy subjects, 5 functional variants (males with E66Q), and various Fabry patients (9 classic Fabry males/9 mutations; 7 later-onset Fabry males/5 mutations; and 10 Fabry females/9 mutations). The results revealed that the mean lyso-Gb3 and lyso-Gb3(-2) concentrations in all the Fabry patient subgroups were statistically higher, especially in the classic Fabry males, than those in the functional variants and healthy subjects. The plasma concentrations of lyso-Gb3 and its analogues in healthy subjects, functional variants, and some Fabry patients with specific mutations (R112H and M296I) that cannot be established by conventional techniques were successfully determined by means of nano-LC-MS/MS. The lyso-Gb3 and lyso-Gb3(-2) concentrations in male patients with these mutations were lower than those in most Fabry patients having other mutations, but higher than those in the functional variants and healthy subjects. This new method is expected to be useful for sensitive determination of the plasma concentrations of lyso-Gb3 and its analogues. This study also revealed that not only lyso-Gb3 but also lyso-Gb3(-2) in plasma is a useful biomarker for the diagnosis of Fabry disease. PMID:25965380

Effect of transition metal impurities on the strength of grain boundaries in vanadium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Xuebang; Kong, Xiang-Shan; You, Yu-Wei

2016-09-07

Effects of 3d (Ti-Ni), 4d (Zr-Pd), and 5d (Hf-Pt) transition metal impurities on strength of two representative vanadium grain boundaries (GBs), symmetric Σ3(111) and asymmetric Σ5(210), were studied by first-principles calculations within the framework of the Rice-Wang thermodynamic model and within the computational tensile test. The desirable elements to increase the GB cohesion were predicted based on their segregation and strengthening behaviors across the different GB sites. It reveals that the elements Ti, Zr, Hf, Nb, and Ta are good choices for the GB cohesion enhancers. In addition, the GB strengthening by solutes is sensitive to the GB structures. Themore » elements Cr, Mn, Fe, Co, and Ni decrease the GB strength of the Σ3(111) GB but they can increase the cohesion of the Σ5(210) GB. Furthermore, the origin of Ti-induced change of the GB strength was uncovered by analyzing the atomic bonds and electronic structures as well as the tensile strength. This work provides a theoretical guidance to screen promising alloying elements in V-based materials with improved resistance to GB decohesion and also helps us to understand the formation mechanism of Ti-rich precipitates in the V-Cr-Ti alloys under neutron or ion irradiation environments.« less

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.

PubMed

Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Prager, Eric M; Almeida-Suhett, Camila P; Apland, James P; Braga, Maria F M

2015-04-15

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD50 of 62μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2mg/kg, administered 20 min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1h post-exposure, prevents brain pathology and behavioral deficits. Published by Elsevier Inc.

Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.

PubMed

Price, Matthew E; Docx, Cerys J; Rice, Helen; Fairhall, Sarah J; Poole, Sarah J C; Bird, Michael; Whiley, Luke; Flint, Daniel P; Green, A Christopher; Timperley, Christopher M; Tattersall, John E H

2016-02-26

Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Increasing nerve agent treatment efficacy by P-glycoprotein inhibition.

PubMed

Joosen, Marloes J A; Vester, Stefanie M; Hamelink, Jouk; Klaassen, Steven D; van den Berg, Roland M

2016-11-25

One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of nerve agent treatment when administered as a pretreatment. In the present study soman-induced seizures were also substantially prevented when the animals were intravenously treated with tariquidar post-poisoning, in addition to HI-6 and atropine. In these animals, approximately twice as much AChE activity was present in their brain as compared to control rats. The finding that tariquidar did not affect distribution of soman to the brain indicates that the potentiating effects were a result of interactions of Pgp inhibition with drug distribution. In line with this, atropine appeared to be a substrate for Pgp in in vitro studies in a MDR1/MDCK cell model. This indicates that tariquidar might induce brain region specific effects on atropine distribution, which could contribute to the therapeutic efficacy increase found. Furthermore, the therapeutic enhancement by tariquidar was compared to that of the less specific and less potent Pgp inhibitor cyclosporine A. This compound appeared to induce a protective effect similar to tariquidar. In conclusion, treatment with a Pgp inhibitor resulted in enhanced therapeutic efficacy of HI-6 and atropine in a soman-induced seizure model in the rat. The mechanism underlying these effects should be further investigated. To that end, the potentiating effect of nerve agent treatment should be addressed against a broader range of nerve agents, for oximes and atropine separately, and for those at lower doses. In particular when efficacy against more nerve agents is shown, a Pgp inhibitor such as tariquidar might be a valid addition to nerve agent antidotes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

8 x 120 Gb/s unrepeatered transmission over 444 km (76.6 dB) using distributed Raman amplification and ROPA without discrete amplification.

PubMed

Chang, Do Il; Pelouch, Wayne; Patki, Pallavi; McLaughlin, John

2011-12-12

Unrepeatered transmission of 8 x 120 Gb/s over 444.2 km (76.6 dB) and multi-rate transmission of 8 x 120 Gb/s and 9 x 10.7 Gb/s over a 75.4 dB span have been demonstrated with off-line digital processing for the coherent 120 Gb/s channels. Transmission of 2 x 120 Gb/s with 7 x 12.5 Gb/s over 78 dB is also demonstrated with a real-time ASIC processor. All transmission results have been achieved using standard effective-area pure-silica-core fiber using forward and backward distributed Raman amplification and remotely-pumped erbium fiber. ASIC real-time processed results match well with off-line processing. © 2011 Optical Society of America

16. Photocopy of photograph, U.S. Army, ca. 1955 (original print ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

16. Photocopy of photograph, U.S. Army, ca. 1955 (original print located at Rocky Mountain Arsenal, Commerce City, Colorado). BUILDING 1501. VIEW TO SOUTHEAST. - Rocky Mountain Arsenal, Sarin Manufacturing Building, 3350 feet South of Ninth Avenue; 250 feet East of Road NS-4, Commerce City, Adams County, CO

GRAIN BOUNDARY STRENGTHENING PROPERTIES OF TUNGSTEN ALLOYS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Setyawan, Wahyu; Kurtz, Richard J.

2012-10-10

Density functional theory was employed to investigate grain boundary (GB) properties of W alloys. A range of substitutional solutes across the Periodic Table was investigated to understand the behavior of different electronic orbitals in changing the GB cleavage energy in the Σ27a[110]{525} GB. A number of transition metals were predicted to enhance the GB cohesion. This includes Ru, Re, Os, Ir, V, Cr, Mn, Fe, Co, Ti, Hf, Ta and Nb. While lanthanides, s and p elements were tended to cause GB embrittlement.

In vivo biodistribution of ginkgolide B, a constituent of Ginkgo biloba, visualized by MicroPET.

PubMed

Suehiro, Makiko; Simpson, Norman R; Underwood, Mark D; Castrillon, John; Nakanishi, Koji; van Heertum, Ronald

2005-07-01

The in vivo dynamic behavior of ginkgolide B (GB), a terpene lactone constituent of the Ginkgo biloba extracts, in the living animal was visualized by positron emission tomographic (PET) imaging using a GB analogue labeled with the positron emitter (18)F. The in vivo imaging studies, combined with ex vivo dissection experiments, reveal that GB exists in 2 forms in the body: the original GB with its lactone rings closed and a second form with one of the rings open. The original GB in plasma is taken up rapidly by various organs including the liver, the intestine and possibly the stomach. Consequently, in plasma, the proportion of the ionized form of GB increases dramatically with time. Thereafter the ratio between the 2 forms appears to shift slowly towards equilibrium. The results suggest that more attention needs to be focused on in vivo dynamics between the 2 forms of GB.

Photoluminescence enhancement through vertical stacking of defect-engineered Ge on Si quantum dots

NASA Astrophysics Data System (ADS)

Groiss, Heiko; Spindlberger, Lukas; Oberhumer, Peter; Schäffler, Friedrich; Fromherz, Thomas; Grydlik, Martyna; Brehm, Moritz

2017-02-01

In this work, we show that the room-temperature photoluminescence intensity from Ge ion-bombarded (GIB) epitaxial Ge on Si quantum dots (QD) can be improved by their vertical stacking. We stress that the growth of GIB-QD multilayers is more demanding compared to all-crystalline epitaxial QDs, as a consequence of local amorphous regions within the GIB-QDs required during their genesis. We show that in spite of those amorphous regions, for accurately chosen growth temperatures of the Si spacer layers separating the GIB-QD layers, multiple GIB-QD layers can be stacked without detrimental break-down of epitaxial growth. Compared to a single GIB-QD layer, we observe a 650% increase in PL intensity for an eleven-layer GIB-QD stack, indicating that such multilayers are promising candidates as gain material for all-group-IV nano-photonic lasers.

Suppressed expression of choline monooxygenase in sugar beet on the accumulation of glycine betaine.

PubMed

Yamada, Nana; Takahashi, Hiroyuki; Kitou, Kunihide; Sahashi, Kosuke; Tamagake, Hideto; Tanaka, Yoshito; Takabe, Teruhiro

2015-11-01

Glycine betaine (GB) is an important osmoprotectant and synthesized by two-step oxidation of choline. Choline monooxygenase (CMO) catalyzes the first step of the pathway and is believed to be a rate limiting step for GB synthesis. Recent studies have shown the importance of choline-precursor supply for GB synthesis. In order to investigate the role of CMO for GB accumulation in sugar beet (Beta vulgaris), transgenic plants carrying the antisense BvCMO gene were developed. The antisense BvCMO plants showed the decreased activity of GB synthesis from choline compared to wild-type (WT) plants which is well related to the suppressed level of BvCMO protein. However, GB contents were similar between transgenic and WT plants with the exception of young leaves and storage roots. Transgenic plants showed enhanced susceptibility to salt stress than WT plants. These results suggest the importance of choline-precursor-supply for GB accumulation, and young leaves and storage root are sensitive sites for GB accumulation. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper

PubMed Central

Doly, Stéphane; Shirvani, Hamasseh; Gäta, Gabriel; Meye, Frank; Emerit, Michel-Boris; Enslen, Hervé; Achour, Lamia; Pardo-Lopez, Liliana; Kwon, Yang Seung; Armand, Vincent; Gardette, Robert; Giros, Bruno; Gassmann, Martin; Bettler, Bernhard; Mameli, Manuel; Darmon, Michèle; Marullo, Stefano

2016-01-01

Summary Endoplasmic reticulum (ER) release and cell surface export of many G protein-coupled receptors (GPCRs), are tightly regulated. For GABAB receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gate-keepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function. PMID:26033241

Coupled grain boundary motion in aluminium: the effect of structural multiplicity

NASA Astrophysics Data System (ADS)

Cheng, Kuiyu; Zhang, Liang; Lu, Cheng; Tieu, Kiet

2016-05-01

The shear-induced coupled grain boundary motion plays an important role in the deformation of nanocrystalline (NC) materials. It has been known that the atomic structure of the grain boundary (GB) is not necessarily unique for a given set of misorientation and inclination of the boundary plane. However, the effect of the structural multiplicity of the GB on its coupled motion has not been reported. In the present study we investigated the structural multiplicity of the symmetric tilt Σ5(310) boundary in aluminium and its influence on the GB behaviour at a temperature range of 300 K-600 K using molecular dynamic simulations. Two starting atomic configurations were adopted in the simulations which resulted in three different GB structures at different temperatures. Under the applied shear deformation each GB structure exhibited its unique GB behaviour. A dual GB behaviour, namely the transformation of one GB behaviour to another during deformation, was observed for the second starting configuration at a temperature of 500 K. The atomistic mechanisms responsible for these behaviour were analysed in detail. The result of this study implicates a strong relationship between GB structures and their behaviour, and provides a further information of the grain boundary mediated plasticity in nanocrystalline materials.

Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus.

PubMed

Hamada, Yoshimasa; Bando, Tetsuya; Nakamura, Taro; Ishimaru, Yoshiyasu; Mito, Taro; Noji, Sumihare; Tomioka, Kenji; Ohuchi, Hideyo

2015-09-01

Hemimetabolous insects such as the cricket Gryllus bimaculatus regenerate lost tissue parts using blastemal cells, a population of dedifferentiated proliferating cells. The expression of several factors that control epigenetic modification is upregulated in the blastema compared with differentiated tissue, suggesting that epigenetic changes in gene expression might control the differentiation status of blastema cells during regeneration. To clarify the molecular basis of epigenetic regulation during regeneration, we focused on the function of the Gryllus Enhancer of zeste [Gb'E(z)] and Ubiquitously transcribed tetratricopeptide repeat gene on the X chromosome (Gb'Utx) homologues, which regulate methylation and demethylation of histone H3 lysine 27 (H3K27), respectively. Methylated histone H3K27 in the regenerating leg was diminished by Gb'E(z)(RNAi) and was increased by Gb'Utx(RNAi). Regenerated Gb'E(z)(RNAi) cricket legs exhibited extra leg segment formation between the tibia and tarsus, and regenerated Gb'Utx(RNAi) cricket legs showed leg joint formation defects in the tarsus. In the Gb'E(z)(RNAi) regenerating leg, the Gb'dac expression domain expanded in the tarsus. By contrast, in the Gb'Utx(RNAi) regenerating leg, Gb'Egfr expression in the middle of the tarsus was diminished. These results suggest that regulation of the histone H3K27 methylation state is involved in the repatterning process during leg regeneration among cricket species via the epigenetic regulation of leg patterning gene expression. © 2015. Published by The Company of Biologists Ltd.

Ultrasound follow-up for gallbladder polyps less than 6 mm may not be necessary.

PubMed

Pedersen, Malene Roland V; Dam, Claus; Rafaelsen, Søren Rafael

2012-10-01

The management of ultrasound (US) detected gallbladder (GB) polyps remains a dilemma. The aim of this study was to assess the size distribution and the outcome of US follow-up of GB polyps. The study was approved by the Danish Data Protection Agency. US reports from patients examined with abdominal US in our department from January 2008 to the end of December 2009 were reviewed with a view to including all patients with GB polyps. Patients with GB polyps are routinely recommended a 2-year follow-up with US every six months. The GB polyp size was recorded at baseline and at subsequent US reports. Pathology reports were finally reviewed for all patients with GB polyps to check who underwent cholecystectomy and to register the histological diagnosis. A total of 203 patients (median age 54 years; range 19-95 years) with GB polyps were included; 89 (44%) men and 114 (56%) women. The mean polyp size was 5 mm (range 2-40 mm). In 143 patients (70%) the GB polyp diameter was less than 6 mm. The first US follow-up was performed in 120 patients (59%), and only 31 (15%) completed the full 2-year US follow-up programme. Polyp size was stable in 100 patients, decreased in five patients, increased in eight and resolved in 15 patients. A total of 13 patients (6%) underwent cholecystectomy. Of the 203 patients, none showed neoplastic or malignant GB polyps. We recommend that follow-up US of patients with GB polyps < 6 mm is avoided. Alternatively, the intervals between US follow-up of GB polyps < 6 mm may be extended. not relevant. not relevant.

Ginkgo biloba Extract (GbE) Stimulates the Hypothalamic Serotonergic System and Attenuates Obesity in Ovariectomized Rats

PubMed Central

Banin, Renata M.; de Andrade, Iracema S.; Cerutti, Suzete M.; Oyama, Lila M.; Telles, Mônica M.; Ribeiro, Eliane B.

2017-01-01

Menopause is associated with increased risk to develop obesity but the mechanisms involved are not fully understood. We have shown that Ginkgo biloba extract (GbE) improved diet-induced obesity. Since GbE might be effective in the treatment of obesity related to menopause, avoiding the side effects of hormone replacement therapy, we investigated the effect of GbE on hypothalamic systems controlling energy homeostasis. Wistar rats were either ovariectomized (OVX) or Sham-operated. After 2 months, either 500 mg.kg-1 of GbE or vehicle were administered daily by gavage for 14 days. A subset of animals received an intracerebroventricular (i.c.v.) injection of serotonin (300 μg) or vehicle and food intake was measured after 12 and 24 h. Another subset was submitted to in vivo microdialysis and 5-HT levels of the medial hypothalamus were measured by high performance liquid chromatography, before and up to 2 h after the administration of 500 mg.kg-1 of GbE. Additional animals were used for quantification of 5-HT1A, 5-HT1B, 5-HT2C, 5-HTT, and pro-opiomelanocortin hypothalamic protein levels by Western blotting. OVX increased food intake and body weight and adiposity while GbE attenuated these alterations. i.c.v. serotonin significantly reduced food intake in Sham, Sham + GbE, and OVX + GbE groups while it failed to do so in the OVX group. In the OVX rats, GbE stimulated 5-HT microdialysate levels while it reduced hypothalamic 5-HTT protein levels. The results indicate that GbE improved the ovariectomy-induced resistance to serotonin hypophagia, at least in part through stimulation of the hypothalamic serotonergic activity. Since body weight gain is one of the most important consequences of menopause, the stimulation of the serotonergic transmission by GbE may represent a potential alternative therapy for menopause-related obesity. PMID:28928661

Good’s buffers as a basis for developing self-buffering and biocompatible ionic liquids for biological research†

PubMed Central

Taha, Mohamed; e Silva, Francisca A.; Quental, Maria V.; Ventura, Sónia P. M.; Freire, Mara G.; Coutinho, João A. P.

2014-01-01

This work reports a promising approach to the development of novel self-buffering and biocompatible ionic liquids for biological research in which the anions are derived from biological buffers (Good’s buffers, GB). Five Good’s buffers (Tricine, TES, CHES, HEPES, and MES) were neutralized with four suitable hydroxide bases (1-ethyl-3-methylimidazolium, tetramethylammonium, tetraethylammonium, and tetrabutylammonium) producing 20 Good’s buffer ionic liquids (GB-ILs). The presence of the buffering action of the synthesized GB-ILs was ascertained by measuring their pH-profiles in water. Moreover, a series of mixed GB-ILs with wide buffering ranges were formulated as universal buffers. The impact of GB-ILs on bovine serum albumin (BSA), here used as a model protein, is discussed and compared with more conventional ILs using spectroscopic techniques, such as infrared and dynamic light scattering. They appear to display, in general, a greater stabilizing effect on the protein secondary structure than conventional ILs. A molecular docking study was also carried out to investigate on the binding sites of GB-IL ions to BSA. We further used the QSAR-human serum albumin binding model, log K(HSA), to calculate the binding affinity of some conventional ILs/GB-ILs to HSA. The toxicity of the GB and GB-ILs was additionally evaluated revealing that they are non-toxic against Vitro fischeri. Finally, the GB-ILs were also shown to be able to form aqueous biphasic systems when combined with aqueous solutions of inorganic or organic salts, and we tested their extraction capability for BSA. These systems were able to extract BSA with an outstanding extraction efficiency of 100% in a single step for the GB-IL-rich phase, and, as a result, the use of GB-IL-based ABS for the separation and extraction of other added-value biomolecules is highly encouraging and worthy of further investigation. PMID:25729325

Effects of GABAB receptors in the insula on recognition memory observed with intellicage.

PubMed

Wu, Nan; Wang, Feng; Jin, Zhe; Zhang, Zhen; Wang, Lian-Kun; Zhang, Chun; Sun, Tao

2017-04-17

Insular function has gradually become a topic of intense study in cognitive research. Recognition memory is a commonly studied type of memory in memory research. GABA B R has been shown to be closely related to memory formation. In the present study, we used intellicage, which is a new intelligent behavioural test system, and a bilateral drug microinjection technique to inject into the bilateral insula, to examine the relationship between GABA B R and recognition memory. Male Sprague-Dawley rats were randomly divided into control, Sham, Nacl, baclofen and CGP35348 groups. Different testing procedures were employed using intellicage to detect changes in rat recognition memory. The expression of GABA B R (GB1, GB2) in the insula of rats was determined by immunofluorescence and western blotting at the protein level. In addition, the expression of GABA B R (GB 1 , GB 2 ) was detected by RT-PCR at the mRNA level. The results of the intellicage test showed that recognition memory was impaired in terms of position learning, punitive learning and punitive reversal learning by using baclofen and CGP35348. In position reversal learning, no significant differences were found in terms of cognitive memory ability between the control groups and the CGP and baclofen groups. Immunofluorescence data showed GABA B R (GB1, GB2) expression in the insula, while data from RT-PCR and western blot analysis demonstrated that the relative expression of GB1 and GB2 was significantly increased in the baclofen group compared with the control groups. In the CGP35348 group, the expression of GB1 and GB2 was significantly decreased, but there was no significant difference in GB1 or GB2 expression in the control groups. GABA B R expression in the insula plays an important role in the formation of recognition memory in rats.

Development of a novel niosomal system for oral delivery of Ginkgo biloba extract

PubMed Central

Jin, Ye; Wen, Jingyuan; Garg, Sanjay; Liu, Da; Zhou, Yulin; Teng, Lirong; Zhang, Weiyu

2013-01-01

Background The aim of this study was to develop an optimal niosomal system to deliver Ginkgo biloba extract (GbE) with improved oral bioavailability and to replace the conventional GbE tablets. Methods In this study, the film dispersion-homogenization method was used to prepare GbE niosomes. The resulting GbE niosome suspension was freeze-dried or spray-dried to improve the stability of the niosomes. GbE-loaded niosomes were formulated and characterized in terms of their morphology, particle size, zeta potential, entrapment efficiency, and angle of repose, and differential scanning calorimetry analysis was performed. In vitro release and in vivo distribution studies were also carried out. Results The particle size of the optimal delivery system prepared with Tween 80, Span 80, and cholesterol was about 141 nm. There was a significant difference (P < 0.05) in drug entrapment efficiency between the spray-drying method (about 77.5%) and the freeze-drying method (about 50.1%). The stability study revealed no significant change in drug entrapment efficiency for the GbE niosomes at 4°C and 25°C after 3 months. The in vitro release study suggested that GbE niosomes can prolong the release of flavonoid glycosides in phosphate-buffered solution (pH 6.8) for up to 48 hours. The in vivo distribution study showed that the flavonoid glycoside content in the heart, lung, kidney, brain, and blood of rats treated with the GbE niosome carrier system was greater than in the rats treated with the oral GbE tablet (P < 0.01). No flavonoid glycosides were detected in the brain tissue of rats given the oral GbE tablets, but they were detected in the brain tissue of rats given the GbE niosomes. Conclusion Niosomes are a promising oral system for delivery of GbE to the brain. PMID:23378764

Herpes Simplex Virus Glycoprotein B Associates with Target Membranes via Its Fusion Loops▿

PubMed Central

Hannah, Brian P.; Cairns, Tina M.; Bender, Florent C.; Whitbeck, J. Charles; Lou, Huan; Eisenberg, Roselyn J.; Cohen, Gary H.

2009-01-01

Herpes simplex virus (HSV) glycoproteins gB, gD, and gH/gL are necessary and sufficient for virus entry into cells. Structural features of gB are similar to those of vesicular stomatitis virus G and baculovirus gp64, and together they define the new class III group of fusion proteins. Previously, we used mutagenesis to show that three hydrophobic residues (W174, Y179, and A261) within the putative gB fusion loops are integral to gB function. Here we expanded our analysis, using site-directed mutagenesis of each residue in both gB fusion loops. Mutation of most of the nonpolar or hydrophobic amino acids (W174, F175, G176, Y179, and A261) had severe effects on gB function in cell-cell fusion and null virus complementation assays. Of the six charged amino acids, mutation of H263 or R264 also negatively affected gB function. To further analyze the mutants, we cloned the ectodomains of the W174R, Y179S, H263A, and R264A mutants into a baculovirus expression system and compared them with the wild-type (WT) form, gB730t. As shown previously, gB730t blocks virus entry into cells, suggesting that gB730t competes with virion gB for a cell receptor. All four mutant proteins retained this function, implying that fusion loop activity is separate from gB-receptor binding. However, unlike WT gB730t, the mutant proteins displayed reduced binding to cells and were either impaired or unable to bind naked, cholesterol-enriched liposomes, suggesting that it may be gB-lipid binding that is disrupted by the mutations. Furthermore, monoclonal antibodies with epitopes proximal to the fusion loops abrogated gB-liposome binding. Taken together, our data suggest that gB associates with lipid membranes via a fusion domain of key hydrophobic and hydrophilic residues and that this domain associates with lipid membranes during fusion. PMID:19369321

Grain boundary premelting and activated sintering in binary refractory alloys

NASA Astrophysics Data System (ADS)

Shi, Xiaomeng

Quasi-liquid intergranular film (IGF) which has been widely observed in ceramic systems can persist into sub-solidus region whereby an analogy to Grain boundary (GB) premelting can be made. In this work, a grain boundary (GB) premelting/prewetting model in a metallic system was firstly built based on the Benedictus' model and computational thermodynamics, predicting that GB disordering can start at 60-85% of the bulk solidus temperatures in selected systems. This model quantitatively explains the long-standing mystery of subsolidus activated sintering in W-Pd, W-Ni, W-Co, W-Fe and W-Cu, and it has broad applications for understanding GB-controlled transport kinetics and physical properties. Furthermore, this study demonstrates the necessity of developing GB phase diagrams as a tool for materials design. Subsequently, Grain boundary (GB) wetting and prewetting in Ni-doped Mo are systematically evaluated via characterizing well-quenched specimens and thermodynamic modeling. In contrast to prior reports, the delta-NiMo phase does not wet Mo GBs in the solid state. In the solid-liquid two-phase region, the Ni-rich liquid wets Mo GBs completely. Furthermore, high-resolution transmission electron microscopy demonstrates that nanometer-thick quasi-liquid IGFs persist at GBs into the single-phase region where the bulk liquid phase is no longer stable; this is interpreted as a case of GB prewetting. An analytical thermodynamic model is developed and validated, and this model can be extended to other systems. Furthermore, the analytical model was refined based upon Beneditus' model with correction in determining interaction contribution of interfacial energy. A calculation-based GB phase diagram for Ni-Mo binary system was created and validated by comparing with GB diffusivities determined through a series of controlled sintering experiments. The dependence of GB diffusivity on doping level and temperature was examined and compared with model-predicted GB phase diagram. The consistency between GB phase diagram and GB diffusivity was evidently observed. This study revealed the existence of quasi-liquid IGF in Ni-Mo and re-confirmed our prior hypothesis proposed through work in Ni-W system. It also demonstrated further the necessity of a GB phase diagram as a new tool to guide the materials processing or design, such as selection of sintering aid and heat-treatment.

Malathion Administration: Effects on Physiological and Physical Performance in the Heat,

DTIC Science & Technology

1982-12-09

Physiol. 51:62-67, 1981. 12. Harris, L. W., D. L. Stitcher , and W. C. Heyl. The effects of pretreatments with carbamates, atropine and mecamylamine on...survival and on soman-induced alterations in rat and rabbit brain acetylcholine. Life Sci. 26:1885-1891, 1980. 13. Harris, L. W., D. L. Stitcher , W. C

Pyridostigmine-Induced Cholinesterase Inhibition: Effects on the Ability to Work in the Heat,

DTIC Science & Technology

1983-05-27

Physiol. Biochem. 5:370- 372, 1975. 11. Harris, L.W., D.L Stitcher , and W.C. Heyl. The effects of pretreatments with carbamates, atropine and mecamylamine...on survival and on soman-induced alterations in rat and rabbit brain acetylcholine. Life Sci. 26:1885-189 1, 1980. 12. Harris, L.W., D.L. Stitcher

Computer Simulation of the Effect of Pretreatment with Reversible Acetylcholinesterase Inhibitors on the Protection Against Soman Poisoning

DTIC Science & Technology

1993-12-01

dr. U.A. Th. Brinkmnan 31* Directeur van het Medisch Biologisch Laboratorium TNO Prof. dr. W.R.F. Notten 32 PML-TNO, Directeur; daarna reserve 33 PML...Generaal Personeel Ministerie van Defensie 8* Adviseur van het Prins Maurits Laboratorium TNO Chemnische Research Prof. dr. G. Dijkstra 9* lid van de

The shear response of copper bicrystals with Σ11 symmetric and asymmetric tilt grain boundaries by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Zhang, Liang; Lu, Cheng; Tieu, Kiet; Zhao, Xing; Pei, Linqing

2015-04-01

Grain boundaries (GBs) are important microstructure features and can significantly affect the properties of nanocrystalline materials. Molecular dynamics simulation was carried out in this study to investigate the shear response and deformation mechanisms of symmetric and asymmetric Σ11<1 1 0> tilt GBs in copper bicrystals. Different deformation mechanisms were reported, depending on GB inclination angles and equilibrium GB structures, including GB migration coupled to shear deformation, GB sliding caused by local atomic shuffling, and dislocation nucleation from GB. The simulation showed that migrating Σ11(1 1 3) GB under shear can be regarded as sliding of GB dislocations and their combination along the boundary plane. A non-planar structure with dissociated intrinsic stacking faults was prevalent in Σ11 asymmetric GBs of Cu. This type of structure can significantly increase the ductility of bicrystal models under shear deformation. A grain boundary can be a source of dislocation and migrate itself at different stress levels. The intrinsic free volume involved in the grain boundary area was correlated with dislocation nucleation and GB sliding, while the dislocation nucleation mechanism can be different for a grain boundary due to its different equilibrium structures.Grain boundaries (GBs) are important microstructure features and can significantly affect the properties of nanocrystalline materials. Molecular dynamics simulation was carried out in this study to investigate the shear response and deformation mechanisms of symmetric and asymmetric Σ11<1 1 0> tilt GBs in copper bicrystals. Different deformation mechanisms were reported, depending on GB inclination angles and equilibrium GB structures, including GB migration coupled to shear deformation, GB sliding caused by local atomic shuffling, and dislocation nucleation from GB. The simulation showed that migrating Σ11(1 1 3) GB under shear can be regarded as sliding of GB dislocations and their combination along the boundary plane. A non-planar structure with dissociated intrinsic stacking faults was prevalent in Σ11 asymmetric GBs of Cu. This type of structure can significantly increase the ductility of bicrystal models under shear deformation. A grain boundary can be a source of dislocation and migrate itself at different stress levels. The intrinsic free volume involved in the grain boundary area was correlated with dislocation nucleation and GB sliding, while the dislocation nucleation mechanism can be different for a grain boundary due to its different equilibrium structures. Electronic supplementary information (ESI) available: Movies show the evolution of different grain boundaries under shear deformation: S-0, S-54.74, S-70.53-A, S-70.53-B, S-90. See DOI: 10.1039/c4nr07496c

78 FR 50132 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-16

... into the System for execution. Each of BX's current connection offerings uses different switches... 10Gb Ultra low latency fiber connection option, and provide a waiver of installation fees for... to the Exchange, including a 40Gb fiber connection, a 10Gb fiber connection, a 1Gb fiber connection...

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Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-11

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2013-02-11

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50 CFR 648.85 - Special management programs.

Code of Federal Regulations, 2011 CFR

2011-10-01

... overall ACL for a particular stock in a given fishing year, specified pursuant to § 648.90(a)(4), is... Eastern GB cod and Eastern GB haddock proportional to the sector's allocation of the overall ACL for these... percent of the GB haddock ACL, it will also be allocated 10 percent of the Eastern GB haddock TAC for that...

50 CFR 648.85 - Special management programs.

Code of Federal Regulations, 2012 CFR

2012-10-01

... overall ACL for a particular stock in a given fishing year, specified pursuant to § 648.90(a)(4), is... Eastern GB cod and Eastern GB haddock proportional to the sector's allocation of the overall ACL for these... percent of the GB haddock ACL, it will also be allocated 10 percent of the Eastern GB haddock TAC for that...

Impact of the Grameen Bank on childhood mortality in Bangladesh.

PubMed

Rahman, M; Davanzo, J; Sutradhar, S C

1996-01-01

The Grameen Bank (GB) is a highly innovative and well-supervised credit program for the rural poor in Bangladesh. About 95% of over 2 million participants are women. GB can positively affect child survival among its participants through its income-generation and consciousness-raising activities. The study examines if GB influences childhood mortality among its participants. An integrated family life survey was carried out during 1993-94 among about 2500 married women in landless households who are eligible for membership in GB. The survey was carried out among randomly selected married women regardless of GB membership in 3 thanas of Tangail district and 1 thana of Mymensingh district. The study permits an analysis in a "before-after" and "treatment-comparison" framework for measuring the impact of GB on childhood mortality. Estimation was done through proportional hazards models, where the effects of confounding factors like calendar year, maternal age, parity, maternal education, economic conditions, and areal variation were controlled for. There was a 34% and significant reduction in childhood (under-5) mortality after the mothers joined the GB. Similar effects of other NGOs on childhood mortality were also observed. Childhood mortality was similar between the GB members before joining the Bank and never-members, indicating that the GB members were not from a selective group. Childhood mortality was 21% and significantly lower among women who worked for income generation than those women who did not work. Income generation and social development programs modeled after the GB and other NGOs can reduce childhood mortality in Bangladesh and similar settings.

Effects of Php Gene-Associated versus Induced Resistance to Tobacco Cyst Nematode in Flue-Cured Tobacco

PubMed Central

Johnson, Charles S.; Eisenback, Jon D.

2009-01-01

Effects of the systemic acquired resistance (SAR)-inducing compound acibenzolar-S-methyl (ASM) and the plant-growth promoting rhizobacterial mixture Bacillus subtilis A13 and B. amyloliquefaciens IN937a (GB99+GB122) were assessed on the reproduction of a tobacco cyst nematode (TCN- Globodera tabacum solanacearum) under greenhouse conditions. Two sets of two independent experiments were conducted, each involving soil or root sampling. Soil sample experiments included flue-cured tobacco cultivars with (Php+: NC71 and NC102) and without (Php-: K326 and K346) a gene (Php) suppressing TCN parasitism. Root sample experiments examined TCN root parasitism of NC71 and K326. Cultivars possessing the Php gene (Php+) were compared with Php- cultivars to assess the effects of resistance mediated via Php gene vs. induced resistance to TCN. GB99+GB122 consistently reduced nematode reproductive ratio on both Php+ and Php- cultivars, but similar effects of ASM across Php- cultivars were less consistent. In addition, ASM application resulted in leaf yellowing and reduced root weight. GB99+GB122 consistently reduced nematode development in roots of both Php+ and Php- cultivars, while similar effects of ASM were frequently less consistent. The results of this study indicate that GB99+GB122 consistently reduced TCN reproduction in all flue-cured tobacco cultivars tested, while the effects of ASM were only consistent in Php+ cultivars. Under most circumstances, GB99+GB122 suppressed nematode reproduction more consistently than ASM compared to the untreated control. PMID:22736824

Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy.

PubMed

van Breemen, Mariëlle J; Rombach, Saskia M; Dekker, Nick; Poorthuis, Ben J; Linthorst, Gabor E; Zwinderman, Aeilko H; Breunig, Frank; Wanner, Christoph; Aerts, Johannes M; Hollak, Carla E

2011-01-01

Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients. Copyright © 2010 Elsevier B.V. All rights reserved.

Synergistic Effects of Bacillus amyloliquefaciens (GB03) and Water Retaining Agent on Drought Tolerance of Perennial Ryegrass

PubMed Central

Su, An-Yu; Niu, Shu-Qi; Liu, Yuan-Zheng; He, Ao-Lei; Zhao, Qi; Li, Meng-Fei; Han, Qing-Qing; Ali Khan, Sardar

2017-01-01

Water retaining agent (WRA) is widely used for soil erosion control and agricultural water saving. Here, we evaluated the effects of the combination of beneficial soil bacterium Bacillus amyloliquefaciens strain GB03 and WRA (the compound is super absorbent hydrogels) on drought tolerance of perennial ryegrass (Lolium perenne L.). Seedlings were subjected to natural drought for maximum 20 days by stopping watering and then rewatered for seven days. Plant survival rate, biomass, photosynthesis, water status and leaf cell membrane integrity were measured. The results showed that under severe drought stress (20-day natural drought), compared to control, GB03, WRA and GB03+WRA all significantly improved shoot fresh weight, dry weight, relative water content (RWC) and chlorophyll content and decreased leaf relative electric conductivity (REC) and leaf malondialdehyde (MDA) content; GB03+WRA significantly enhanced chlorophyll content compared to control and other two treatments. Seven days after rewatering, GB03, WRA and GB03+WRA all significantly enhanced plant survival rate, biomass, RWC and maintained chlorophyll content compared to control; GB03+WRA significantly enhanced plant survival rate, biomass and chlorophyll content compared to control and other two treatments. The results established that GB03 together with water retaining agent promotes ryegrass growth under drought conditions by improving survival rate and maintaining chlorophyll content. PMID:29232909

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Sukun; University of Chinese Academy of Sciences, Beijing 100049; Hu, Kai

HSV-2 is the major cause of genital herpes and its infection increases the risk of HIV-1 acquisition and transmission. HSV-2 glycoprotein B together with glycoproteins D, H and L are indispensable for viral entry, of which gB, as a class III fusogen, plays an essential role. HSV-2 gB has seven potential N-linked glycosylation (N-CHO) sites, but their significance has yet to be determined. For the first time, we systematically analyzed the contributions of N-linked glycans on gB to cell–cell fusion and viral entry. Our results demonstrated that, of the seven potential N-CHO sites on gB, mutation at N390, N483 ormore » N668 decreased cell–cell fusion and viral entry, while mutation at N133 mainly affected protein expression and the production of infectious virus particles by blocking the transport of gB from the endoplasmic reticulum to Golgi. Our findings highlight the significance of N-linked glycans on HSV-2 gB expression and function. - Highlights: • N-linked glycan at N133 is important for gB intracellular trafficking and maturation. • N-linked glycans at N390, N483 and N668 on gB are necessary for optimal cell–cell fusion. • N-linked glycans at N390, N483 and N668 on gB are necessary for optimal viral entry.« less

Synergistic Effects of Bacillus amyloliquefaciens (GB03) and Water Retaining Agent on Drought Tolerance of Perennial Ryegrass.

PubMed

Su, An-Yu; Niu, Shu-Qi; Liu, Yuan-Zheng; He, Ao-Lei; Zhao, Qi; Paré, Paul W; Li, Meng-Fei; Han, Qing-Qing; Ali Khan, Sardar; Zhang, Jin-Lin

2017-12-11

Water retaining agent (WRA) is widely used for soil erosion control and agricultural water saving. Here, we evaluated the effects of the combination of beneficial soil bacterium Bacillus amyloliquefaciens strain GB03 and WRA (the compound is super absorbent hydrogels) on drought tolerance of perennial ryegrass ( Lolium perenne L.). Seedlings were subjected to natural drought for maximum 20 days by stopping watering and then rewatered for seven days. Plant survival rate, biomass, photosynthesis, water status and leaf cell membrane integrity were measured. The results showed that under severe drought stress (20-day natural drought), compared to control, GB03, WRA and GB03+WRA all significantly improved shoot fresh weight, dry weight, relative water content (RWC) and chlorophyll content and decreased leaf relative electric conductivity (REC) and leaf malondialdehyde (MDA) content; GB03+WRA significantly enhanced chlorophyll content compared to control and other two treatments. Seven days after rewatering, GB03, WRA and GB03+WRA all significantly enhanced plant survival rate, biomass, RWC and maintained chlorophyll content compared to control; GB03+WRA significantly enhanced plant survival rate, biomass and chlorophyll content compared to control and other two treatments. The results established that GB03 together with water retaining agent promotes ryegrass growth under drought conditions by improving survival rate and maintaining chlorophyll content.

Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it?

PubMed

Smith, Eric P; Polanco, Georgina; Yaqub, Abid; Salehi, Marzieh

2018-06-01

Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG. Copyright © 2017 Elsevier Inc. All rights reserved.

18. Photocopy of photograph, U.S. Army, ca. 1955 (original print ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

18. Photocopy of photograph, U.S. Army, ca. 1955 (original print located at Rocky Mountain Arsenal, Commerce City, Colorado). DETAIL OF BUILDING 1501. VIEW TO NORTHEAST. - Rocky Mountain Arsenal, Sarin Manufacturing Building, 3350 feet South of Ninth Avenue; 250 feet East of Road NS-4, Commerce City, Adams County, CO

17. Photocopy of photograph, U.S. Army, ca. 1955 (original print ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

17. Photocopy of photograph, U.S. Army, ca. 1955 (original print located at Rocky Mountain Arsenal, Commerce City, Colorado). DETAIL OF BUILDING 1501. VIEW TO SOUTHEAST - Rocky Mountain Arsenal, Sarin Manufacturing Building, 3350 feet South of Ninth Avenue; 250 feet East of Road NS-4, Commerce City, Adams County, CO

Biodegradation of an Organophosphate Chemical Warfare Agent Simulant by Activated Sludge with Varying Solid Retention Times

DTIC Science & Technology

2013-03-21

cause a response in the membrane (Robert, 1992). The transmitter must then be quickly removed to prevent abnormal excitation of the membranes (Robert...Health, 95(8), 1382-1388. Chapman, S., Kadar, T., & Gilat, E. (2006). Seizure duration following sarin exposure affects neuro -inflammatory markers

40 CFR 180.1111 - Bacillus subtilis GB03; exemption from the requirement of a tolerance.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Bacillus subtilis GB03; exemption from... FOOD Exemptions From Tolerances § 180.1111 Bacillus subtilis GB03; exemption from the requirement of a tolerance. The biofungicide Bacillus subtilis GB03 is exempted from the requirement of a tolerance in or on...

77 FR 15169 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-14

... Exchange, including a 10Gb fiber connection, a 1Gb copper connection, and a 100 MB connection.\\4\\ In... enable its clients a more efficient connection to the Exchange. The Exchange proposes a 40G [sic] fiber... orders of 10Gb and 40Gb fiber connectivity to the Exchange completed between the effectiveness of this...

78 FR 49308 - Self-Regulatory Organizations; The NASDAQ Stock Market LLC; Notice of Filing and Immediate...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-13

... latency fiber connection option, and provide a waiver of installation fees for subscriptions through..., including a 40Gb fiber connection, a 10Gb fiber connection, a 1Gb fiber connection, and a 1Gb copper... fiber connection offering, which uses new ultra- low latency switches.\\4\\ A switch is a type of network...

CryoSat Ice Processor: Known Processor Anomalies and Potential Future Product Evolutions

NASA Astrophysics Data System (ADS)

Mannan, R.; Webb, E.; Hall, A.; Bouffard, J.; Femenias, P.; Parrinello, T.; Bouffard, J.; Brockley, D.; Baker, S.; Scagliola, M.; Urien, S.

2016-08-01

Launched in 2010, CryoSat was designed to measure changes in polar sea ice thickness and ice sheet elevation. To reach this goal the CryoSat data products have to meet the highest performance standards and are subjected to a continual cycle of improvement achieved through upgrades to the Instrument Processing Facilities (IPFs). Following the switch to the Baseline-C Ice IPFs there are already planned evolutions for the next processing Baseline, based on recommendations from the Scientific Community, Expert Support Laboratory (ESL), Quality Control (QC) Centres and Validation campaigns. Some of the proposed evolutions, to be discussed with the scientific community, include the activation of freeboard computation in SARin mode, the potential operation of SARin mode over flat-to-slope transitory land ice areas, further tuning of the land ice retracker, the switch to NetCDF format and the resolution of anomalies arising in Baseline-C. This paper describes some of the anomalies known to affect Baseline-C in addition to potential evolutions that are planned and foreseen for Baseline-D.

Lessons learned from the Syrian sarin attack: evaluation of a clinical syndrome through social media.

PubMed

Rosman, Yossi; Eisenkraft, Arik; Milk, Nadav; Shiyovich, Arthur; Ophir, Nimrod; Shrot, Shai; Kreiss, Yitshak; Kassirer, Michael

2014-05-06

On the night of 21 August 2013, sarin was dispersed in the eastern outskirts of Damascus, killing 1400 civilians and severely affecting thousands more. This article aims to delineate the clinical presentation and management of a mass casualty event caused by a nerve agent as shown in the social media. Authors searched YouTube for videos uploaded of this attack and identified 210 videos. Of these, 67 met inclusion criteria and were evaluated in the final analysis.These videos displayed 130 casualties; 119 (91.5%) of which were defined as moderately injured or worse. The most common clinical signs were dyspnea (53.0%), diaphoresis (48.5%), and loss of consciousness (40.7%). Important findings included a severe shortage of supporting measures and lack of antidotal autoinjectors. Decontamination, documented in 25% of the videos, was done in an inefficient manner. Protective gear was not noticed, except for sporadic use of latex gloves and surgical masks.This is believed to be the first time that social media was used to evaluate clinical data and management protocols to better prepare against future possible events.

Σ 3 (111 ) grain boundary of body-centered cubic Ti-Mo and Ti-V alloys: First-principles and model calculations

NASA Astrophysics Data System (ADS)

Yan, Jia-Yi; Ehteshami, Hossein; Korzhavyi, Pavel A.; Borgenstam, Annika

2017-07-01

The energetics and atomic structures of Σ 3 [1 1 ¯0 ] (111 ) grain boundary (GB) of body-centered cubic (bcc) Ti-Mo and Ti-V alloys are investigated using density-functional-theory calculations and virtual crystal approximation. The electron density in bcc structure and the atomic displacements and excess energy of the GB are correlated to bcc-ω phase stability. Model calculations based on pairwise interplanar interactions successfully reproduce the chemical part of GB energy. The chemical GB energy can be expressed as a sum of excess pairwise interactions between bcc (111) layers, which are obtained from Gaussian elimination of the total energies of a number of periodic structures. The energy associated with the relaxation near the GB is solved by numerical minimization using the derivatives of the excess interactions. Anharmonic interlayer interactions are necessary for obtaining accurate relaxation energy and excess GB volume from model calculations. The effect of GB on vibrational spectrum is also investigated. Segregation energies of B and Y to a substitutional site on the GB plane are calculated. Preliminary results suggest that Y tends to segregate, while B tends to antisegregate.

Alanine substitution of conserved residues in the cytoplasmic tail of herpes simplex virus gB can enhance or abolish cell fusion activity and viral entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruel, Nancy; Zago, Anna; Spear, Patricia G.

2006-03-01

Herpes simplex virus (HSV) glycoprotein B (gB) is one of the four viral glycoproteins required for viral entry and cell fusion and is highly conserved among herpesviruses. Mutants of HSV type 2 gB were generated by substituting conserved residues in the cytoplasmic tail with alanine or by deleting 41 amino acids from the C-terminus. Some of the mutations abolished cell fusion activity and also prevented transport of gB to the cell surface, identifying residues in the gB cytoplasmic tail that are critical for intracellular transport of this glycoprotein. These mutations also prevented production of infectious virus, possibly because the mutantmore » forms of gB were not transported to the site of envelopment. Other mutations, particularly the deletion, significantly enhanced cell fusion activity. These mutations, as well as others described previously, identify regions of the gB cytoplasmic domain that modulate cell fusion activity.« less

Indirect-blocking ELISA for detecting antibodies against glycoprotein B (gB) of porcine cytomegalovirus (PCMV).

PubMed

Liu, Xiao; Zhu, Ling; Shi, Xiaohong; Xu, Zhiwen; Mei, Miao; Xu, Weiwei; Zhou, Yuancheng; Guo, Wanzhu; Wang, Xiaoyu

2012-12-01

The major epitope region of the glycoprotein B (gB) gene of the porcine cytomegalovirus (PCMV), with a length of 270 bp, was cloned and expressed in Escherichia coli Rosetta (DE3). The major gB epitope was detected using an agar gel precipitation and Western blot analysis with the polyclonal antibodies specific for the major epitope. An indirect-blocking enzyme-linked immunosorbent assay (ELISA) was developed using the expressed major gB epitope as a coating antigen for the detection of PCMV antibodies. The results of the tests show that the indirect-blocking ELISA has 98% specificity and 97.8% sensitivity. No cross-reactions were observed between the major gB epitope and the antibodies against other virus, which indicates that the gB epitope is specific for PCMV antibodies. The indirect-blocking ELISA is a highly specific, sensitive method for detecting anti-PCMV gB antibodies. Copyright © 2012 Elsevier B.V. All rights reserved.

100 Gbit Interconnects and Above: The Need for Speed

DTIC Science & Technology

2007-01-01

100Tb/s9 Board-board (~1m)2 $1/Gb 200Gb/ch3,6 $0.5/G/b 1Tb $0.1/G 5Tb Rack-rack (10-100m)1 $5/Gb $3/G 20Gb/ ch 100G...Critical need today $1/G 400G $0.25/G 1Tb/ ch 1. This market driven primarily by price 2. These markets are driven by needs/performance advantages...505) 272- 7845 Email: huffaker@chtm.unm.edu David Iams OIDA 1133 Connecticut Avenue, NW Suite 600 Washington, DC 20036-4329 Tel: (202) 785

Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tyler, Andreas, E-mail: andreas.tyler@medbio.umu.se; Johansson, Anders; Karlsson, Terese

Background: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expressionmore » of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance. Methods: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analyzed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72 h on expression and cisplatin cytotoxicity was tested. Results: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. Conclusions: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells. - Highlights: • The cisplatin-resistant cells had increased cell surface Gb3 and MDR1. • PPMP decreased extracellular Gb3 in the resistant cell lines. • Cyclosporin A decreased extracellular Gb3 and MDR1 in H1299 cells. • PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells. • Resistance to inhibitors of MDR1 and Gb3 could explain aggressiveness of NSCLC and MPM.« less

Contrast-Enhanced Ultrasound in the Diagnosis of Gallbladder Diseases: A Multi-Center Experience

PubMed Central

Liu, Lin-Na; Xu, Hui-Xiong; Lu, Ming-De; Xie, Xiao-Yan; Wang, Wen-Ping; Hu, Bing; Yan, Kun; Ding, Hong; Tang, Shao-Shan; Qian, Lin-Xue; Luo, Bao-Ming; Wen, Yan-Ling

2012-01-01

Objective To assess the usefulness of contrast–enhanced ultrasound (CEUS) in differentiating malignant from benign gallbladder (GB) diseases. Methods This study had institutional review board approval. 192 patients with GB diseases from 9 university hospitals were studied. After intravenous bonus injection of a phospholipid-stabilized shell microbubble contrast agent, lesions were scanned with low acoustic power CEUS. A multiple logistic regression analysis was performed to identify diagnostic clues from 17 independent variables that enabled differentiation between malignant and benign GB diseases. Receiver operating characteristic (ROC) curve analysis was performed. Results Among the 17 independent variables, multiple logistic regression analysis showed that the following 4 independent variables were associated with the benign nature of the GB diseases, including the patient age, intralesional blood vessel depicted on CEUS, contrast washout time, and wall intactness depicted on CEUS (all P<0.05). ROC analysis showed that the patient age, intralesional vessels on CEUS, and the intactness of the GB wall depicted on CEUS yielded an area under the ROC curve (Az) greater than 0.8 in each and Az for the combination of the 4 significant independent variables was 0.915 [95% confidence interval (CI): 0.857–0.974]. The corresponding Az, sensitivity, and specificity for the age were 0.805 (95% CI: 0.746–0.863), 92.2%%, and 59.6%; for the intralesional vessels on CEUS were 0.813 (95% CI: 0.751–0.875), 59.8%, and 98.0%; and for the GB wall intactness were 0.857 (95% CI: 0.786–0.928), 78.4%, and 92.9%. The cut-off values for benign GB diseases were patient age <53.5 yrs, dotted intralesional vessels on CEUS and intact GB wall on CEUS. Conclusion CEUS is valuable in differentiating malignant from benign GB diseases. Branched or linear intralesional vessels and destruction of GB wall on CEUS are the CEUS features highly suggestive of GB malignancy and the patient age >53.5 yrs is also a clue for GB malignancy. PMID:23118996

The evolution of interaction between grain boundary and irradiation-induced point defects: Symmetric tilt GB in tungsten

NASA Astrophysics Data System (ADS)

Li, Hong; Qin, Yuan; Yang, Yingying; Yao, Man; Wang, Xudong; Xu, Haixuan; Phillpot, Simon R.

2018-03-01

Molecular dynamics method is used and scheme of calculational tests is designed. The atomic evolution view of the interaction between grain boundary (GB) and irradiation-induced point defects is given in six symmetric tilt GB structures of bcc tungsten with the energy of the primary knock-on atom (PKA) EPKA of 3 and 5 keV and the simulated temperature of 300 K. During the collision cascade with GB structure there are synergistic mechanisms to reduce the number of point defects: one is vacancies recombine with interstitials, and another is interstitials diffuse towards the GB with vacancies almost not move. The larger the ratio of the peak defect zone of the cascades overlaps with the GB region, the statistically relative smaller the number of surviving point defects in the grain interior (GI); and when the two almost do not overlap, vacancy-intensive area generally exists nearby GBs, and has a tendency to move toward GB with the increase of EPKA. In contrast, the distribution of interstitials is relatively uniform nearby GBs and is affected by the EPKA far less than the vacancy. The GB has a bias-absorption effect on the interstitials compared with vacancies. It shows that the number of surviving vacancies statistically has increasing trend with the increase of the distance between PKA and GB. While the number of surviving interstitials does not change much, and is less than the number of interstitials in the single crystal at the same conditions. The number of surviving vacancies in the GI is always larger than that of interstitials. The GB local extension after irradiation is observed for which the interstitials absorbed by the GB may be responsible. The designed scheme of calculational tests in the paper is completely applicable to the investigation of the interaction between other types of GBs and irradiation-induced point defects.

Temporal Trends, Predictors, and Outcomes of In-Hospital Gastrointestinal Bleeding Associated With Percutaneous Coronary Intervention.

PubMed

Patel, Nileshkumar J; Pau, Dhaval; Nalluri, Nikhil; Bhatt, Parth; Thakkar, Badal; Kanotra, Ritesh; Agnihotri, Kanishk; Ainani, Nitesh; Patel, Nilay; Patel, Nish; Shah, Sapna; Kadavath, Sabeeda; Arora, Shilpkumar; Sheikh, Azfar; Badheka, Apurva O; Lafferty, James; Alfonso, Carlos; Cohen, Mauricio

2016-10-15

Since the introduction of new antiplatelet and anticoagulant agents in the last decade, large-scale data studying gastrointestinal bleeding (GIB) in patients undergoing percutaneous coronary intervention (PCI) are lacking. Using the Nationwide Inpatient Sample, we identified all hospitalizations from 2006 to 2012 that required PCI. Temporal trends in the incidence and multivariate predictors of GIB associated with PCI were analyzed. A total of 4,376,950 patients underwent PCI in the United States during the study period. The incidence of GIB was 1.1%. Mortality rate in the GIB group was significantly higher (9.71% vs 1.1%, p <0.0001). Although the incidence of GIB remained stable during the study period (0.97% in 2006 to 1.19% in 2012), in-hospital mortality rate increased significantly from 7.9% in 2006 to 10.78% in 2012, with a peak of 12% in 2010. The GIB group had a longer median length of stay (5.80 vs 1.57 days) and an increased median cost of hospitalization ($26,564 vs $16,879). The predictors of GIB included cardiovascular co-morbidities such as acute myocardial infarction, cardiogenic shock, atrial fibrillation, congestive heart failure, valvular heart diseases, and a history of transient ischemic attack/stroke. Gastrointestinal co-morbidities including diverticulosis, esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, rectosigmoid cancer, gastrointestinal ulcer, and liver disease were predictors of GIB. Interestingly, a lower risk of GIB was associated with obese patients and patients with private insurance. A higher risk of GIB was noted in urgent versus elective admissions and weekend versus weekday admissions. In conclusion, the incidence of GIB in patients who underwent PCI remained stable from 2006 to 2012; however, the in-hospital mortality increased significantly. Identifying patients at higher risk for GIB is critically important to develop preventive strategies to reduce morbidity and mortality. Copyright © 2016 Elsevier Inc. All rights reserved.

Acetylcholinesterases of Rhipicephalus (Boophilus) microplus – Multiple gene expression presents an opportune model system for elucidation of multiple functions of AChEs.

USDA-ARS?s Scientific Manuscript database

Acetylcholinesterase (AChE) is a key neural enzyme of both vertebrates and invertebrates, and is the biochemical target of organophosphate and carbamate pesticides for invertebrates, as well as vertebrate nerve agents, e.g., soman, tabun, VX, and others. AChE inhibitors are also key drugs among thos...

Effect of toxic threat nerve agents on anesthetic requirements of representative pr-anesthetic medicants and inhalant and parenteral general anesthetic in the cat. Annual report, 15 July 1985-14 July 1986

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webb, A.I.

1986-07-30

The effect of soman on anesthetic requirements of halothane and isoflurane was studied before and after administration of acepromazine maleate (0.2 mg/kg). Insufficient data has been obtained to date to draw conclusions on any possible drug interactions.

Simultaneous Time-concentration Analysis of Soman and VX Adducts to Butyrylcholinesterase and Albumin by LC-MS-MS.

PubMed

Lee, Jin Young; Kim, Changhwan; Lee, Yong Han

2018-06-01

A sensitive method for the purification and determination of two protein adducts, organophosphorus (OP)-BChE and OP-albumin adducts, in a single sample using a simultaneous sample preparation method was developed and validated using liquid chromatography-tandem mass spectrometry. First, we isolated O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) and O-pinacolyl methylphosphonofluoridate (soman, GD)-BChE adducts using an immunomagnetic separation (IMS) method and the HiTrap™ Blue affinity column was subsequently used to isolate and purify VX and GD-albumin adducts from the plasma of rhesus monkeys exposed to nerve agents. Additionally, we examined the time-concentration profiles of two biomarkers, VX and GD-nonapeptides and VX and GD-tyrosines, derived from OP-BChE and OP-albumin adducts up to 8 weeks after exposure. Based on the results, we determined that VX and GD-tyrosine is more suitable than VX and GD-nonapeptide as a biomarker owing to its longevity. This integrated approach is expected to be applicable for the quantification of other OP-BChE and OP-albumin adducts in human plasma, thus serving as a potential generic assay for exposure to nerve agents.

Polymer-based lanthanide luminescent sensor for detection of the hydrolysis product of the nerve agent Soman in water.

PubMed

Jenkins, A L; Uy, O M; Murray, G M

1999-01-15

The techniques of molecular imprinting and sensitized lanthanide luminescence have been combined to create the basis for a sensor that can selectively measure the hydrolysis product of the nerve agent Soman in water. The sensor functions by selectively and reversibly binding the phosphonate hydrolysis product of this agent to a functionality-imprinted copolymer possessing a coordinatively bound luminescent lanthanide ion, Eu3+. Instrumental support for this device is designed to monitor the appearance of a narrow luminescence band in the 610-nm region of the Eu3+ spectrum that results when the analyte is coordinated to the copolymer. The ligand field shifted luminescence was excited using 1 mW of the 465.8-nm line of an argon ion laser and monitored via an optical fiber using a miniature spectrometer. For this configuration, the limit of detection for the hydrolysis product is 7 parts per trillion (ppt) in solution with a linear range from 10 ppt to 10 ppm. Chemical and spectroscopic selectivities have been combined to reduce the likelihood of false positive analyses. Chemically analogous organophosphorus pesticides tested against the sensor have been shown to not interfere with determination.

FungalBraid: A GoldenBraid-based modular cloning platform for the assembly and exchange of DNA elements tailored to fungal synthetic biology.

PubMed

Hernanz-Koers, Miguel; Gandía, Mónica; Garrigues, Sandra; Manzanares, Paloma; Yenush, Lynne; Orzaez, Diego; Marcos, Jose F

2018-07-01

Current challenges in the study and biotechnological exploitation of filamentous fungi are the optimization of DNA cloning and fungal genetic transformation beyond model fungi, the open exchange of ready-to-use and standardized genetic elements among the research community, and the availability of universal synthetic biology tools and rules. The GoldenBraid (GB) cloning framework is a Golden Gate-based DNA cloning system developed for plant synthetic biology through Agrobacterium tumefaciens-mediated genetic transformation (ATMT). In this study, we develop reagents for the adaptation of GB version 3.0 from plants to filamentous fungi through: (i) the expansion of the GB toolbox with the domestication of fungal-specific genetic elements; (ii) the design of fungal-specific GB structures; and (iii) the ATMT and gene disruption of the plant pathogen Penicillium digitatum as a proof of concept. Genetic elements domesticated into the GB entry vector pUPD2 include promoters, positive and negative selection markers and terminators. Interestingly, some GB elements can be directly exchanged between plants and fungi, as demonstrated with the marker hph for Hyg R or the fluorescent protein reporter YFP. The iterative modular assembly of elements generates an endless number of diverse transcriptional units and other higher order combinations in the pDGB3α/pDGB3Ω destination vectors. Furthermore, the original plant GB syntax was adapted here to incorporate specific GB structures for gene disruption through homologous recombination and dual selection. We therefore have successfully adapted the GB technology for the ATMT of fungi. We propose the name of FungalBraid (FB) for this new branch of the GB technology that provides open, exchangeable and collaborative resources to the fungal research community. Copyright © 2018 Elsevier Inc. All rights reserved.

Interactions of glycine betaine with proteins: insights from volume and compressibility measurements.

PubMed

Shek, Yuen Lai; Chalikian, Tigran V

2013-01-29

We report the first application of volume and compressibility measurements to characterization of interactions between cosolvents (osmolytes) and globular proteins. Specifically, we measure the partial molar volumes and adiabatic compressibilities of cytochrome c, ribonuclease A, lysozyme, and ovalbumin in aqueous solutions of the stabilizing osmolyte glycine betaine (GB) at concentrations between 0 and 4 M. The fact that globular proteins do not undergo any conformational transitions in the presence of GB provides an opportunity to study the interactions of GB with proteins in their native states within the entire range of experimentally accessible GB concentrations. We analyze our resulting volumetric data within the framework of a statistical thermodynamic model in which each instance of GB interaction with a protein is viewed as a binding reaction that is accompanied by release of four water molecules. From this analysis, we calculate the association constants, k, as well as changes in volume, ΔV(0), and adiabatic compressibility, ΔK(S0), accompanying each GB-protein association event in an ideal solution. By comparing these parameters with similar characteristics determined for low-molecular weight analogues of proteins, we conclude that there are no significant cooperative effects involved in interactions of GB with any of the proteins studied in this work. We also evaluate the free energies of direct GB-protein interactions. The energetic properties of GB-protein association appear to scale with the size of the protein. For all proteins, the highly favorable change in free energy associated with direct protein-cosolvent interactions is nearly compensated by an unfavorable free energy of cavity formation (excluded volume effect), yielding a modestly unfavorable free energy for the transfer of a protein from water to a GB/water mixture.

Loktanella spp. Gb03 as an algicidal bacterium, isolated from the culture of Dinoflagellate Gambierdiscus belizeanus.

PubMed

Bloh, Anmar Hameed; Usup, Gires; Ahmad, Asmat

2016-02-01

Bacteria associated with harmful algal blooms can play a crucial role in regulating algal blooms in the environment. This study aimed at isolating and identifying algicidal bacteria in Dinoflagellate culture and to determine the optimum growth requirement of the algicidal bacteria, Loktanella sp. Gb-03. The Dinoflagellate culture used in this study was supplied by Professor Gires Usup's Laboratory, School of Environmental and Natural Resources Sciences, Faculty of Science and Technology, University Kebangsaan Malaysia, Malaysia. The culture was used for the isolation of Loktanella sp., using biochemical tests, API 20 ONE kits. The fatty acid content of the isolates and the algicidal activity were further evaluated, and the phenotype was determined through the phylogenetic tree. Gram-negative, non-motile, non-spore-forming, short rod-shaped, aerobic bacteria (Gb01, Gb02, Gb03, Gb04, Gb05, and Gb06) were isolated from the Dinoflagellate culture. The colonies were pink in color, convex with a smooth surface and entire edge. The optimum growth temperature for the Loktanella sp. Gb03 isolate was determined to be 30°C, in 1% of NaCl and pH7. Phylogenetic analysis based on 16S rRNA gene sequences showed that the bacterium belonged to the genus Loktanella of the class Alphaproteobacteria and formed a tight cluster with the type strain of Loktanella pyoseonensis (97.0% sequence similarity). On the basis of phenotypic, phylogenetic data and genetic distinctiveness, strain Gb-03, were placed in the genus Loktanella as the type strain of species. Moreover, it has algicidal activity against seven toxic Dinoflagellate. The algicidal property of the isolated Loktanella is vital, especially where biological control is needed to mitigate algal bloom or targeted Dinoflagellates.

Loktanella spp. Gb03 as an algicidal bacterium, isolated from the culture of Dinoflagellate Gambierdiscus belizeanus

PubMed Central

Bloh, Anmar Hameed; Usup, Gires; Ahmad, Asmat

2016-01-01

Aim: Bacteria associated with harmful algal blooms can play a crucial role in regulating algal blooms in the environment. This study aimed at isolating and identifying algicidal bacteria in Dinoflagellate culture and to determine the optimum growth requirement of the algicidal bacteria, Loktanella sp. Gb-03. Materials and Methods: The Dinoflagellate culture used in this study was supplied by Professor Gires Usup's Laboratory, School of Environmental and Natural Resources Sciences, Faculty of Science and Technology, University Kebangsaan Malaysia, Malaysia. The culture was used for the isolation of Loktanella sp., using biochemical tests, API 20 ONE kits. The fatty acid content of the isolates and the algicidal activity were further evaluated, and the phenotype was determined through the phylogenetic tree. Results: Gram-negative, non-motile, non-spore-forming, short rod-shaped, aerobic bacteria (Gb01, Gb02, Gb03, Gb04, Gb05, and Gb06) were isolated from the Dinoflagellate culture. The colonies were pink in color, convex with a smooth surface and entire edge. The optimum growth temperature for the Loktanella sp. Gb03 isolate was determined to be 30°C, in 1% of NaCl and pH7. Phylogenetic analysis based on 16S rRNA gene sequences showed that the bacterium belonged to the genus Loktanella of the class Alphaproteobacteria and formed a tight cluster with the type strain of Loktanella pyoseonensis (97.0% sequence similarity). Conclusion: On the basis of phenotypic, phylogenetic data and genetic distinctiveness, strain Gb-03, were placed in the genus Loktanella as the type strain of species. Moreover, it has algicidal activity against seven toxic Dinoflagellate. The algicidal property of the isolated Loktanella is vital, especially where biological control is needed to mitigate algal bloom or targeted Dinoflagellates. PMID:27051199

TGF-β signaling in insects regulates metamorphosis via juvenile hormone biosynthesis.

PubMed

Ishimaru, Yoshiyasu; Tomonari, Sayuri; Matsuoka, Yuji; Watanabe, Takahito; Miyawaki, Katsuyuki; Bando, Tetsuya; Tomioka, Kenji; Ohuchi, Hideyo; Noji, Sumihare; Mito, Taro

2016-05-17

Although butterflies undergo a dramatic morphological transformation from larva to adult via a pupal stage (holometamorphosis), crickets undergo a metamorphosis from nymph to adult without formation of a pupa (hemimetamorphosis). Despite these differences, both processes are regulated by common mechanisms that involve 20-hydroxyecdysone (20E) and juvenile hormone (JH). JH regulates many aspects of insect physiology, such as development, reproduction, diapause, and metamorphosis. Consequently, strict regulation of JH levels is crucial throughout an insect's life cycle. However, it remains unclear how JH synthesis is regulated. Here, we report that in the corpora allata of the cricket, Gryllus bimaculatus, Myoglianin (Gb'Myo), a homolog of Drosophila Myoglianin/vertebrate GDF8/11, is involved in the down-regulation of JH production by suppressing the expression of a gene encoding JH acid O-methyltransferase, Gb'jhamt In contrast, JH production is up-regulated by Decapentaplegic (Gb'Dpp) and Glass-bottom boat/60A (Gb'Gbb) signaling that occurs as part of the transcriptional activation of Gb'jhamt Gb'Myo defines the nature of each developmental transition by regulating JH titer and the interactions between JH and 20E. When Gb'myo expression is suppressed, the activation of Gb'jhamt expression and secretion of 20E induce molting, thereby leading to the next instar before the last nymphal instar. Conversely, high Gb'myo expression induces metamorphosis during the last nymphal instar through the cessation of JH synthesis. Gb'myo also regulates final insect size. Because Myo/GDF8/11 and Dpp/bone morphogenetic protein (BMP)2/4-Gbb/BMP5-8 are conserved in both invertebrates and vertebrates, the present findings provide common regulatory mechanisms for endocrine control of animal development.

Structure-function analysis of herpes simplex virus glycoprotein B with fusion-from-without activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roller, Devin G.; Dollery, Stephen J.; Doyle, James L.

2008-12-20

Fusion-from-without (FFWO) is the rapid induction of cell fusion by virions in the absence of viral protein synthesis. The combination of two amino acid mutations in envelope glycoprotein B (gB), one in the ectodomain and one in the cytoplasmic tail, can confer FFWO activity to wild type herpes simplex virus (HSV). In this report, we analyzed the entry and cell fusion phenotypes of HSV that contains FFWO gB, with emphasis on the cellular receptors for HSV, nectin-1, nectin-2 and HVEM. The ability of an HSV strain with FFWO gB to efficiently mediate FFWO via a specific gD-receptor correlated with itsmore » ability to mediate viral entry by that receptor. A FFWO form of gB was not sufficient to switch the entry of HSV from a pH-dependent, endocytic pathway to a direct fusion, pH-independent pathway. The conformation of gB with FFWO activity was not globally altered relative to wild type. However, distinct monoclonal antibodies had reduced reactivity with FFWO gB, suggesting an altered antigenic structure relative to wild type. FFWO was blocked by preincubation of virions with neutralizing antibodies to gB or gD. Together with previous studies, the results indicate that the roles of gB in FFWO and in virus-cell fusion during entry are related but not identical. This study also suggests that the FFWO function of gB is not a specific determinant for the selection of HSV entry pathway and that antigenic differences in FFWO gB may reflect its enhanced fusion activity.« less

Molecular cloning and characterization of enhanced disease susceptibility 1 (EDS1) from Gossypium barbadense.

PubMed

Su, Xiaofeng; Qi, Xiliang; Cheng, Hongmei

2014-06-01

Arabidopsis enhanced disease susceptibility 1 (EDS1) plays an important role in plant defense against biotrophic and necrotrophic pathogens. The necrotrophic pathogen Verticillium dahliae infection of Gossypium barbadense could lead to Verticillium wilt which seriously reduces the cotton production. Here, we cloned and characterized a G. barbadense homolog of EDS1, designated as GbEDS1. The full-length cDNA of the GbEDS1 gene was obtained by the technique of rapid-amplification of cDNA ends. The open reading frame of the GbEDS1 gene was 1,647 bp long and encoded a protein of 548 amino acids residues. Comparison of the cDNA and genomic DNA sequence of GbEDS1 indicated that this gene contained a single intron and two exons. Like other EDS1s, GbEDS1 contained a conserved N-terminal lipase domain and an EDS1-specific KNEDT motif. Subcellular localization assay revealed that GbEDS1-green fluorescence protein fusion protein was localized in both cytosol and nucleus. Interestingly, the transcript levels of GbEDS1 were dramatically increased in response to pathogen V. dahliae infection. To investigate the role of GbEDS1 in plant resistance against V. dahliae, a conserved fragment derived from GbEDS1 was used to knockdown the endogenous EDS1 in Nicotiana benthamiana by heterologous virus-induced gene silencing. Our data showed that silencing of NbEDS1 resulted in increased susceptibility to V. dahliae infection in N. benthamiana, suggesting a possible involvement of the novelly isolated GbEDS1 in the regulation of plant defense against V. dahliae.

Daily Planet Imagery: GIBS MODIS Products on ArcGIS Online

NASA Astrophysics Data System (ADS)

Plesea, L.

2015-12-01

The NASA EOSDIS Global Imagery Browse Services (GIBS) is rapidly becoming an invaluable GIS resource for the science community and for the public at large. Reliable, fast access to historical as well as near real time, georeferenced images form a solid basis on which many innovative applications and projects can be built. Esri has recognized the value of this effort and is a GIBS user and collaborator. To enable the use of GIBS services within the ArcGIS ecosystem, Esri has built a GIBS reflector server at http://modis.arcgis.com, server which offers the facilities of a time enabled Mosaic Service on top of the GIBS provided images. Currently the MODIS reflectance products are supported by this mosaic service, possibilities of handling other GIBS products are being explored. This reflector service is deployed on the Amazon Elastic Compute Cloud platform, and is freely available to the end users. Due to the excellent response time from GIBS, image tiles do not have to be stored by the Esri mosaic server, all needed data being retrieved directly from GIBS when needed, continuously reflecting the state of GIBS, and greatly simplifying the maintenance of this service. Response latency is usually under one second, making it easy to interact with the data. The remote data access is achieved by using the Geospatial Data Abstraction Library (GDAL) Tiled Web Map Server (TWMS) driver. The response time of this server is excellent, usually under one second. The MODIS imagery has proven to be one of the most popular ones on the ArcGIS Online platform, where it is frequently use to provide temporal context to maps, or by itself, to tell a compelling story.

Design and construction of multigenic constructs for plant biotechnology using the GoldenBraid cloning strategy.

PubMed

Sarrion-Perdigones, Alejandro; Palaci, Jorge; Granell, Antonio; Orzaez, Diego

2014-01-01

GoldenBraid (GB) is an iterative and standardized DNA assembling system specially designed for Multigene Engineering in Plant Synthetic Biology. GB is based on restriction-ligation reactions using type IIS restriction enzymes. GB comprises a collection of standard DNA pieces named "GB parts" and a set of destination plasmids (pDGBs) that incorporate the multipartite assembly of standardized DNA parts. GB reactions are extremely efficient: two transcriptional units (TUs) can be assembled from several basic GBparts in one T-DNA less than 24 h. Moreover, larger assemblies comprising 4-5 TUs are routinely built in less than 2 working weeks. Here we provide a detailed view of the GB methodology. As a practical example, a Bimolecular Fluorescence Complementation construct comprising four TUs in a 12 kb DNA fragment is presented.

Faceting of {sigma}3 and {sigma}9 grain boundaries in Cu-Bi alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Straumal, B.B.; Polyakov, S.A.; Max-Planck-Institut fuer Metallforschung and Institut fuer Metallkunde, Heisenbergstr. 3, 70569 Stuttgart

2005-01-10

The faceting of {sigma}3 and {sigma}9 tilt grain boundaries (GBs) has been studied in bicrystals of pure Cu and Cu-Bi alloys containing 2.5 x 10{sup -3}, 10 x 10{sup -3} and 16 x 10{sup -3} at.% Bi. The {sigma}3(1 0 0), {sigma}9(1 0 0), {sigma}9(-1 1 0), and {sigma}9(-1 2 0) facets and non-CSL {sigma}3 82 deg 9R facet were observed, where {sigma} is the inverse density of coincidence sites. The ratio between GB energy, {sigma}{sub GB}, and surface energy, {sigma}{sub sur}, was measured by atomic force microscopy using the GB thermal-groove method. The GB energy and thermal-groove deepening ratemore » increased slightly between 0 and 10 x 10{sup -3} at.% Bi for all facets studied. However, between 10 x 10{sup -3} and 16 x 10{sup -3} at.% Bi the GB energy increased dramatically [from a factor 2 for the {sigma}9(1 1 0) facet to 15 times larger for the {sigma}3(1 0 0) facet]. The thermal-groove deepening rate also increased by a factor of 10 in this concentration range. This change corresponds well with the GB solidus line (i.e., the formation of a stable layer of a liquid-like GB phase called GB prewetting) observed previously. Wulff diagrams were constructed using measured {sigma}{sub GB}/{sigma}{sub sur} values.« less

CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.

PubMed

Han, Jianfeng; Chu, Jianhong; Keung Chan, Wing; Zhang, Jianying; Wang, Youwei; Cohen, Justus B; Victor, Aaron; Meisen, Walter H; Kim, Sung-hak; Grandi, Paola; Wang, Qi-En; He, Xiaoming; Nakano, Ichiro; Chiocca, E Antonio; Glorioso, Joseph C; Kaur, Balveen; Caligiuri, Michael A; Yu, Jianhua

2015-07-09

Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL, and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.

Betaine Aldehyde Dehydrogenase expression during physiological cardiac hypertrophy induced by pregnancy.

PubMed

Rosas-Rodríguez, Jesús Alfredo; Soñanez-Organis, José Guadalupe; Godoy-Lugo, José Arquimides; Espinoza-Salazar, Juan Alberto; López-Jacobo, Cesar Jeravy; Stephens-Camacho, Norma Aurora; González-Ochoa, Guadalupe

2017-08-26

Betaine Aldehyde Dehydrogenase (betaine aldehyde: NAD(P) + oxidoreductase, (E.C. 1.2.1.8; BADH) catalyze the irreversible oxidation of betaine aldehyde (BA) to glycine betaine (GB) and is essential for polyamine catabolism, γ-aminobutyric acid synthesis, and carnitine biosynthesis. GB is an important osmolyte that regulates the homocysteine levels, contributing to a vascular risk factor reduction. In this sense, distinct investigations describe the physiological roles of GB, but there is a lack of information about the GB novo synthesis process and regulation during cardiac hypertrophy induced by pregnancy. In this work, the BADH mRNA expression, protein level, and activity were quantified in the left ventricle before, during, and after pregnancy. The mRNA expression, protein content and enzyme activity along with GB content of BADH increased 2.41, 1.95 and 1.65-fold respectively during late pregnancy compared to not pregnancy, and returned to basal levels at postpartum. Besides, the GB levels increased 1.53-fold during pregnancy and remain at postpartum. Our results demonstrate that physiological cardiac hypertrophy induced BADH mRNA expression and activity along with GB production, suggesting that BADH participates in the adaptation process of physiological cardiac hypertrophy during pregnancy, according to the described GB role in cellular osmoregulation, osmoprotection and reduction of vascular risk. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of P impurity on mechanical properties of NiAl Σ5 grain boundary: From perspectives of stress and energy

NASA Astrophysics Data System (ADS)

Hu, Xue-Lan; Zhao, Ruo-Xi; Deng, Jiang-Ge; Hu, Yan-Min; Song, Qing-Gong

2018-03-01

In this paper, we employ the first-principle total energy method to investigate the effect of P impurity on mechanical properties of NiAl grain boundary (GB). According to “energy”, the segregation of P atom in NiAlΣ5 GB reduces the cleavage energy and embrittlement potential, demonstrating that P impurity embrittles NiAlΣ5 GB. The first-principle computational tensile test is conducted to determine the theoretical tensile strength of NiAlΣ5 GB. It is demonstrated that the maximum ideal tensile strength of NiAlΣ5 GB with P atom segregation is 144.5 GPa, which is lower than that of the pure NiAlΣ5 GB (164.7 GPa). It is indicated that the segregation of P weakens the theoretical strength of NiAlΣ5 GB. The analysis of atomic configuration shows that the GB fracture is caused by the interfacial bond breaking. Moreover, P is identified to weaken the interactions between Al–Al bonds and enhance Ni–Ni bonds. Project supported by the National Natural Science Foundation of China (Grant Nos. 11404396 and 51201181) and the Subject Construction Fund of Civil Aviation University of China (Grant No. 000032041102).

Ginkgolide B Exerts Cardioprotective Properties against Doxorubicin-Induced Cardiotoxicity by Regulating Reactive Oxygen Species, Akt and Calcium Signaling Pathways In Vitro and In Vivo.

PubMed

Gao, Junqing; Chen, Tao; Zhao, Deqiang; Zheng, Jianpu; Liu, Zongjun

2016-01-01

The aim of this study was to evaluate the effect of Ginkgolide B (GB) on doxorubicin (DOX) induced cardiotoxicity in vitro and in vivo. Rat cardiomyocyte cell line H9c2 was pretreated with GB and subsequently subjected to doxorubicin treatment. Cell viability and cell apoptosis were assessed by MTT assay and Hoechst staining, respectively. Reactive oxygen species (ROS), Akt phosphorylation and intracellular calcium were equally determined in order to explore the underlying molecular mechanism. To verify the in vivo therapeutic effect of GB, we established a mouse model of cardiotoxicity and determined left ventricle ejection fraction (LVEF) and left ventricular mass (LVM). The in vitro experimental results indicated that pretreatment with GB significantly decreases the viability and apoptosis of H9c2 cells by decreasing ROS and intracellular calcium levels and activating Akt phosphorylation. In the in vivo study, we recorded an improved LVEF and a decreased LVM in the group of cardiotoxic rats treated with GB. Altogether, our findings anticipate that GB exerts a cardioprotective effect through possible regulation of the ROS, Akt and calcium pathways. The findings suggest that combination of GB with DOX in chemotherapy could help avoid the cardiotoxic side effects of GB.

A study of the determination of grain boundary diffusivity and energy through the thermally grown oxide ridges on a Fe-22Cr alloy surface

NASA Astrophysics Data System (ADS)

Lin, Yu; Laughlin, David E.; Zhu, Jingxi

2017-03-01

The grain boundaries (GBs) present in polycrystalline materials are important with respect to materials behaviour and properties. During the transient stage of oxidation, the higher GB diffusivity results in heterogeneous oxidation structures in the form of oxide ridges that emerge along the alloy GBs. In an attempt to delve into the more fundamental aspects of the GBs, such as GB energy, the size of the oxide ridges was quantitatively measured by atomic force microscopy on the post oxidation surface of a Fe-22 wt % Cr alloy after an oxidation exposure at 800 °C in dry air. The GB diffusivity was calculated utilising the ridge size data and the relationship between the GB diffusivity and the GB characteristics was determined. Furthermore, the GB energy was calculated from the GB diffusivity data, also to make comparison with the data available in the literature. The absolute value of the calculated GB energy was quite close to the values reported in the literature. However, compared to the extremely low temperature (0 K) data-set from the literature, the data-set obtained from this study showed much less spread. The smaller variation range may be attributed to the higher temperature condition (1073 K) in this study.

A Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometric Assay for the Quantification of Fabry Disease Biomarker Globotriaosylceramide (GB3) in Fabry Model Mouse.

PubMed

Shin, Seok-Ho; Park, Min-Ho; Byeon, Jin-Ju; Lee, Byeong Ill; Park, Yuri; Ko, Ah-Ra; Seong, Mi-Ran; Lee, Soyeon; Kim, Mi Ra; Seo, Jinwook; Jung, Myung Eun; Jin, Dong-Kyu; Shin, Young G

2018-06-07

Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to determine this biomarker in plasma and in all relevant tissues related to this disease simultaneously is required. However, the limited sample volume, as well as the various levels of GB3 in different matrices makes the GB3 quantitation very challenging. Hereby we developed a rapid method to identify GB3 in mouse plasma and various tissues. Preliminary stability tests were also performed in three different conditions: short-term, freeze-thaw, long-term. The calibration curve was well fitted over the concentration range of 0.042⁻10 μg/mL for GB3 in plasma and 0.082⁻20 μg/g for GB3 in various tissues. This method was successfully applied for the comparison of GB3 levels in Fabry model mice (B6;129-Gla tm1Kul /J), which has not been performed previously to the best of our knowledge.

Refinement of Generalized Born Implicit Solvation Parameters for Nucleic Acids and their Complexes with Proteins

PubMed Central

Nguyen, Hai; Pérez, Alberto; Bermeo, Sherry; Simmerling, Carlos

2016-01-01

The Generalized Born (GB) implicit solvent model has undergone significant improvements in accuracy for modeling of proteins and small molecules. However, GB still remains a less widely explored option for nucleic acid simulations, in part because fast GB models are often unable to maintain stable nucleic acid structures, or they introduce structural bias in proteins, leading to difficulty in application of GB models in simulations of protein-nucleic acid complexes. Recently, GB-neck2 was developed to improve the behavior of protein simulations. In an effort to create a more accurate model for nucleic acids, a similar procedure to the development of GB-neck2 is described here for nucleic acids. The resulting parameter set significantly reduces absolute and relative energy error relative to Poisson Boltzmann for both nucleic acids and nucleic acid-protein complexes, when compared to its predecessor GB-neck model. This improvement in solvation energy calculation translates to increased structural stability for simulations of DNA and RNA duplexes, quadruplexes, and protein-nucleic acid complexes. The GB-neck2 model also enables successful folding of small DNA and RNA hairpins to near native structures as determined from comparison with experiment. The functional form and all required parameters are provided here and also implemented in the AMBER software. PMID:26574454

Phase transformations at interfaces: Observations from atomistic modeling

DOE PAGES

Frolov, T.; Asta, M.; Mishin, Y.

2016-10-01

Here, we review the recent progress in theoretical understanding and atomistic computer simulations of phase transformations in materials interfaces, focusing on grain boundaries (GBs) in metallic systems. Recently developed simulation approaches enable the search and structural characterization of GB phases in single-component metals and binary alloys, calculation of thermodynamic properties of individual GB phases, and modeling of the effect of the GB phase transformations on GB kinetics. Atomistic simulations demonstrate that the GB transformations can be induced by varying the temperature, loading the GB with point defects, or varying the amount of solute segregation. The atomic-level understanding obtained from suchmore » simulations can provide input for further development of thermodynamics theories and continuous models of interface phase transformations while simultaneously serving as a testing ground for validation of theories and models. They can also help interpret and guide experimental work in this field.« less

Secure multiple access for indoor optical wireless communications with time-slot coding and chaotic phase.

PubMed

Liang, Tian; Wang, Ke; Lim, Christina; Wong, Elaine; Song, Tingting; Nirmalathas, Ampalavanapillai

2017-09-04

In this paper, we report a novel mechanism to simultaneously provide secure connections for multiple users in indoor optical wireless communication systems by employing the time-slot coding scheme together with chaotic phase sequence. The chaotic phase sequence is generated according to the logistic map and applied to each symbol to secure the transmission. Proof-of-concept experiments are carried out for multiple system capacities based on both 4-QAM and 16-QAM modulation formats, i.e. 1.25 Gb/s, 2 Gb/s and 2.5 Gb/s for 4-QAM, and 2.5 Gb/s, 3.33 Gb/s and 4 Gb/s for 16-QAM. Experimental results show that in all cases the added chaotic phase does not degrade the legitimate user's signal quality while the illegal user cannot detect the signal without the key.

Combination of bypassing stomach and vagus dissection in high-fat diet-induced obese rats-a long-term investigation.

PubMed

Wang, Yong; Liu, Jingang

2010-03-01

Gastric bypass is the most popular technique in obesity therapy. We hypothesize that bypass surgery can help to control the body weight in morbid obesity, and this effect can be enhanced by vagus dissection. Thirty-six Wistar rats were used in this investigation. They were randomly allocated into six groups. Rats in the gastric bypass group (GB1 and GB2) and the bypass with vagus dissection group (VD1 and VD2) received surgery. Rats in the control group (CO1 and CO2) received sham operation. Twenty days later, rats in the CO1, GB1, and VD1 groups were killed and data on body weights, food intakes, fasting glucose, plasma ghrelin and leptin levels, and GHS-R1a and leptin receptor protein expression in the hypothalamus were collected and summarized. One hundred days later, rats in the CO2, GB2, and VD2 groups were also killed and the same experiments were repeated. Body weights of rats were 258 +/- 4.2 and 232 +/- 2.4 g in the GB1 and VD1 groups, respectively, much lower than the CO1 group (303 +/- 6.9 g). Body weights of rats were 316 +/- 12.3 and 315 +/- 10.3 g in the GB2 and VD2 groups, respectively, much lower than the CO2 group. Food intake in the VD1 group was lower than in the GB1 group, while there were no statistical differences between the VD2 and GB2 groups. Fasting glucose in the GB1 and GB2 groups was much lower than the CO1 and CO2 groups. Plasma ghrelin concentrations were much lower in the GB1 and VD1 groups compared to the CO1 group. One hundred days after surgery, the ghrelin concentrations in the GB2 and VD2 groups were also much lower than the CO2 group. Leptin concentrations decreased significantly with weight loss after bypass surgery. GHS-R1a protein expression in the hypothalamus was much lower in the GB1 and VD1 groups compared to the CO1 group. GHS-R1a protein expressions in the GB2 and VD2 groups were lower than the CO2 group. There were no statistical differences in leptin receptor expression in the hypothalamus (not shown). Vagus nerve dissection is effective on body weight control in the early stage, but not in the long term. The hypothalamus is important in weight control by modulating ghrelin and leptin expressions. Bypass surgery can modulate the expression of ghrelin and its receptor. Leptin is also modulated by bypass surgery.

The Neutralizing Linear Epitope of Human Herpesvirus 6A Glycoprotein B Does Not Affect Virus Infectivity.

PubMed

Wakata, Aika; Kanemoto, Satoshi; Tang, Huamin; Kawabata, Akiko; Nishimura, Mitsuhiro; Jasirwan, Chyntia; Mahmoud, Nora Fahmy; Mori, Yasuko

2018-03-01

Human herpesvirus 6A (HHV-6A) glycoprotein B (gB) is a glycoprotein consisting of 830 amino acids and is essential for the growth of the virus. Previously, we reported that a neutralizing monoclonal antibody (MAb) called 87-y-13 specifically reacts with HHV-6A gB, and we identified its epitope residue at asparagine (Asn) 347 on gB. In this study, we examined whether the epitope recognized by the neutralizing MAb is essential for HHV-6A infection. We constructed HHV-6A bacterial artificial chromosome (BAC) genomes harboring substitutions at Asn347, namely, HHV-6A BACgB(N347K) and HHV-6A BACgB(N347A). These mutant viruses could be reconstituted and propagated in the same manner as the wild type and their revertants, and MAb 87-y-13 could not inhibit infection by either mutant. In a cell-cell fusion assay, Asn at position 347 on gB was found to be nonessential for cell-cell fusion. In addition, in building an HHV-6A gB homology model, we found that the epitope of the neutralizing MAb is located on domain II of gB and is accessible to solvents. These results indicate that Asn at position 347, the linear epitope of the neutralizing MAb, does not affect HHV-6A infectivity. IMPORTANCE Glycoprotein B (gB) is one of the most conserved glycoproteins among all herpesviruses and is a key factor for virus entry. Therefore, antibodies targeted to gB may neutralize virus entry. Human herpesvirus 6A (HHV-6A) encodes gB, which is translated to a protein of about 830 amino acids (aa). Using a monoclonal antibody (MAb) for HHV-6A gB, which has a neutralizing linear epitope, we analyzed the role of its epitope residue, N347, in HHV-6A infectivity. Interestingly, this gB linear epitope residue, N347, was not essential for HHV-6A growth. By constructing a homology model of HHV-6A gB, we found that N347 was located in the region corresponding to domain II. Therefore, with regard to its neutralizing activity against HHV-6A infection, the epitope on gB might be exposed to solvents, suggesting that it might be a target of the immune system. Copyright © 2018 American Society for Microbiology.

An Acidic Cluster in the Cytosolic Domain of Human Cytomegalovirus Glycoprotein B Is a Signal for Endocytosis from the Plasma Membrane

PubMed Central

Tugizov, Sharof; Maidji, Ekaterina; Xiao, Jianqiao; Pereira, Lenore

1999-01-01

We previously reported that human cytomegalovirus (CMV) glycoprotein B (gB) is transported to apical membranes in CMV-infected polarized retinal pigment epithelial (ARPE-19) cells and in Madin-Darby canine kidney (MDCK) epithelial cells constitutively expressing gB. The cytosolic domain of gB contains a cluster of acidic amino acids, a motif that plays a pivotal role in vectorial trafficking in polarized epithelial cells and may also function as a signal for entry into the endocytic pathway. Here we compared gB internalization and recycling to the plasma membrane in CMV-infected human fibroblasts (HF) and ARPE-19 cells by using antibody-internalization experiments. Immunofluorescence and quantitative assays showed that gB was internalized from the cell surface into clathrin-coated transport vesicles and then recycled to the plasma membrane. gB colocalized with clathrin-coated vesicles containing the transferrin receptor in the early endocytic/recycling pathway, indicating that gB traffics in this pathway. The specific role of the acidic cluster in regulating the sorting of gB-containing vesicles in the early endocytic/recycling pathway was examined in MDCK cells expressing mutated gB derivatives. Immunofluorescence assays showed that derivatives lacking the acidic cluster were impaired in internalization and failed to recycle. These findings, together with our earlier observation that the acidic cluster is a key determinant for targeting gB molecules to apical membranes in epithelial cells, establish that this signal is recognized by cellular proteins that participate in polarized sorting and transport in the early endocytic/recycling pathway. PMID:10482621

Assessment of safety of performing percutaneous coronary intervention after a recent episode of gastrointestinal bleeding.

PubMed

Karim, Saima; Ador-Dionisio, Sweetheart T; Karim, Munira; Karim, Mohammad; Khan, Sadaf S; Atreja, Ashish; Ellis, Stephen

2016-03-01

Little literature exists on the risk of performing coronary intervention (PCI) on patients who have had recent gastrointestinal bleeding (GIB), although bleeding after PCI has been identified as a risk factor for long-term mortality. Patients within the Cleveland Clinic PCI database who had acute GIB within 30 days preceding PCI during the same hospitalization (n = 79) were retrospectively compared to those who had PCI without recent GIB (n = 10 979) for mortality and need for revascularization. Baseline characteristics, laboratory values, procedures, morbidities, and mortality were compared using chi-square test for categorical variables and using Wilcoxon rank sum test for continuous variables. Mortality data was obtained using Social Security Death Index and demonstrated using Kaplan-Meier method. The GIB group had more prevalent history of peptic ulcer disease, GIB, gastrointestinal or liver disease (P < 0.0001), transient ischemic accident (P = 0.017), peripheral vascular disease (P = 0.0002), significant carotid artery occlusion (P = 0.023), and myocardial infarction (P < 0.0001). 47% of patients had upper GIB with 20% needing endoscopic intervention. This group had more anemia (P < 0.0001), heart failure (P = 0.0001), cardiogenic shock (10% versus 1.4%, P < 0.001), cardiac arrest (7.6% versus 1%, P < 0.001). GIB group had worse in-hospital mortality (P < 0.0001), long-term mortality (P < 0.001), and a 7.6% re-bleeding incidence. Overall, the patients who had GIB preceding PCI had higher in-hospital mortality and long-term mortality compared with those without GIB before PCI.

Epstein-Barr virus glycoprotein gB and gHgL can mediate fusion and entry in trans, and heat can act as a partial surrogate for gHgL and trigger a conformational change in gB.

PubMed

Chesnokova, Liudmila S; Ahuja, Munish K; Hutt-Fletcher, Lindsey M

2014-11-01

Epstein-Barr virus (EBV) fusion with an epithelial cell requires virus glycoproteins gHgL and gB and is triggered by an interaction between gHgL and integrin αvβ5, αvβ6, or αvβ8. Fusion with a B cell requires gHgL, gp42, and gB and is triggered by an interaction between gp42 and human leukocyte antigen class II. We report here that, like alpha- and betaherpesviruses, EBV, a gammaherpesvirus, can mediate cell fusion if gB and gHgL are expressed in trans. Entry of a gH-null virus into an epithelial cell is possible if the epithelial cell expresses gHgL, and entry of the same virus, which phenotypically lacks gHgL and gp42, into a B cell expressing gHgL is possible in the presence of a soluble integrin. Heat is capable of inducing the fusion of cells expressing only gB, and the proteolytic digestion pattern of gB in virions changes in the same way following the exposure of virus to heat or to soluble integrins. It is suggested that the Gibbs free energy released as a result of the high-affinity interaction of gHgL with an integrin contributes to the activation energy required to cause the refolding of gB from a prefusion to a postfusion conformation. The core fusion machinery of herpesviruses consists of glycoproteins gB and gHgL. We demonstrate that as in alpha- and betaherpesvirus, gB and gHgL of the gammaherpesvirus EBV can mediate fusion and entry when expressed in trans in opposing membranes, implicating interactions between the ectodomains of the proteins in the activation of fusion. We further show that heat and exposure to a soluble integrin, both of which activate fusion, result in the same changes in the proteolytic digestion pattern of gB, possibly representing the refolding of gB from its prefusion to its postfusion conformation. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Glycoprotein gB and gHgL Can Mediate Fusion and Entry in trans, and Heat Can Act as a Partial Surrogate for gHgL and Trigger a Conformational Change in gB

PubMed Central

Chesnokova, Liudmila S.; Ahuja, Munish K.

2014-01-01

ABSTRACT Epstein-Barr virus (EBV) fusion with an epithelial cell requires virus glycoproteins gHgL and gB and is triggered by an interaction between gHgL and integrin αvβ5, αvβ6, or αvβ8. Fusion with a B cell requires gHgL, gp42, and gB and is triggered by an interaction between gp42 and human leukocyte antigen class II. We report here that, like alpha- and betaherpesviruses, EBV, a gammaherpesvirus, can mediate cell fusion if gB and gHgL are expressed in trans. Entry of a gH-null virus into an epithelial cell is possible if the epithelial cell expresses gHgL, and entry of the same virus, which phenotypically lacks gHgL and gp42, into a B cell expressing gHgL is possible in the presence of a soluble integrin. Heat is capable of inducing the fusion of cells expressing only gB, and the proteolytic digestion pattern of gB in virions changes in the same way following the exposure of virus to heat or to soluble integrins. It is suggested that the Gibbs free energy released as a result of the high-affinity interaction of gHgL with an integrin contributes to the activation energy required to cause the refolding of gB from a prefusion to a postfusion conformation. IMPORTANCE The core fusion machinery of herpesviruses consists of glycoproteins gB and gHgL. We demonstrate that as in alpha- and betaherpesvirus, gB and gHgL of the gammaherpesvirus EBV can mediate fusion and entry when expressed in trans in opposing membranes, implicating interactions between the ectodomains of the proteins in the activation of fusion. We further show that heat and exposure to a soluble integrin, both of which activate fusion, result in the same changes in the proteolytic digestion pattern of gB, possibly representing the refolding of gB from its prefusion to its postfusion conformation. PMID:25142593

The fusion loops and membrane proximal region of Epstein-Barr virus glycoprotein B (gB) can function in the context of herpes simplex virus 1 gB when substituted individually but not in combination.

PubMed

Zago, Anna; Connolly, Sarah A; Spear, Patricia G; Longnecker, Richard

2013-01-01

Among the herpesvirus glycoprotein B (gB) fusion proteins, the hydrophobic content of fusion loops and membrane proximal regions (MPRs) are inversely correlated with each other. We examined the functional importance of the hydrophobicity of these regions by replacing them in herpes simplex virus type 1 gB with corresponding regions from Epstein-Barr virus gB. We show that fusion activity is dependent on the structural context in which the specific loops and MPR sequences exist, rather than a simple hydrophobic relationship. Copyright © 2012 Elsevier B.V. All rights reserved.

"Newer, bigger, older" with NASA GIBS

NASA Astrophysics Data System (ADS)

Schmaltz, J. E.; Alarcon, C.; Boller, R. A.; Cechini, M. F.; De Cesare, C.; De Luca, A. P.; Hall, J. R.; Huang, T.; King, J.; Plesea, L.; Pressley, N. N.; Roberts, J. T.; Rodriguez, J. D.; Thompson, C. K.

2015-12-01

The year 2015 witnessed a vast expansion of NASA's Global Imagery Browse Services (GIBS) in a number of dimensions. Near real time imagery was added from a slew of additional sensors including GPM, SMAP, AMSR2, VIIRS, CERES, MOPITT, SSMI, and Aquarius, many of these representing measurements that had not been available in GIBS previously. The SMAP layers are also pioneering a new capability for GIBS to display individual granules. Higher resolution imagery, up to 30m/pixel, is now available in GIBS for some sensors, including ASTER GDEM and L1T and Web-Enabled Landsat Data (WELD). The imagery record is being extended into the past with the entire record of data from MODIS and AMSR-E reprocessing campaigns.

WinHPC System Configuration | High-Performance Computing | NREL

Science.gov Websites

CPUs with 48GB of memory. Node 04 has dual Intel Xeon E5530 CPUs with 24GB of memory. Nodes 05-20 have dual AMD Opteron 2374 HE CPUs with 16GB of memory. Nodes 21-30 have been decommissioned. Nodes 31-35 have dual Intel Xeon X5675 CPUs with 48GB of memory. Nodes 36-37 have dual Intel Xeon E5-2680 CPUs with

Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Backovic, Marija; Longnecker, Richard; Jardetzky, Theodore S

Epstein-Barr virus (EBV) is a herpesvirus that is associated with development of malignancies of lymphoid tissue. EBV infections are life-long and occur in >90% of the population. Herpesviruses enter host cells in a process that involves fusion of viral and cellular membranes. The fusion apparatus is comprised of envelope glycoprotein B (gB) and a heterodimeric complex made of glycoproteins H and L. Glycoprotein B is the most conserved envelope glycoprotein in human herpesviruses, and the structure of gB from Herpes simplex virus 1 (HSV-1) is available. Here, we report the crystal structure of the secreted EBV gB ectodomain, which formsmore » 16-nm long spike-like trimers, structurally homologous to the postfusion trimers of the fusion protein G of vesicular stomatitis virus (VSV). Comparative structural analyses of EBV gB and VSV G, which has been solved in its pre and postfusion states, shed light on gB residues that may be involved in conformational changes and membrane fusion. Also, the EBV gB structure reveals that, despite the high sequence conservation of gB in herpesviruses, the relative orientations of individual domains, the surface charge distributions, and the structural details of EBV gB differ from the HSV-1 protein, indicating regions and residues that may have important roles in virus-specific entry.« less

Evidence for preferential flux flow at the grain boundaries of superconducting RF-quality niobium

NASA Astrophysics Data System (ADS)

Sung, Z.-H.; Lee, P. J.; Gurevich, A.; Larbalestier, D. C.

2018-04-01

The question of whether grain boundaries (GBs) in niobium can be responsible for lowered operating field (B RF) or quality factor (Q 0) in superconducting radio frequency (SRF) cavities is still controversial. Here, we show by direct DC transport across planar GBs isolated from a slice of very large-grain SRF-quality Nb that vortices can preferentially flow along the grain boundary when the external magnetic field lies in the GB plane. However, increasing the misalignment between the GB plane and the external magnetic field vector markedly reduces preferential flux flow along the GB. Importantly, we find that preferential GB flux flow is more prominent for a buffered chemical polished than for an electropolished bi-crystal. The voltage-current characteristics of GBs are similar to those seen in low angle grain boundaries of high temperature superconductors where there is clear evidence of suppression of the superconducting order parameter at the GB. While local weakening of superconductivity at GBs in cuprates and pnictides is intrinsic, deterioration of current transparency of GBs in Nb appears to be extrinsic, since the polishing method clearly affect the local GB degradation. The dependence of preferential GB flux flow on important cavity preparation and experimental variables, particularly the final chemical treatment and the angle between the magnetic field and the GB plane, suggests two more reasons why real cavity performance can be so variable.

Supramolecular structure of glibenclamide and β-cyclodextrins complexes.

PubMed

Lucio, David; Irache, Juan Manuel; Font, María; Martínez-Ohárriz, María Cristina

2017-09-15

Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-βCDs inclusion complexes was carried out using different methods, βCD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for βCD and head-to-tail for HPβCD and RMβCD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-βCD complexes. The arrangement of these structures depended on the GB:βCD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease.

PubMed

Ouyang, Yan; Chen, Bing; Pan, Xiaoxia; Wang, Zhaohui; Ren, Hong; Xu, Yaowen; Ni, Liyan; Yu, Xialian; Yang, Li; Chen, Nan

2018-04-01

Although plasma globotriaosylsphingosine (lyso-Gb3) is a promising biomarker of Fabry disease (FD), few studies have assessed the impact of lyso-Gb3 in patients with FD. A total of 38 patients diagnosed with FD at Ruijin Hospital between January 2012 and December 2014 were recruited in the current study. An additional 120 unrelated healthy individuals were selected as healthy controls. A simplified liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to determine lyso-Gb3 levels in plasma. Protein precipitation and glycolipid extraction were conducted using acetone/methanol. Clinical performance, including diagnostic value and disease surveillance, were compared between plasma lyso-Gb3 levels and α-galactosidase A (α-gal A) enzyme activity. The overall coefficient of variation values between inter- and intra-days varied between 2.8 and 18.9% and linearity correlation coefficients were ≥0.99 for all assays. Therefore, the effectiveness of the LC-MS/MS method was validated. Furthermore, a cut-off value of 0.81 ng/ml plasma lyso-Gb3 was able to separate patients with FD from healthy individuals. The sensitivity of this cut-off was 94.7% and the specificity was 100%. Compared with α-gal A enzyme activity, the diagnostic rate of patients assessed using plasma lyso-Gb3 levels was similar; however, there was a tighter correlation between plasma lyso-Gb3 levels and the mainz severity score index score in male patients (r=0.711 vs. r=-0.687). The sensitivity of plasma lyso-Gb3 in diagnosing female patients with FD was higher than α-gal A enzyme activity (82.4 vs. 23.5%). To the best of our knowledge, the present study is the first to report the effectiveness of plasma lyso-Gb3 levels in diagnosing Chinese patients with FD. Using α-gal A activity as a reference, the results of current study indicated that plasma lyso-Gb3 levels are more useful at diagnosing female patients with FD. Furthermore, plasma lyso-Gb3 levels are more suitable at determining overall disease severity in male patients.

Construction and properties of a cell line constitutively expressing the herpes simplex virus glycoprotein B dependent on functional alpha 4 protein synthesis.

PubMed Central

Arsenakis, M; Hubenthal-Voss, J; Campadelli-Fiume, G; Pereira, L; Roizman, B

1986-01-01

We report the construction of a cell line constitutively expressing the glycoprotein B (gB) of herpes simplex virus (HSV) 1. The cell line was constructed in two steps. In the first, a baby hamster kidney cell line was transfected with the DNA of a plasmid containing the neomycin phosphotransferase gene that confers resistance to the antibiotic G418 and the gene specifying a temperature-sensitive (ts-) alpha 4 protein of HSV-1, the major viral regulatory protein. A clonal cell line, alpha 4/c113, selected for resistance to the antibiotic G418, expressed high levels of alpha 4 protein constitutively. Superinfection of these cells with HSV-2 resulted in twofold induction of the resident HSV-1 alpha 4 gene. In the second step, alpha 4/c113 cells were transfected with the DNA of a plasmid carrying the gB gene and the mouse methotrexate resistance dihydrofolate reductase gene. A clonal cell line, alpha 4/c113/gB, selected for methotrexate resistance expressed gB constitutively. Expression of both gB and alpha 4 continued unabated for at least 32 serial passages. Cells passaged serially in medium containing both methotrexate and G418 after passage 10 contained a higher copy number of the alpha 4 gene and produced larger amounts of both gB and alpha 4 proteins than did cells maintained in medium containing methotrexate alone. Expression of gB was dependent on the presence of functional alpha 4 protein inasmuch as expression of gB ceased on shift up to nonpermissive temperatures, when shifted to permissive temperatures, the cell line reinitiated expression of gB after a delay commensurate with the length of incubation at the nonpermissive temperature, and the cell-resident HSV-1 gB gene was expressed at the nonpermissive temperature in cells infected with a recombinant expressing a ts+ alpha 4 protein and an HSV-2 gB. The properties of the alpha 4/c113 cell line suggest that it may express other viral genes induced by alpha 4 protein constitutively, provided that the product is not toxic to the cells. Images PMID:3022001

Impaired Auditory and Contextual Fear Conditioning in Soman-Exposed Rats

DTIC Science & Technology

2011-01-01

include the piriform cortex, amygdala, thalamus and hippocampus (Carpentier et al., 1990; Petras , 1994; Shih et al., 2003). Often the resulting... Martin M, Shah R, Bertchume A, Colvin J, Dong H. Cholinesterase inhibitors ameliorate behavioral deficits induced by MK-801 in mice. Neuropsy...Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse

Development of Optimized Guidelines for Therapeutic Strategies for Organophosphate Poisoning

DTIC Science & Technology

2011-03-01

compounds (Cannard, 2006). Pyridostigmine bromide , a pretreatment for a potential soman exposure, is a member of the carbamate family (Cannard, 2006...others, 2005) and later expanded that model to incorporate the nerve agent pretreatment by carbamates such as pyridostigmine (Worek and others, 2007...model developed in 2005 to incorporate pretreatment by a carbamate such as pyridostigmine (Worek and others, 2007). Both sets of researchers show

Characterization of Soman Toxicity in Atropine and Oxime (HI-6 and MMB- 4) Treated Rhesus Monkeys

DTIC Science & Technology

1991-03-30

observation period in which a;ni:als died minus the onset time for nonsurvivors. S ). 1 31 .4w~ ~ -.. -- - ’-0 4 .4W .,- aai Iw CA 0 Q C) z ൰ a -’. - -L...Animal Care and Use Comitte ( IACUC ) prior to initiation of the study. The Program Oirector accepts responsibility for the proper care and use of

The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schultz, M.K.; Wright, L.K.M.; Stone, M.F.

2012-03-15

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA{sub A}) receptors. However, seizure activity itself causes the endocytosis of GABA{sub A} receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min followingmore » seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD{sub 50}; 132 μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ► PHY attenuated GD-induced seizure development, but not seizure duration.« less

Herpesvirus gB-induced fusion between the virion envelope and outer nuclear membrane during virus egress is regulated by the viral US3 kinase.

PubMed

Wisner, Todd W; Wright, Catherine C; Kato, Akihisa; Kawaguchi, Yasushi; Mou, Fan; Baines, Joel D; Roller, Richard J; Johnson, David C

2009-04-01

Herpesvirus capsids collect along the inner surface of the nuclear envelope and bud into the perinuclear space. Enveloped virions then fuse with the outer nuclear membrane (NM). We previously showed that herpes simplex virus (HSV) glycoproteins gB and gH act in a redundant fashion to promote fusion between the virion envelope and the outer NM. HSV mutants lacking both gB and gH accumulate enveloped virions in herniations, vesicles that bulge into the nucleoplasm. Earlier studies had shown that HSV mutants lacking the viral serine/threonine kinase US3 also accumulate herniations. Here, we demonstrate that HSV gB is phosphorylated in a US3-dependent manner in HSV-infected cells, especially in a crude nuclear fraction. Moreover, US3 directly phosphorylated the gB cytoplasmic (CT) domain in in vitro assays. Deletion of gB in the context of a US3-null virus did not add substantially to defects in nuclear egress. The majority of the US3-dependent phosphorylation of gB involved the CT domain and amino acid T887, a residue present in a motif similar to that recognized by US3 in other proteins. HSV recombinants lacking gH and expressing either gB substitution mutation T887A or a gB truncated at residue 886 displayed substantial defects in nuclear egress. We concluded that phosphorylation of the gB CT domain is important for gB-mediated fusion with the outer NM. This suggested a model in which the US3 kinase is incorporated into the tegument layer (between the capsid and envelope) in HSV virions present in the perinuclear space. By this packaging, US3 might be brought close to the gB CT tail, leading to phosphorylation and triggering fusion between the virion envelope and the outer NM.

Methylammonium lead iodide grain boundaries exhibit depth-dependent electrical properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacDonald, Gordon A.; Yang, Mengjin; Berweger, Samuel

In this paper, the nanoscale through-film and lateral photo-response and conductivity of large-grained methylammonium lead iodide (MAPbI 3) thin films are studied. In perovskite solar cells (PSC), these films result in efficiencies >17%. The grain boundaries (GBs) show high resistance at the top surface of the film, and act as an impediment to photocurrent collection. However, lower resistance pathways between grains exist below the top surface of the film, indicating that there exists a depth-dependent resistance of GBs (R GB(z)). Furthermore, lateral conductivity measurements indicate that R GB(z) exhibits GB-to-GB heterogeneity. These results indicate that increased photocurrent collection along GBsmore » is not a prerequisite for high-efficiency PSCs. Rather, better control of depth-dependent GB electrical properties, and an improvement in the homogeneity of the GB-to-GB electrical properties, must be managed to enable further improvements in PSC efficiency. Finally, these results refute the implicit assumption seen in the literature that the electrical properties of GBs, as measured at the top surface of the perovskite film, necessarily reflect the electrical properties of GBs within the thickness of the film.« less

Differential diagnosis between gallbladder adenomas and cholesterol polyps on contrast-enhanced harmonic endoscopic ultrasonography.

PubMed

Park, Chan Hyuk; Chung, Moon Jae; Oh, Tak Geun; Park, Jeong Youp; Bang, Seungmin; Park, Seung Woo; Kim, Hyunki; Hwang, Ho Kyoung; Lee, Woo Jung; Song, Si Young

2013-04-01

Differential diagnosis between gallbladder (GB) adenomas and cholesterol polyps based on ultrasonography or endoscopic ultrasonography (EUS) is challenging because they have similar echogenicity and morphology. We evaluated the usefulness of contrast-enhanced harmonic EUS (CEH-EUS) for differentiating between GB adenomas and cholesterol polyps. Between June 2010 and December 2011, a total of 87 patients with GB polyps who underwent a CEH-EUS were reviewed retrospectively. Of the 87 patients, 57 had a cholecystectomy. Of these, 34 patients were diagnosed with adenoma, cholesterol polyp, adenocarcinoma, or adenomyomatosis pathology. The remaining 23 patients were not diagnosed with GB polyps because their lesions separated from the GB mucosal layer during pathological sampling. On CEH-EUS, homogeneous and heterogeneous enhancement was shown in 6 and 2 patients with adenoma and in 4 and 8 patients with cholesterol polyps, respectively. Sensitivity and specificity of CEH-EUS for differential diagnosis of GB adenomas from cholesterol polyps based on the enhancement pattern were 75.0 and 66.6 %, respectively. CEH-EUS might be useful for distinguishing GB adenomas and cholesterol polyps based on enhancement patterns. However, an additional technique such as quantitative perfusion analysis is necessary because visual assessment of CEH-EUS images is subjective.

Manganese (Mn) Oxidation Increases Intracellular Mn in Pseudomonas putida GB-1

PubMed Central

Banh, Andy; Chavez, Valarie; Doi, Julia; Nguyen, Allison; Hernandez, Sophia; Ha, Vu; Jimenez, Peter; Espinoza, Fernanda; Johnson, Hope A.

2013-01-01

Bacterial manganese (Mn) oxidation plays an important role in the global biogeochemical cycling of Mn and other compounds, and the diversity and prevalence of Mn oxidizers have been well established. Despite many hypotheses of why these bacteria may oxidize Mn, the physiological reasons remain elusive. Intracellular Mn levels were determined for Pseudomonas putida GB-1 grown in the presence or absence of Mn by inductively coupled plasma mass spectrometry (ICP-MS). Mn oxidizing wild type P. putida GB-1 had higher intracellular Mn than non Mn oxidizing mutants grown under the same conditions. P. putida GB-1 had a 5 fold increase in intracellular Mn compared to the non Mn oxidizing mutant P. putida GB-1-007 and a 59 fold increase in intracellular Mn compared to P. putida GB-1 ∆2665 ∆2447. The intracellular Mn is primarily associated with the less than 3 kDa fraction, suggesting it is not bound to protein. Protein oxidation levels in Mn oxidizing and non oxidizing cultures were relatively similar, yet Mn oxidation did increase survival of P. putida GB-1 when oxidatively stressed. This study is the first to link Mn oxidation to Mn homeostasis and oxidative stress protection. PMID:24147089

Data storage and retrieval system

NASA Technical Reports Server (NTRS)

Nakamoto, Glen

1991-01-01

The Data Storage and Retrieval System (DSRS) consists of off-the-shelf system components integrated as a file server supporting very large files. These files are on the order of one gigabyte of data per file, although smaller files on the order of one megabyte can be accommodated as well. For instance, one gigabyte of data occupies approximately six 9 track tape reels (recorded at 6250 bpi). Due to this large volume of media, it was desirable to shrink the size of the proposed media to a single portable cassette. In addition to large size, a key requirement was that the data needs to be transferred to a (VME based) workstation at very high data rates. One gigabyte (GB) of data needed to be transferred from an archiveable media on a file server to a workstation in less than 5 minutes. Equivalent size, on-line data needed to be transferred in less than 3 minutes. These requirements imply effective transfer rates on the order of four to eight megabytes per second (4-8 MB/s). The DSRS also needed to be able to send and receive data from a variety of other sources accessible from an Ethernet local area network.

Data storage and retrieval system

NASA Technical Reports Server (NTRS)

Nakamoto, Glen

1992-01-01

The Data Storage and Retrieval System (DSRS) consists of off-the-shelf system components integrated as a file server supporting very large files. These files are on the order of one gigabyte of data per file, although smaller files on the order of one megabyte can be accommodated as well. For instance, one gigabyte of data occupies approximately six 9-track tape reels (recorded at 6250 bpi). Due to this large volume of media, it was desirable to 'shrink' the size of the proposed media to a single portable cassette. In addition to large size, a key requirement was that the data needs to be transferred to a (VME based) workstation at very high data rates. One gigabyte (GB) of data needed to be transferred from an archiveable media on a file server to a workstation in less than 5 minutes. Equivalent size, on-line data needed to be transferred in less than 3 minutes. These requirements imply effective transfer rates on the order of four to eight megabytes per second (4-8 MB/s). The DSRS also needed to be able to send and receive data from a variety of other sources accessible from an Ethernet local area network.

Methylammonium lead iodide grain boundaries exhibit depth-dependent electrical properties

DOE PAGES

MacDonald, Gordon A.; Yang, Mengjin; Berweger, Samuel; ...

2016-09-23

In this paper, the nanoscale through-film and lateral photo-response and conductivity of large-grained methylammonium lead iodide (MAPbI 3) thin films are studied. In perovskite solar cells (PSC), these films result in efficiencies >17%. The grain boundaries (GBs) show high resistance at the top surface of the film, and act as an impediment to photocurrent collection. However, lower resistance pathways between grains exist below the top surface of the film, indicating that there exists a depth-dependent resistance of GBs (R GB(z)). Furthermore, lateral conductivity measurements indicate that R GB(z) exhibits GB-to-GB heterogeneity. These results indicate that increased photocurrent collection along GBsmore » is not a prerequisite for high-efficiency PSCs. Rather, better control of depth-dependent GB electrical properties, and an improvement in the homogeneity of the GB-to-GB electrical properties, must be managed to enable further improvements in PSC efficiency. Finally, these results refute the implicit assumption seen in the literature that the electrical properties of GBs, as measured at the top surface of the perovskite film, necessarily reflect the electrical properties of GBs within the thickness of the film.« less

Density Functional Theory plus Hubbard U Study of the Segregation of Pt to the CeO2- x Grain Boundary.

PubMed

Zhou, Guoli; Li, Pan; Ma, Qingmin; Tian, Zhixue; Liu, Ying

2018-03-14

Grain boundaries (GBs) can be used as traps for solute atoms and defects, and the interaction between segregants and GBs is crucial for understanding the properties of nanocrystalline materials. In this study, we have systematically investigated the Pt segregation and Pt-oxygen vacancies interaction at the ∑3 (111) GB in ceria (CeO 2 ). The Pt atom has a stronger tendency to segregate to the ∑3 (111) GB than to the (111) and (110) free surfaces, but the tendency is weaker than to (112) and (100). Lattice distortion plays a dominant role in Pt segregation. At the Pt-segregated-GB (Pt@GB), oxygen vacancies prefer to form spontaneously near Pt in the GB region. However, at the pristine GB, oxygen vacancies can only form under O-poor conditions. Thus, Pt segregation to the GB promotes the formation of oxygen vacancies, and their strong interactions enhance the interfacial cohesion. We propose that GBs fabricated close to the surfaces of nanocrystalline ceria can trap Pt from inside the grains or other types of surface, resulting in the suppression of the accumulation of Pt on the surface under redox reactions, especially under O-poor conditions.

Towards the Truly Predictive 3D Modeling of Recrystallization and Grain Growth in Advanced Technical Alloys

DTIC Science & Technology

2010-06-11

MODELING WITH IMPLEMENTED GBI AND MD DATA (STEADY STATE GB MIGRATION) PAGE 48 5. FORMATION AND ANALYSIS OF GB PROPERTIES DATABASE PAGE 53 5.1...Relative GB energy for specified GBM averaged on possible GBIs PAGE 53 5.2. Database validation on available experimental data PAGE 56 5.3. Comparison...PAGE 70 Fig. 6.11. MC Potts Rex. and GG software: (a) modeling volume analysis; (b) searching for GB energy value within included database . PAGE

Risk of death in heart disease is associated with elevated urinary globotriaosylceramide.

PubMed

Schiffmann, Raphael; Forni, Sabrina; Swift, Caren; Brignol, Nastry; Wu, Xiaoyang; Lockhart, David J; Blankenship, Derek; Wang, Xuan; Grayburn, Paul A; Taylor, Matthew R G; Lowes, Brian D; Fuller, Maria; Benjamin, Elfrida R; Sweetman, Lawrence

2014-02-04

Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease. We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α-galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near-term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. clinicaltrials.gov. Unique Identifier: NCT01019629.

Risk of Death in Heart Disease is Associated With Elevated Urinary Globotriaosylceramide

PubMed Central

Schiffmann, Raphael; Forni, Sabrina; Swift, Caren; Brignol, Nastry; Wu, Xiaoyang; Lockhart, David J.; Blankenship, Derek; Wang, Xuan; Grayburn, Paul A.; Taylor, Matthew R. G.; Lowes, Brian D.; Fuller, Maria; Benjamin, Elfrida R.; Sweetman, Lawrence

2014-01-01

Background Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X‐linked lysosomal disorder that is a risk factor for most types of heart disease. Methods and Results We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α‐galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow‐up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). Conclusions In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near‐term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. Clinical Trial Registration URL: clinicaltrials.gov. Unique Identifier: NCT01019629. PMID:24496231

Noncanonical Gβ Gib2 is a scaffolding protein promoting cAMP signaling through functions of Ras1 and Cac1 proteins in Cryptococcus neoformans.

PubMed

Wang, Yanli; Shen, Gui; Gong, Jinjun; Shen, Danyu; Whittington, Amy; Qing, Jiang; Treloar, Joshua; Boisvert, Scott; Zhang, Zhengguang; Yang, Cai; Wang, Ping

2014-05-02

Gβ-like/RACK1 functions as a key mediator of various pathways and contributes to numerous cellular functions in eukaryotic organisms. In the pathogenic fungus Cryptococcus neoformans, noncanonical Gβ Gib2 promotes cAMP signaling in cells lacking normal Gpa1 function while displaying versatility in interactions with Gα Gpa1, protein kinase Pkc1, and endocytic intersectin Cin1. To elucidate the Gib2 functional mechanism(s), we demonstrate that Gib2 is required for normal growth and virulence. We show that Gib2 directly binds to Gpa1 and Gγ Gpg1/Gpg2 and that it interacts with phosphodiesterase Pde2 and monomeric GTPase Ras1. Pde2 remains functionally dispensable, but Ras1 is found to associate with adenylyl cyclase Cac1 through the conserved Ras association domain. In addition, the ras1 mutant exhibits normal capsule formation, whereas the ras1 gpa1 mutant displays enhanced capsule formation, and the ras1 gpa1 cac1 mutant is acapsular. Collectively, these findings suggest that Gib2 promotes cAMP levels by relieving an inhibitory function of Ras1 on Cac1 in the absence of Gpa1. In addition, using GST affinity purification combined with mass spectrometry, we identified 47 additional proteins that interact with Gib2. These proteins have putative functions ranging from signal transduction, energy generation, metabolism, and stress response to ribosomal function. After establishing and validating a protein-protein interactive network, we believe Gib2 to be a key adaptor/scaffolding protein that drives the formation of various protein complexes required for growth and virulence. Our study reveals Gib2 as an essential component in deciphering the complexity of regulatory networks that control growth and virulence in C. neoformans.

Characteristics of belching, swallowing, and gastroesophageal reflux in belching patients based on Rome III criteria.

PubMed

Li, Jianbo; Xiao, Yinglian; Peng, Sui; Lin, Jinkun; Chen, Minhu

2013-08-01

Belching is a common disorder with undetermined pathogenesis. With the combined multichannel intraluminal impedance pH monitoring, two different models of belching have been defined: gastric belching (GB) and supragastric belching (SB). The aim of this study was to assess whether SB was associated with air swallowing as compared with GB or healthy volunteers based on Rome III criteria. Consecutive patients who presented with troublesome repetitive belching were recruited. Both upper endoscopy and multichannel intraluminal impedance pH monitoring were performed. Patients were divided into two groups: SB and GB groups according to the percentage of the predominant belching types. Twenty volunteers were enrolled as healthy controls. The number of air swallowing, regular swallowing, and gastroesophageal reflux profile was compared among the three groups. Thirty-seven patients were included in the study: 25 in the SB group and 12 in GB group. SB patients presented more belching events than GB patients (P < 0.05). There were no significant differences among the SB, GB patients, and healthy volunteers concerning the episodes of air swallowing and regular swallowing (P > 0.05). No significant difference was found among the three groups in regard with the reflux parameters (P > 0.05). The number of gas-containing reflux episodes were 33.0 (20.0, 48.0), 39.5 (29.5, 47.5), and 30.5 (27.0, 41.8) among SB, GB, and healthy volunteers (P = 0.383), respectively. SB patients presented with more belching events compared with GB patients. However, air swallowing and reflux profile were similar among the SB, GB patients, and normal controls. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

A study of variation characteristics of Gobi broadband emissivity based on field observational experiments in northwestern China

NASA Astrophysics Data System (ADS)

Zheng, Zhi-yuan; Wei, Zhi-gang; Wen, Zhi-ping; Dong, Wen-jie; Li, Zhen-chao; Wen, Xiao-hang; Zhu, Xian; Chen, Chen; Hu, Shan-shan

2018-02-01

Land surface emissivity is a significant variable in energy budgets, land cover assessments, and environment and climate studies. However, the assumption of an emissivity constant is being used in Gobi broadband emissivity (GbBE) parameterization scheme in numerical models because of limited knowledge surrounding the spatiotemporal variation characteristics of GbBE. To address this issue, we analyzed the variation characteristics of GbBE and possible impact factor-surface soil moisture based on long-term continuous and high temporal resolution field observational experiments over a typical Gobi underlying surface in arid and semiarid areas in northwestern China. The results indicate that GbBE has obvious daily and diurnal variation features, especially diurnal cycle characteristics. The multi-year average of the daily average of GbBE is in the range of 0.932 to 0.970 with an average of 0.951 ± 0.008, and the average diurnal GbBE is in the range of 0.880 to 0.940 with an average of 0.906 ± 0.018. GbBE varies with surface soil moisture content. We observed a slight decrease in GbBE with an increase in soil moisture, although this change was not very obvious because of the low soil moisture in this area. Nevertheless, we think that soil moisture must be one of the most significant impact factors on GbBE in arid and semiarid areas. Soil moisture must be taken into account into the parameterization schemes of bare soil broadband emissivity in land surface models. Additional field experiments and studies should be carried out in order to clarify this issue.

Comparison of detection methods for cell surface globotriaosylceramide.

PubMed

Kim, Minji; Binnington, Beth; Sakac, Darinka; Fernandes, Kimberly R; Shi, Sheryl P; Lingwood, Clifford A; Branch, Donald R

2011-08-31

The cell surface-expressed glycosphingolipid (GSL), globotriaosylceramide (Gb(3)), is becoming increasingly important and is widely studied in the areas of verotoxin (VT)-mediated cytotoxicity, human immunodeficiency virus (HIV) infection, immunology and cancer. However, despite its diverse roles and implications, an optimized detection method for cell surface Gb(3) has not been determined. GSLs are differentially organized in the plasma membrane which can affect their availability for protein binding. To examine various detection methods for cell surface Gb(3), we compared four reagents for use in flow cytometry analysis. A natural ligand (VT1B) and three different monoclonal antibodies (mAbs) were optimized and tested on various human cell lines for Gb(3) detection. A differential detection pattern of cell surface Gb(3) expression, which was influenced by the choice of reagent, was observed. Two mAb were found to be suboptimal. However, two other methods were found to be useful as defined by their high percentage of positivity and mean fluorescence intensity (MFI) values. Rat IgM anti-Gb(3) mAb (clone 38-13) using phycoerythrin-conjugated secondary antibody was found to be the most specific detection method while the use of VT1B conjugated to Alexa488 fluorochrome was found to be the most sensitive; showing a rare crossreactivity only when Gb(4) expression was highly elevated. The findings of this study demonstrate the variability in detection of Gb(3) depending on the reagent and cell target used and emphasize the importance of selecting an optimal methodology in studies for the detection of cell surface expression of Gb(3). Copyright © 2011 Elsevier B.V. All rights reserved.

A differential equation for the Generalized Born radii.

PubMed

Fogolari, Federico; Corazza, Alessandra; Esposito, Gennaro

2013-06-28

The Generalized Born (GB) model offers a convenient way of representing electrostatics in complex macromolecules like proteins or nucleic acids. The computation of atomic GB radii is currently performed by different non-local approaches involving volume or surface integrals. Here we obtain a non-linear second-order partial differential equation for the Generalized Born radius, which may be solved using local iterative algorithms. The equation is derived under the assumption that the usual GB approximation to the reaction field obeys Laplace's equation. The equation admits as particular solutions the correct GB radii for the sphere and the plane. The tests performed on a set of 55 different proteins show an overall agreement with other reference GB models and "perfect" Poisson-Boltzmann based values.

Generation and transmission of DPSK signals using a directly modulated passive feedback laser.

PubMed

Karar, Abdullah S; Gao, Ying; Zhong, Kang Ping; Ke, Jian Hong; Cartledge, John C

2012-12-10

The generation of differential-phase-shift keying (DPSK) signals is demonstrated using a directly modulated passive feedback laser at 10.709-Gb/s, 14-Gb/s and 16-Gb/s. The quality of the DPSK signals is assessed using both noncoherent detection for a bit rate of 10.709-Gb/s and coherent detection with digital signal processing involving a look-up table pattern-dependent distortion compensator. Transmission over a passive link consisting of 100 km of single mode fiber at a bit rate of 10.709-Gb/s is achieved with a received optical power of -45 dBm at a bit-error-ratio of 3.8 × 10(-3) and a 49 dB loss margin.

Disconnections kinks and competing modes in shear-coupled grain boundary migration

NASA Astrophysics Data System (ADS)

Combe, N.; Mompiou, F.; Legros, M.

2016-01-01

The response of small-grained metals to mechanical stress is investigated by a theoretical study of the elementary mechanisms occurring during the shear-coupled migration of grain boundaries (GB). Investigating a model Σ 17 (410 ) GB in a copper bicrystal, both <110 > and <100 > GB migration modes are studied focusing on both the structural and energetic characteristics. The minimum energy paths of these shear-coupled GB migrations are computed using the nudge elastic band method. For both modes, the GB migration occurs through the nucleation and motion of disconnections. However, the atomic mechanisms of both modes qualitatively differ: While the <110 > mode presents no metastable state, the <100 > mode shows multiple metastable states, some of them evidencing some kinks along the disconnection lines. Disconnection kinks nucleation and motion activation energies are evaluated. Besides, the activation energies of the <100 > mode are smaller than those of the <110 > one except for very high stresses. These results significantly improve our knowledge of the GB migration mechanisms and the conditions under which they occur.

Demonstration of 20Gb/s polarization-insensitive wavelength switching system for high-speed free-space optical network

NASA Astrophysics Data System (ADS)

Qian, Feng-chen; Ye, Ya-lin; Wen, Yu; Duan, Tao; Feng, Huan

2015-10-01

A 20Gb/s polarization-insensitive all-optical wavelength switching system for high-speed free-space optical communication (FSO) network is experimentally demonstrated All-optical wavelength conversion (AOWC) is implemented using four-wave mixing (FWM) by highly-nonlinear fiber (HNLF). In the experimental setup, a simple actively mode-locked fiber ring laser (AML-FRL) with repetition frequency from 1 to 15 GHz is used to generate eight 2.5Gb/s tributary signals, which are multiplexed into one 20Gb/s optical data stream. At the receiver, the 20 Gb/s OTDM data stream is demultiplexed down to 2.5 Gb/s via a polarization-insensitive FWM scheme. The whole space communication distance is over 10 meters in building hallway. The experimental results show that this system can stably run over 24 hours at 10-9 BER level, thus the proposed architecture can work at higher rate with wavelength-division multiplexing (WDM) and high order modulation schemes.

Improved Growth and Metabolite Accumulation in Codonopsis pilosula (Franch.) Nannf. by Inoculation of Bacillus amyloliquefaciens GB03.

PubMed

Zhao, Qi; Wu, Yong-Na; Fan, Qin; Han, Qing-Qing; Paré, Paul W; Xu, Rui; Wang, Yin-Quan; Wang, Suo-Min; Zhang, Jin-Lin

2016-11-02

Codonopsis pilosula (Franch.) Nannf. is a traditional Chinese herbal medicinal plant and a low-cost succedaneum for Panax ginseng and contains various bioactivity components. In this work, we first evaluated the effects of the inoculation of the plant growth-promoting rhizobacteria Bacillus amyloliquefaciens strain GB03 on growth and metabolite accumulation of C. pilosula. The results demonstrated that application of B. amyloliquefaciens GB03 significantly improved the growth of C. pilosula compared to DH5α, Luria broth medium, and water treatment, respectively. On the other hand, we observed that the content of lobetyolin, one of the most important secondary metabolites in C. pilosula, was obviously improved by inoculation of GB03 and almost reached twice that compared to the other three treatments. In addition, some amino acids of roots were elevated by GB03, although not significantly. In conclusion, B. amyloliquefaciens GB03 could induce positive effects on the growth and further stimulate accumulation of secondary metabolites in C. pilosula.

Neuroprotective Effect of Ginkgolide B on Bupivacaine-Induced Apoptosis in SH-SY5Y Cells

PubMed Central

Li, Le; Zhang, Qing-guo; Lai, Lu-ying; Wen, Xian-jie; Zheng, Ting; Cheung, Chi-wai; Zhou, Shu-qin; Xu, Shi-yuan

2013-01-01

Local anesthetics are used routinely and effectively. However, many are also known to activate neurotoxic pathways. We tested the neuroprotective efficacy of ginkgolide B (GB), an active component of Ginkgo biloba, against ROS-mediated neurotoxicity caused by the local anesthetic bupivacaine. SH-SY5Y cells were treated with different concentrations of bupivacaine alone or following preincubation with GB. Pretreatment with GB increased SH-SY5Y cell viability and attenuated intracellular ROS accumulation, apoptosis, mitochondrial dysfunction, and ER stress. GB suppressed bupivacaine-induced mitochondrial depolarization and mitochondria complex I and III inhibition and increased cleaved caspase-3 and Htra2 expression, which was strongly indicative of activation of mitochondria-dependent apoptosis with concomitantly enhanced expressions of Grp78, caspase-12 mRNA, protein, and ER stress. GB also improved ultrastructural changes indicative of mitochondrial and ER damage induced by bupivacaine. These results implicate bupivacaine-induced ROS-dependent mitochondria, ER dysfunction, and apoptosis, which can be attenuated by GB through its antioxidant property. PMID:24228138

Atomistic modeling of La3+ doping segregation effect on nanocrystalline yttria-stabilized zirconia.

PubMed

Zhang, Shenli; Sha, Haoyan; Castro, Ricardo H R; Faller, Roland

2018-05-16

The effect of La3+ doping on the structure and ionic conductivity change in nanocrystalline yttria-stabilized zirconia (YSZ) was studied using a combination of Monte Carlo and molecular dynamics simulations. The simulation revealed the segregation of La3+ at eight tilt grain boundary (GB) structures and predicted an average grain boundary (GB) energy decrease of 0.25 J m-2, which is close to the experimental values reported in the literature. Cation stabilization was found to be the main reason for the GB energy decrease, and energy fluctuations near the grain boundary are smoothed out with La3+ segregation. Both dynamic and energetic analysis on the Σ13(510)/[001] GB structure revealed La3+ doping hinders O2- diffusion in the GB region, where the diffusion coefficient monotonically decreases with increasing La3+ doping concentration. The effect was attributed to the increase in the site-dependent migration barriers for O2- hopping caused by segregated La3+, which also leads to anisotropic diffusion at the GB.

Should Helicopters Transport Patients Who Become Sick After a Chemical, Biological, Radiological, Nuclear, and Explosive Attack?

PubMed

Yanagawa, Youichi; Ishikawa, Kouhei; Takeuchi, Ikuto; Nagasawa, Hiroki; Jitsuiki, Kei; Ohsaka, Hiromichi; Omori, Kazuhiko

The local fire department executed a training simulation for chemical and explosive incidents at a large sports facility. In this training simulation, a physician-staffed helicopter arrived at the request of the fire department and landed just outside the cold zone in the parking area. The doctor and nurse of the helicopter were escorted to a red area in the cold zone, which was selected based on the results of postdecontamination triage. After the patients had been treated, they were air medically evacuated to the base hospital. In the Tokyo subway sarin attack in 1995, St Luke's International Hospital admitted over 600 victims. During this incident, 23.2% of medical staff suffered secondary injury from sarin exposure. If air medial crews respond with subsequent postexposure effects during flight, an affected pilot could lose control of the helicopter, resulting in a fatal crash. Based on potential safety concerns for air medical and ground personnel, our recommendation would be that air medical helicopters not be dispatched to sites of chemical, biological, radiological, nuclear, and explosive incidents. Copyright © 2018 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

Qualitative and Quantitative Imaging Evaluation of Renal Cell Carcinoma Subtypes with Grating-based X-ray Phase-contrast CT

NASA Astrophysics Data System (ADS)

Braunagel, Margarita; Birnbacher, Lorenz; Willner, Marian; Marschner, Mathias; De Marco, Fabio; Viermetz, Manuel; Notohamiprodjo, Susan; Hellbach, Katharina; Auweter, Sigrid; Link, Vera; Woischke, Christine; Reiser, Maximilian F.; Pfeiffer, Franz; Notohamiprodjo, Mike; Herzen, Julia

2017-03-01

Current clinical imaging methods face limitations in the detection and correct characterization of different subtypes of renal cell carcinoma (RCC), while these are important for therapy and prognosis. The present study evaluates the potential of grating-based X-ray phase-contrast computed tomography (gbPC-CT) for visualization and characterization of human RCC subtypes. The imaging results for 23 ex vivo formalin-fixed human kidney specimens obtained with phase-contrast CT were compared to the results of the absorption-based CT (gbCT), clinical CT and a 3T MRI and validated using histology. Regions of interest were placed on each specimen for quantitative evaluation. Qualitative and quantitative gbPC-CT imaging could significantly discriminate between normal kidney cortex (54 ± 4 HUp) and clear cell (42 ± 10), papillary (43 ± 6) and chromophobe RCCs (39 ± 7), p < 0.05 respectively. The sensitivity for detection of tumor areas was 100%, 50% and 40% for gbPC-CT, gbCT and clinical CT, respectively. RCC architecture like fibrous strands, pseudocapsules, necrosis or hyalinization was depicted clearly in gbPC-CT and was not equally well visualized in gbCT, clinical CT and MRI. The results show that gbPC-CT enables improved discrimination of normal kidney parenchyma and tumorous tissues as well as different soft-tissue components of RCCs without the use of contrast media.

A molecular dynamics study of tilt grain boundary resistance to slip and heat transfer in nanocrystalline silicon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Xiang; Chen, Youping; Xiong, Liming

2014-12-28

We present a molecular dynamics study of grain boundary (GB) resistance to dislocation-mediated slip transfer and phonon-mediated heat transfer in nanocrystalline silicon bicrystal. Three most stable 〈110〉 tilt GBs in silicon are investigated. Under mechanical loading, the nucleation and growth of hexagonal-shaped shuffle dislocation loops are reproduced. The resistances of different GBs to slip transfer are quantified through their constitutive responses. Results show that the Σ3 coherent twin boundary (CTB) in silicon exhibits significantly higher resistance to dislocation motion than the Σ9 GB in glide symmetry and the Σ19 GB in mirror symmetry. The distinct GB strengths are explained bymore » the atomistic details of the dislocation-GB interaction. Under thermal loading, based on a thermostat-induced heat pulse model, the resistances of the GBs to transient heat conduction in ballistic-diffusive regime are characterized. In contrast to the trend found in the dislocation-GB interaction in bicrystal models with different GBs, the resistances of the same three GBs to heat transfer are strikingly different. The strongest dislocation barrier Σ3 CTB is almost transparent to heat conduction, while the dislocation-permeable Σ9 and Σ19 GBs exhibit larger resistance to heat transfer. In addition, simulation results suggest that the GB thermal resistance not only depends on the GB energy but also on the detailed atomic structure along the GBs.« less

Comparative genome analysis of Lactobacillus plantarum GB-LP3 provides candidates of survival-related genetic factors.

PubMed

Jeon, Soomin; Jung, Jaehoon; Kim, Kwondo; Yoo, DongAhn; Lee, Chanho; Kang, Jungsun; Cho, Kyungjin; Kang, Dae-Kyung; Kwak, Woori; Yoon, Sook Hee; Kim, Heebal; Cho, Seoae

2017-09-01

Lactobacillus plantarum is found in various environmental niches such as in the gastrointestinal tract of an animal host or a fermented food. This species isolated from a certain environment is known to possess a variety of properties according to inhabited environment's adaptation. However, a causal relationship of a genetic factor and phenotype affected by a specific environment has not been systematically comprehended. L. plantarum GB-LP3 strain was isolated from Korean traditional fermented vegetable and the whole genome of GB-LP3 was sequenced. Comparative genome analysis of GB-LP3, with other 14 L. plantarum strains, was conducted. In addition, genomic island regions were investigated. The assembled whole GB-LP3 genome contained a single circular chromosome of 3,206,111bp with the GC content of 44.7%. In the phylogenetic tree analysis, GB-LP3 was in the closest distance from ZJ316. The genomes of GB-LP3 and ZJ316 have the high level of synteny. Functional genes that are related to prophage, bacteriocin, and quorum sensing were found through comparative genomic analysis with ZJ316 and investigation of genomic islands. dN/dS analysis identified that the gene coding for phosphonate ABC transporter ATP-binding protein is evolutionarily accelerated in GB-LP3. Our study found that potential candidate genes that are affected by environmental adaptation in Korea traditional fermented vegetable. Copyright © 2017. Published by Elsevier B.V.

Evidence for preferential flux flow at the grain boundaries of superconducting RF-quality niobium

DOE PAGES

Sung, Z. -H.; Lee, P. J.; Gurevich, A.; ...

2018-02-19

Here, the question of whether grain boundaries (GBs) in niobium can be responsible for lowered operating field (B RF) or quality factor (Q 0) in superconducting radio-frequency (SRF) cavities is still controversial. Here, we show by direct DC transport across planar grain boundaries isolated from a slice of very large-grain SRF-quality Nb that vortices can preferentially flow along the grain boundary when the external magnetic field lies in the GB plane. However, increasing the misalignment between the GB plane and the external magnetic field vector markedly reduces preferential flux flow along GB. Importantly, we find that preferential GB flux flowmore » is more prominent for a buffered chemical polished than for an electropolished bi-crystal. The voltage-current characteristics of GBs are similar to those seen in low angle grain boundaries of high temperature superconductors where there is clear evidence of suppression of the superconducting order parameter at the GB. While local weakening of superconductivity at GBs in cuprates and pnictides is intrinsic, deterioration of current transparency of GBs in Nb appears to be extrinsic, since the polishing method clearly affect the local GB degradation. The dependence of preferential GB flux flow on important cavity preparation and experimental variables, particularly, the final chemical treatment and the angle between the magnetic field and the GB plane, suggests two more reasons why real cavity performance can be so variable.« less

Evidence for preferential flux flow at the grain boundaries of superconducting RF-quality niobium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sung, Z. -H.; Lee, P. J.; Gurevich, A.

Here, the question of whether grain boundaries (GBs) in niobium can be responsible for lowered operating field (B RF) or quality factor (Q 0) in superconducting radio-frequency (SRF) cavities is still controversial. Here, we show by direct DC transport across planar grain boundaries isolated from a slice of very large-grain SRF-quality Nb that vortices can preferentially flow along the grain boundary when the external magnetic field lies in the GB plane. However, increasing the misalignment between the GB plane and the external magnetic field vector markedly reduces preferential flux flow along GB. Importantly, we find that preferential GB flux flowmore » is more prominent for a buffered chemical polished than for an electropolished bi-crystal. The voltage-current characteristics of GBs are similar to those seen in low angle grain boundaries of high temperature superconductors where there is clear evidence of suppression of the superconducting order parameter at the GB. While local weakening of superconductivity at GBs in cuprates and pnictides is intrinsic, deterioration of current transparency of GBs in Nb appears to be extrinsic, since the polishing method clearly affect the local GB degradation. The dependence of preferential GB flux flow on important cavity preparation and experimental variables, particularly, the final chemical treatment and the angle between the magnetic field and the GB plane, suggests two more reasons why real cavity performance can be so variable.« less

Prospective randomized trial comparing magnetic resonance imaging (MRI)-guided in-bore biopsy to MRI-ultrasound fusion and transrectal ultrasound-guided prostate biopsy in patients with prior negative biopsies.

PubMed

Arsov, Christian; Rabenalt, Robert; Blondin, Dirk; Quentin, Michael; Hiester, Andreas; Godehardt, Erhard; Gabbert, Helmut E; Becker, Nikolaus; Antoch, Gerald; Albers, Peter; Schimmöller, Lars

2015-10-01

A significant proportion of prostate cancers (PCas) are missed by conventional transrectal ultrasound-guided biopsy (TRUS-GB). It remains unclear whether the combined approach using targeted magnetic resonance imaging (MRI)-ultrasound fusion-guided biopsy (FUS-GB) and systematic TRUS-GB is superior to targeted MRI-guided in-bore biopsy (IB-GB) for PCa detection. To compare PCa detection between IB-GB alone and FUS-GB + TRUS-GB in patients with at least one negative TRUS-GB and prostate-specific antigen ≥4 ng/ml. Patients were prospectively randomized after multiparametric prostate MRI to IB-GB (arm A) or FUS-GB + TRUS-GB (arm B) from November 2011 to July 2014. The study was powered at 80% to demonstrate an overall PCa detection rate of ≥60% in arm B compared to 40% in arm A. Secondary endpoints were the distribution of highest Gleason scores, the rate of detection of significant PCa (Gleason ≥7), the number of biopsy cores to detect one (significant) PCa, the positivity rate for biopsy cores, and tumor involvement per biopsy core. The study was halted after interim analysis because the primary endpoint was not met. The trial enrolled 267 patients, of whom 210 were analyzed (106 randomized to arm A and 104 to arm B). PCa detection was 37% in arm A and 39% in arm B (95% confidence interval for difference, -16% to 11%; p=0.7). Detection rates for significant PCa (29% vs 32%; p=0.7) and the highest percentage tumor involvement per biopsy core (48% vs 42%; p=0.4) were similar between the arms. The mean number of cores was 5.6 versus 17 (p<0.001). A limitation is the limited number of patients because of early cessation of accrual. This trial failed to identify an important improvement in detection rate for the combined biopsy approach over MRI-targeted biopsy alone. A prospective comparison between MRI-targeted biopsy alone and systematic TRUS-GB is justified. Our randomized study showed similar prostate cancer detection rates between targeted prostate biopsy guided by magnetic resonance imaging and the combination of targeted biopsy and systematic transrectal ultrasound-guided prostate biopsy. An important improvement in detection rates using the combined biopsy approach can be excluded. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Comparison of High Performance Network Options: EDR InfiniBand vs.100Gb RDMA Capable Ethernet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kachelmeier, Luke Anthony; Van Wig, Faith Virginia; Erickson, Kari Natania

These are the slides for a presentation at the HPC Mini Showcase. This is a comparison of two different high performance network options: EDR InfiniBand and 100Gb RDMA capable ethernet. The conclusion of this comparison is the following: there is good potential, as shown with the direct results; 100Gb technology is too new and not standardized, thus deployment effort is complex for both options; different companies are not necessarily compatible; if you want 100Gb/s, you must get it all from one place.

Urgent Virtual Machine Eviction with Enlightened Post-Copy

DTIC Science & Technology

2015-12-01

memory is in use, almost all of which is by Memcached. MySQL : The VMs run MySQL 5.6, and the clients execute OLTPBenchmark [3] using the Twitter...workload with scale factor of 960. The VMs are each allocated 16 cores and 30 GB of memory, and MySQL is configured with a 16 GB buffer pool in memory. The...operation mix for 5 minutes as a warm-up. At the time of migration, MySQL uses approximately 17 GB of memory, and almost all of the 30 GB memory is

[Analysis on the accuracy of simple selection method of Fengshi (GB 31)].

PubMed

Li, Zhixing; Zhang, Haihua; Li, Suhe

2015-12-01

To explore the accuracy of simple selection method of Fengshi (GB 31). Through the study of the ancient and modern data,the analysis and integration of the acupuncture books,the comparison of the locations of Fengshi (GB 31) by doctors from all dynasties and the integration of modern anatomia, the modern simple selection method of Fengshi (GB 31) is definite, which is the same as the traditional way. It is believed that the simple selec tion method is in accord with the human-oriented thought of TCM. Treatment by acupoints should be based on the emerging nature and the individual difference of patients. Also, it is proposed that Fengshi (GB 31) should be located through the integration between the simple method and body surface anatomical mark.

Intraoperative Comparison of Measured Resection and Gap Balancing Using a Force Sensor: A Prospective, Randomized Controlled Trial.

PubMed

Cidambi, Krishna R; Robertson, Nicholas; Borges, Camille; Nassif, Nader A; Barnett, Steven L

2018-07-01

For establishing femoral component position, gap-balancing (GB) and measured resection (MR) techniques were compared using a force sensor. Ninety-one patients were randomized to undergo primary total knee arthroplasty using either MR (n = 43) or GB (n = 48) technique using a single total knee arthroplasty design. GB was performed with an instrumented tensioner. Force sensor data were obtained before the final implantation. GB resulted in greater range of femoral component rotation vs MR (1.5° ± 2.9° vs 3.1° ± 0.5°, P < .05) and posterior condylar cut thickness medially (10.2 ± 2.0 mm vs 9.0 ± 1.3 mm) and laterally (8.5 ± 1.9 mm vs 6.4 ± 1.0 mm). Force sensor data showed a decreased intercompartmental force difference at full flexion in GB (.8 ± 2.3 vs 2.0 ± 3.3u, 1u ≈ 15 N, P < .05). GB resulted in a greater range of femoral component rotation and thicker posterior condylar cuts resulting in an increased flexion space relative to MR. Intercompartmental force difference trended toward a more uniform distribution between full extension and full flexion in the GB vs MR group. Copyright © 2018 Elsevier Inc. All rights reserved.

Association between Metabolic Syndrome and Gallbladder Polyps in Healthy Korean Adults

PubMed Central

Park, Eun Jung; Lee, Hong Soo; Lee, Sang Hwa; Chun, Hye Jin; Kim, Sun Young; Choi, Yu Kyung; Ryu, Hee Jeong

2013-01-01

The goal of this study was to evaluate the association between gallbladder (GB) polyps and metabolic syndrome. A total of 5,685 healthy subjects were included, and 485 of these subjects had GB polyps and 744 had metabolic syndrome. In this study, metabolic syndrome was diagnosed according to standards suggested by the AHA/NHLBI ATP III 2005, and abdominal obesity (≥ 90 cm in men and ≥ 85 cm in women for Korean) was diagnosed according to standards set forth by the Korean Society for Study of Obesity. Biphasic logistic regression adjusted for age and gender was used to evaluate the association between metabolic syndrome and GB polyps. Subjects who were male (OR, 1.493; 95% CI, 1.11-2.00) and hepatitis B suface Ag (HBsAg) positive (OR, 1.591; 95% CI, 1.06-2.38) were significantly more likely to have GB polyps. The metabolic syndrome group had a higher risk of GB polyps (OR, 1.315; 95% CI, 1.01-1.69) than the group without metabolic syndrome. In conclusion, subjects who were HBsAg positive and male appear to be associated with the risk of GB polyps. The presence of metabolic syndrome also appears to be associated with the risk of GB polyps in Koreans. PMID:23772152

Association between metabolic syndrome and gallbladder polyps in healthy Korean adults.

PubMed

Park, Eun Jung; Lee, Hong Soo; Lee, Sang Hwa; Chun, Hye Jin; Kim, Sun Young; Choi, Yu Kyung; Ryu, Hee Jeong; Shim, Kyung Won

2013-06-01

The goal of this study was to evaluate the association between gallbladder (GB) polyps and metabolic syndrome. A total of 5,685 healthy subjects were included, and 485 of these subjects had GB polyps and 744 had metabolic syndrome. In this study, metabolic syndrome was diagnosed according to standards suggested by the AHA/NHLBI ATP III 2005, and abdominal obesity (≥ 90 cm in men and ≥ 85 cm in women for Korean) was diagnosed according to standards set forth by the Korean Society for Study of Obesity. Biphasic logistic regression adjusted for age and gender was used to evaluate the association between metabolic syndrome and GB polyps. Subjects who were male (OR, 1.493; 95% CI, 1.11-2.00) and hepatitis B suface Ag (HBsAg) positive (OR, 1.591; 95% CI, 1.06-2.38) were significantly more likely to have GB polyps. The metabolic syndrome group had a higher risk of GB polyps (OR, 1.315; 95% CI, 1.01-1.69) than the group without metabolic syndrome. In conclusion, subjects who were HBsAg positive and male appear to be associated with the risk of GB polyps. The presence of metabolic syndrome also appears to be associated with the risk of GB polyps in Koreans.

Analysis of canine herpesvirus gB, gC and gD expressed by a recombinant vaccinia virus.

PubMed

Xuan, X; Kojima, A; Murata, T; Mikami, T; Otsuka, H

1997-01-01

The genes encoding the canine herpesvirus (CHV) glycoprotein B (gB), gC and gD homologues have been reported already. However, products of these genes have not been identified yet. Previously, we have identified three CHV glycoproteins, gp 145/112, gp80 and gp47 using a panel of monoclonal antibodies (MAbs). To determine which CHV glycoprotein corresponds to gB, gC or gD, the putative genes of gB, gC, and gD of CHV were inserted into the thymidine kinase gene of vaccinia virus LC16mO strain under the control of the early-late promoter for the vaccinia virus 7.5-kilodalton polypeptide. We demonstrated here that gp145/112, gp80 and gp47 were the translation products of the CHV gB, gC and gD genes, respectively. The antigenic authenticity of recombinant gB, gC and gD were confirmed by a panel of MAbs specific for each glycoprotein produced in CHV-infected cells. Immunization of mice with these recombinants produced high titers of neutralizing antibodies against CHV. These results suggest that recombinant vaccinia viruses expressing CHV gB, gC and gD may be useful to develop a vaccine to control CHV infection.

Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis

PubMed Central

Zhang, Wei; Xu, Li; Cho, Si-Young; Min, Kyung-Jin; Oda, Tatsuya; Zhang, LiJun; Yu, Qing; Jin, Jun-O

2016-01-01

This study investigates the in vivo functions of ginseng berry extract (GB) as a therapy for dextran sodium sulfate (DSS)-induced colitis. C57BL/6 mice were given drinking water containing DSS (3%) for eight days to induce acute colitis. At the same time, the mice received an oral dose of GB (50 mg/kg) once daily. The GB-treated mice were less susceptible to the development of acute colitis than were control mice treated with saline, as determined by weight loss, disease activity, and colon histology. The administration of GB to DSS-treated mice also reduced the numbers and inhibited the activation of colon-infiltrating T cells, neutrophils, intestinal CD103−CD11c+ dendritic cells (cDCs), and macrophages. In addition, GB treatment promoted the migration of CD103+CD11c+ cDCs and expansion of Foxp3+ regulatory T cells in the colons of DSS-treated mice. Similarly, in the DSS-induced chronic colitis model, GB treatment improved the macroscopic and histological appearance of the colon wall when compared to untreated control mice, as indicated by longer colon length and lower histological scores. This is the first report to show that oral administration of GB suppresses immune activation and protects against experimentally induced colitis. PMID:27058552

A receptor-like kinase gene (GbRLK) from Gossypium barbadense enhances salinity and drought-stress tolerance in Arabidopsis

PubMed Central

2013-01-01

Background Cotton (Gossypium spp.) is widely cultivated due to the important economic value of its fiber. However, extreme environmental degradation impedes cotton growth and production. Receptor-like kinase (RLK) proteins play important roles in signal transduction and participate in a diverse range of processes in response to plant hormones and environmental cues. Here, we introduced an RLK gene (GbRLK) from cotton into Arabidopsis and investigated its role in imparting abiotic stress tolerance. Results GbRLK transcription was induced by exogenously supplied abscisic acid (ABA), salicylic acid, methyl jasmonate, mock drought conditions and high salinity. We cloned the promoter sequence of this gene via self-formed adaptor PCR. Sequence analysis revealed that the promoter region contains many cis-acting stress-responsive elements such as ABRE, W-Box, MYB-core, W-Box core, TCA-element and others. We constructed a vector containing a 1,890-bp sequence in the 5′ region upstream of the initiation codon of this promoter and transformed it into Arabidopsis thaliana. GUS histochemical staining analysis showed that GbRLK was expressed mainly in leaf veins, petioles and roots of transgenic Arabidopsis, but not in the cotyledons or root hairs. GbRLK promoter activity was induced by ABA, PEG, NaCl and Verticillium dahliae. Transgenic Arabidopsis with constitutive overexpression of GbRLK exhibited a reduced rate of water loss in leaves in vitro, along with improved salinity and drought tolerance and increased sensitivity to ABA compared with non-transgenic Col-0 Arabidopsis. Expression analysis of stress-responsive genes in GbRLK Arabidopsis revealed that there was increased expression of genes involved in the ABA-dependent signaling pathway (AtRD20, AtRD22 and AtRD26) and antioxidant genes (AtCAT1, AtCCS, AtCSD2 and AtCSD1) but not ion transporter genes (AtNHX1, AtSOS1). Conclusions GbRLK is involved in the drought and high salinity stresses pathway by activating or participating in the ABA signaling pathway. Overexpression of GbRLK may improve stress tolerance by regulating stress-responsive genes to reduce water loss. GbRLK may be employed in the genetic engineering of novel cotton cultivars in the future. Further studying of GbRLK will help elucidate abiotic stress signaling pathways. PMID:23915077

A receptor-like kinase gene (GbRLK) from Gossypium barbadense enhances salinity and drought-stress tolerance in Arabidopsis.

PubMed

Zhao, Jun; Gao, Yulong; Zhang, Zhiyuan; Chen, Tianzi; Guo, Wangzhen; Zhang, Tianzhen

2013-08-06

Cotton (Gossypium spp.) is widely cultivated due to the important economic value of its fiber. However, extreme environmental degradation impedes cotton growth and production. Receptor-like kinase (RLK) proteins play important roles in signal transduction and participate in a diverse range of processes in response to plant hormones and environmental cues. Here, we introduced an RLK gene (GbRLK) from cotton into Arabidopsis and investigated its role in imparting abiotic stress tolerance. GbRLK transcription was induced by exogenously supplied abscisic acid (ABA), salicylic acid, methyl jasmonate, mock drought conditions and high salinity. We cloned the promoter sequence of this gene via self-formed adaptor PCR. Sequence analysis revealed that the promoter region contains many cis-acting stress-responsive elements such as ABRE, W-Box, MYB-core, W-Box core, TCA-element and others. We constructed a vector containing a 1,890-bp sequence in the 5' region upstream of the initiation codon of this promoter and transformed it into Arabidopsis thaliana. GUS histochemical staining analysis showed that GbRLK was expressed mainly in leaf veins, petioles and roots of transgenic Arabidopsis, but not in the cotyledons or root hairs. GbRLK promoter activity was induced by ABA, PEG, NaCl and Verticillium dahliae. Transgenic Arabidopsis with constitutive overexpression of GbRLK exhibited a reduced rate of water loss in leaves in vitro, along with improved salinity and drought tolerance and increased sensitivity to ABA compared with non-transgenic Col-0 Arabidopsis. Expression analysis of stress-responsive genes in GbRLK Arabidopsis revealed that there was increased expression of genes involved in the ABA-dependent signaling pathway (AtRD20, AtRD22 and AtRD26) and antioxidant genes (AtCAT1, AtCCS, AtCSD2 and AtCSD1) but not ion transporter genes (AtNHX1, AtSOS1). GbRLK is involved in the drought and high salinity stresses pathway by activating or participating in the ABA signaling pathway. Overexpression of GbRLK may improve stress tolerance by regulating stress-responsive genes to reduce water loss. GbRLK may be employed in the genetic engineering of novel cotton cultivars in the future. Further studying of GbRLK will help elucidate abiotic stress signaling pathways.

Increased Expression of the Chemokines CXCL1 and MIP-1a by Resident Brain Cells Precedes Neutrophil Infiltration in the Brain Following Prolonged Soman-Induced Status Epilepticus in Rats

DTIC Science & Technology

2011-05-01

brain cytokine concentrations. J Neuroinflammation 2010, 7:40. 12. Manley NC, Bertrand AA, Kinney KS, Hing TC, Sapolsky RM: Characterization of monocyte...neurodegeneration. J Neurosci 2007, 27:9301-9309. 16. Wolpe SD, Davatelis G, Sherry B, Beutler B, Hesse DG, Nguyen HT, Moldawer LL , Nathan CF, Lowry SF

Microglia as Primary Mediators of Nerve Agent Neuropathy

DTIC Science & Technology

2010-01-01

16. Thomas DM, Francescutti-Verbeem DM and Kuhn DM. Methamphetamine -induced neurotoxicity and microglial activation are not mediated by fractalkine...1-24. Berry WK and Davies DR. The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl...633-8. Dirnhuber P, French MC, Green DM, Leadbeater L and Stratton JA. The protection of primates against soman poisoning by pretreatment with

The Neuroprotective Benefits of Central Adenosine Receptor Stimulation in a Soman Nerve Agent Rat Model

DTIC Science & Technology

2014-04-01

irreversibly inhibit acetylcholinesterase (AChE), the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh) in the cholinergic... potential inhibitory compounds and drugs along these lines of neurotransmission perturbations have been investigated (McDonough and Shih 1997; Shih...effects, van Helden et al. (1998) recognized adenosine’s potential as a CWNA countermeasure. In their early study, the A1 adenosine agonist (6

Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings

PubMed Central

Kuca, Kamil; Karasova, Jana Zdarova; Soukup, Ondrej; Kassa, Jiri; Novotna, Eva; Sepsova, Vendula; Horova, Anna; Pejchal, Jaroslav; Hrabinova, Martina; Vodakova, Eva; Jun, Daniel; Nepovimova, Eugenie; Valis, Martin; Musilek, Kamil

2018-01-01

Background Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity. PMID:29563775