Genetics Home Reference: bare lymphocyte syndrome type I

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Targeting Midbodies in Ovarian Cancer Stem Cells as a Therapeutic Strategy

DTIC Science & Technology

2013-10-01

functional spindle assembly. Nat. Cell Biol. 13, 1406–1414. Ori-McKenney, K.M., Jan, L.Y., and Jan, Y.-N. (2012). Golgi outposts shape dendrite morphology...1899. Yadav, S., and Linstedt, A.D. (2011). Golgi positioning. Cold Spring Harb. Perspect . Biol. 3, 3. Zhang, H., Squirrell, J.M., and White, J.G. (2008...implications for recy- cling endosome function . This new liaison has additional impli- cations for a variety of biological processes including cilia

3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening

DTIC Science & Technology

2013-07-01

FabI, but share low sequence identity and are poorly inhibited by triclosan.25,26 S. pneumoniae and P. aeruginosa contain FabK,24 and Vibrio cholerae,27...with 0.2 mM IPTG. The cells were harvested after an overnight induction period at 17 °C. The cells were lysed and sonicated and loaded onto a nickel...of enoyl- (acyl-carrier protein) reductase, FabV, from Vibrio fischeri. Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun. 2012, 68, 78−80. (27

Cold rescue of the thermolabile tailspike intermediate at the junction between productive folding and off-pathway aggregation.

PubMed Central

Betts, S. D.; King, J.

1998-01-01

Off-pathway intermolecular interactions between partially folded polypeptide chains often compete with correct intramolecular interactions, resulting in self-association of folding intermediates into the inclusion body state. Intermediates for both productive folding and off-pathway aggregation of the parallel beta-coil tailspike trimer of phage P22 have been identified in vivo and in vitro using native gel electrophoresis in the cold. Aggregation of folding intermediates was suppressed when refolding was initiated and allowed to proceed for a short period at 0 degrees C prior to warming to 20 degrees C. Yields of refolded tailspike trimers exceeding 80% were obtained using this temperature-shift procedure, first described by Xie and Wetlaufer (1996, Protein Sci 5:517-523). We interpret this as due to stabilization of the thermolabile monomeric intermediate at the junction between productive folding and off-pathway aggregation. Partially folded monomers, a newly identified dimer, and the protrimer folding intermediates were populated in the cold. These species were electrophoretically distinguished from the multimeric intermediates populated on the aggregation pathway. The productive protrimer intermediate is disulfide bonded (Robinson AS, King J, 1997, Nat Struct Biol 4:450-455), while the multimeric aggregation intermediates are not disulfide bonded. The partially folded dimer appears to be a precursor to the disulfide-bonded protrimer. The results support a model in which the junctional partially folded monomeric intermediate acquires resistance to aggregation in the cold by folding further to a conformation that is activated for correct recognition and subunit assembly. PMID:9684883

Three acidic residues are at the active site of a beta-propeller architecture in glycoside hydrolase families 32, 43, 62, and 68.

PubMed

Pons, Tirso; Naumoff, Daniil G; Martínez-Fleites, Carlos; Hernández, Lázaro

2004-02-15

Multiple-sequence alignment of glycoside hydrolase (GH) families 32, 43, 62, and 68 revealed three conserved blocks, each containing an acidic residue at an equivalent position in all the enzymes. A detailed analysis of the site-directed mutations so far performed on invertases (GH32), arabinanases (GH43), and bacterial fructosyltransferases (GH68) indicated a direct implication of the conserved residues Asp/Glu (block I), Asp (block II), and Glu (block III) in substrate binding and hydrolysis. These residues are close in space in the 5-bladed beta-propeller fold determined for Cellvibrio japonicus alpha-L-arabinanase Arb43A [Nurizzo et al., Nat Struct Biol 2002;9:665-668] and Bacillus subtilis endo-1,5-alpha-L-arabinanase. A sequence-structure compatibility search using 3D-PSSM, mGenTHREADER, INBGU, and SAM-T02 programs predicted indistinctly the 5-bladed beta-propeller fold of Arb43A and the 6-bladed beta-propeller fold of sialidase/neuraminidase (GH33, GH34, and GH83) as the most reliable topologies for GH families 32, 62, and 68. We conclude that the identified acidic residues are located at the active site of a beta-propeller architecture in GH32, GH43, GH62, and GH68, operating with a canonical reaction mechanism of either inversion (GH43 and likely GH62) or retention (GH32 and GH68) of the anomeric configuration. Also, we propose that the beta-propeller architecture accommodates distinct binding sites for the acceptor saccharide in glycosyl transfer reaction. Copyright 2003 Wiley-Liss, Inc.

Chimeric β-Lactamases: Global Conservation of Parental Function and Fast Time-Scale Dynamics with Increased Slow Motions

PubMed Central

Clouthier, Christopher M.; Morin, Sébastien; Gobeil, Sophie M. C.; Doucet, Nicolas; Blanchet, Jonathan; Nguyen, Elisabeth; Gagné, Stéphane M.; Pelletier, Joelle N.

2012-01-01

Enzyme engineering has been facilitated by recombination of close homologues, followed by functional screening. In one such effort, chimeras of two class-A β-lactamases – TEM-1 and PSE-4 – were created according to structure-guided protein recombination and selected for their capacity to promote bacterial proliferation in the presence of ampicillin (Voigt et al., Nat. Struct. Biol. 2002 9:553). To provide a more detailed assessment of the effects of protein recombination on the structure and function of the resulting chimeric enzymes, we characterized a series of functional TEM-1/PSE-4 chimeras possessing between 17 and 92 substitutions relative to TEM-1 β-lactamase. Circular dichroism and thermal scanning fluorimetry revealed that the chimeras were generally well folded. Despite harbouring important sequence variation relative to either of the two ‘parental’ β-lactamases, the chimeric β-lactamases displayed substrate recognition spectra and reactivity similar to their most closely-related parent. To gain further insight into the changes induced by chimerization, the chimera with 17 substitutions was investigated by NMR spin relaxation. While high order was conserved on the ps-ns timescale, a hallmark of class A β-lactamases, evidence of additional slow motions on the µs-ms timescale was extracted from model-free calculations. This is consistent with the greater number of resonances that could not be assigned in this chimera relative to the parental β-lactamases, and is consistent with this well-folded and functional chimeric β-lactamase displaying increased slow time-scale motions. PMID:23284969

Structure of the Fusarium oxysporum endoglucanase I with a nonhydrolyzable substrate analogue: substrate distortion gives rise to the preferred axial orientation for the leaving group.

PubMed

Sulzenbacher, G; Driguez, H; Henrissat, B; Schülein, M; Davies, G J

1996-12-03

Endoglucanase I (EG I) is a cellulase, from glycosyl hydrolase family 7, which cleaves the beta-1,4 linkages of cellulose with overall retention of configuration. The structure of the EG I from Fusarium oxysproum, complexed to a nonhydrolyzable thiooligosaccharide substrate analogue, has been determined by X-ray crystallography at a resolution of 2.7 A utilizing the 4-fold noncrystallographic symmetry present in the asymmetric unit. The electron density map clearly reveals the presence of three glucosyl units of the inhibitor, consistent with the known number of sugar-binding subsites, located at the active site of the enzyme in the -2, -1, and +1 subsites, i.e., actually spanning the point of enzymatic cleavage. The pyranose ring at the point of potential enzymatic cleavage is clearly distorted from the standard 4C1 chair as was originally suggested for beta-retaining enzymes by Phillips [Ford, L.O., Johnson, L.N., Machin, P. A., Phillips, D.C., & Tijan, T. (1974) J. Mol. Biol, 88, 349-371]. The distortion observed goes beyond the "sofa" conformation observed in previous studies and results in a conformation whose salient feature is the resulting quasi-axial orientation for the glycosidic bond and leaving group, as predicted by stereoelectronic theory. An almost identical conformation has recently been observed in a complex of chitobiase with its unhydrolyzed substrate [Tews, I., Perrakis, A., Oppenheim, A., Dauter, Z., Wilson, K. S., & Vorgias, C. E. (1996) Nat. Struct. Biol. 3, 638-648]. The striking similarity between these two complexes extends beyond the almost identical pyranose ring distortion. The overlap of the two respective sugars places the enzymatic nucleophile of endoglucanase I in coincidence with the C2 acetamido oxygen of N-acetylglucosamine in the catalytic site of the chitobiase, substantiating the involvement of this group in the catalytic mechanism of chitobiase and related chitinolytic enzymes. The endoglucanase I complex with the thiosaccharide substrate analogue clearly illustrates the potential of nonhydrolyzable sulfur-linked oligosaccharides in the elucidation of substrate binding and catalysis by glycosyl hydrolases.

EGFR-Dependent Regulation of Matrix-Independent Epithelial Cell Survival

DTIC Science & Technology

2006-04-01

ultraviolet (UV) irradiation ( Mudgil et al., 2003), decreased adhesive interactions between tumor cells and adjacent epithelia Much remains to be...historical perspective on integrin signal transduction. Nat. Cell Biol. 4, E83-E90. Mudgil , A. V., Segal, N., Andriani, F., Wang, Y., Fusenig, N. E. and

Single-molecule dataset (SMD): a generalized storage format for raw and processed single-molecule data.

PubMed

Greenfeld, Max; van de Meent, Jan-Willem; Pavlichin, Dmitri S; Mabuchi, Hideo; Wiggins, Chris H; Gonzalez, Ruben L; Herschlag, Daniel

2015-01-16

Single-molecule techniques have emerged as incisive approaches for addressing a wide range of questions arising in contemporary biological research [Trends Biochem Sci 38:30-37, 2013; Nat Rev Genet 14:9-22, 2013; Curr Opin Struct Biol 2014, 28C:112-121; Annu Rev Biophys 43:19-39, 2014]. The analysis and interpretation of raw single-molecule data benefits greatly from the ongoing development of sophisticated statistical analysis tools that enable accurate inference at the low signal-to-noise ratios frequently associated with these measurements. While a number of groups have released analysis toolkits as open source software [J Phys Chem B 114:5386-5403, 2010; Biophys J 79:1915-1927, 2000; Biophys J 91:1941-1951, 2006; Biophys J 79:1928-1944, 2000; Biophys J 86:4015-4029, 2004; Biophys J 97:3196-3205, 2009; PLoS One 7:e30024, 2012; BMC Bioinformatics 288 11(8):S2, 2010; Biophys J 106:1327-1337, 2014; Proc Int Conf Mach Learn 28:361-369, 2013], it remains difficult to compare analysis for experiments performed in different labs due to a lack of standardization. Here we propose a standardized single-molecule dataset (SMD) file format. SMD is designed to accommodate a wide variety of computer programming languages, single-molecule techniques, and analysis strategies. To facilitate adoption of this format we have made two existing data analysis packages that are used for single-molecule analysis compatible with this format. Adoption of a common, standard data file format for sharing raw single-molecule data and analysis outcomes is a critical step for the emerging and powerful single-molecule field, which will benefit both sophisticated users and non-specialists by allowing standardized, transparent, and reproducible analysis practices.

Structures of the Procapsid and Mature Virion of Enterovirus 71 Strain 1095

PubMed Central

Cifuente, Javier O.; Lee, Hyunwook; Yoder, Joshua D.; Shingler, Kristin L.; Carnegie, Michael S.; Yoder, Jennifer L.; Ashley, Robert E.; Makhov, Alexander M.; Conway, James F.

2013-01-01

Enterovirus 71 (EV71) is an important emerging human pathogen with a global distribution and presents a disease pattern resembling poliomyelitis with seasonal epidemics that include cases of severe neurological complications, such as acute flaccid paralysis. EV71 is a member of the Picornaviridae family, which consists of icosahedral, nonenveloped, single-stranded RNA viruses. Here we report structures derived from X-ray crystallography and cryoelectron microscopy (cryo-EM) for the 1095 strain of EV71, including a putative precursor in virus assembly, the procapsid, and the mature virus capsid. The cryo-EM map of the procapsid provides new structural information on portions of the capsid proteins VP0 and VP1 that are disordered in the higher-resolution crystal structures. Our structures solved from virus particles in solution are largely in agreement with those from prior X-ray crystallographic studies; however, we observe small but significant structural differences for the 1095 procapsid compared to a structure solved in a previous study (X. Wang, W. Peng, J. Ren, Z. Hu, J. Xu, Z. Lou, X. Li, W. Yin, X. Shen, C. Porta, T. S. Walter, G. Evans, D. Axford, R. Owen, D. J. Rowlands, J. Wang, D. I. Stuart, E. E. Fry, and Z. Rao, Nat. Struct. Mol. Biol. 19:424–429, 2012) for a different strain of EV71. For both EV71 strains, the procapsid is significantly larger in diameter than the mature capsid, unlike in any other picornavirus. Nonetheless, our results demonstrate that picornavirus capsid expansion is possible without RNA encapsidation and that picornavirus assembly may involve an inward radial collapse of the procapsid to yield the native virion. PMID:23637404

Sweetness determinant sites of brazzein, a small, heat-stable, sweet-tasting protein.

PubMed

Assadi-Porter, F M; Aceti, D J; Markley, J L

2000-04-15

Brazzein, originally isolated from the fruit of the African plant Pentadiplandra brazzeana Baillon, is the smallest, most heat-stable and pH-stable member of the set of proteins known to have intrinsic sweetness. These properties make brazzein an ideal system for investigating the chemical and structural requirements of a sweet-tasting protein. We have used the three-dimensional structure of the protein (J. E. Caldwell et al. (1998) Nat. Struct. Biol. 5, 427-431) as a guide in designing 15 synthetic genes in expression constructs aimed at delineating the sweetness determinants of brazzein. Protein was produced heterologously in Escherichia coli, isolated, and purified as described in the companion paper (Assadi-Porter, F. M., Aceti, D., Cheng, H., and Markley, J. L., this issue). Analysis by one-dimensional (1)H NMR spectroscopy indicated that all but one of these variants had folded properly under the conditions used. A taste panel compared the gustatory properties of solutions of these proteins to those of sucrose and brazzein isolated from fruit. Of the 14 mutations in the des-pGlu1-brazzein background, four exhibited almost no sweetness, six had significantly reduced sweetness, two had taste properties equivalent to des-pGlu1-brazzein (two times as sweet as the major form of brazzein isolated from fruit which contains pGlu1), and two were about twice as sweet as des-pGlu1-brazzein. Overall, the results suggest that two regions of the protein are critical for the sweetness of brazzein: a region that includes the N- and C-termini of the protein, which are located close to one another, and a region that includes the flexible loop around Arg43. Copyright 2000 Academic Press.

The yeasts phosphorelay systems: a comparative view.

PubMed

Salas-Delgado, Griselda; Ongay-Larios, Laura; Kawasaki-Watanabe, Laura; López-Villaseñor, Imelda; Coria, Roberto

2017-06-01

Cells contain signal transduction pathways that mediate communication between the extracellular environment and the cell interior. These pathways control transcriptional programs and posttranscriptional processes that modify cell metabolism in order to maintain homeostasis. One type of these signal transduction systems are the so-called Two Component Systems (TCS), which conduct the transfer of phosphate groups between specific and conserved histidine and aspartate residues present in at least two proteins; the first protein is a sensor kinase which autophosphorylates a histidine residue in response to a stimulus, this phosphate is then transferred to an aspartic residue located in a response regulator protein. There are classical and hybrid TCS, whose difference consists in the number of proteins and functional domains involved in the phosphorelay. The TCS are widespread in bacteria where the sensor and its response regulator are mostly specific for a given stimulus. In eukaryotic organisms such as fungi, slime molds, and plants, TCS are present as hybrid multistep phosphorelays, with a variety of arrangements (Stock et al. in Annu Rev Biochem 69:183-215, 2000; Wuichet et al. in Curr Opin Microbiol 292:1039-1050, 2010). In these multistep phosphorelay systems, several phosphotransfer events take place between different histidine and aspartate residues localized in specific domains present in more than two proteins (Thomason and Kay, in J Cell Sci 113:3141-3150, 2000; Robinson et al. in Nat Struct Biol 7:626-633, 2000). This review presents a brief and succinct description of the Two-component systems of model yeasts, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans, Cryptococcus neoformans and Kluyveromyces lactis. We have focused on the comparison of domain organization and functions of each component present in these phosphorelay systems.

Mismatch Repair Balances Leading and Lagging Strand DNA Replication Fidelity

DTIC Science & Technology

2012-10-11

mismatched base stacks with a conserved phenylalanine in Msh6, and/or (iii) DNA flexibility, since MutSa-bound mismatched DNA is kinked, and a...AB, Watt DL , Watts BE, et al. (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6: 774–781. 24. Poloumienko A

Prostate Cancer Diagnostics and Prognostics Based on Interphase Spatial Genome Positioning

DTIC Science & Technology

2016-03-01

the Drosophila melanogaster genome at the ...and van Steensel, B. (2006). 1176 Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat Genet 38, 1177 1005-1014. doi...region according to the gene distribution pattern in primary genomic sequence . J Cell Biol 174:27–38 Therizols P, Illingworth RS, Courilleau C,

Constraints on voltage sensor movement in the shaker K+ channel.

PubMed

Darman, Rachel B; Ivy, Allison A; Ketty, Vina; Blaustein, Robert O

2006-12-01

In nerve and muscle cells, the voltage-gated opening and closing of cation-selective ion channels is accompanied by the translocation of 12-14 elementary charges across the membrane's electric field. Although most of these charges are carried by residues in the S4 helix of the gating module of these channels, the precise nature of their physical movement is currently the topic of spirited debate. Broadly speaking, two classes of models have emerged: those that suggest that small-scale motions can account for the extensive charge displacement, and those that invoke a much larger physical movement. In the most recent incarnation of the latter type of model, which is based on structural and functional data from the archaebacterial K(+) channel KvAP, a "voltage-sensor paddle" comprising a helix-turn-helix of S3-S4 translocates approximately 20 A through the bilayer during the gating cycle (Jiang, Y., A. Lee, J. Chen, V. Ruta, M. Cadene, B.T. Chait, and R. MacKinnon. 2003. Nature. 423:33-41; Jiang, Y., V. Ruta, J. Chen, A. Lee, and R. MacKinnon. 2003. Nature. 423:42-48.; Ruta, V., J. Chen, and R. MacKinnon. 2005. Cell. 123:463-475). We used two methods to test for analogous motions in the Shaker K(+) channel, each examining the aqueous exposure of residues near S3. In the first, we employed a pore-blocking maleimide reagent (Blaustein, R.O., P.A. Cole, C. Williams, and C. Miller. 2000. Nat. Struct. Biol. 7:309-311) to probe for state-dependent changes in the chemical reactivity of substituted cysteines; in the second, we tested the state-dependent accessibility of a tethered biotin to external streptavidin (Qiu, X.Q., K.S. Jakes, A. Finkelstein, and S.L. Slatin. 1994. J. Biol. Chem. 269:7483-7488; Slatin, S.L., X.Q. Qiu, K.S. Jakes, and A. Finkelstein. 1994. Nature. 371:158-161). In both types of experiments, residues predicted to lie near the top of S3 did not exhibit any change in aqueous exposure during the gating cycle. This lack of state dependence argues against large-scale movements, either axially or radially, of Shaker's S3-S4 voltage-sensor paddle.

Constraints on Voltage Sensor Movement in the Shaker K+ Channel

PubMed Central

Darman, Rachel B.; Ivy, Allison A.; Ketty, Vina; Blaustein, Robert O.

2006-01-01

In nerve and muscle cells, the voltage-gated opening and closing of cation-selective ion channels is accompanied by the translocation of 12–14 elementary charges across the membrane's electric field. Although most of these charges are carried by residues in the S4 helix of the gating module of these channels, the precise nature of their physical movement is currently the topic of spirited debate. Broadly speaking, two classes of models have emerged: those that suggest that small-scale motions can account for the extensive charge displacement, and those that invoke a much larger physical movement. In the most recent incarnation of the latter type of model, which is based on structural and functional data from the archaebacterial K+ channel KvAP, a “voltage-sensor paddle” comprising a helix-turn-helix of S3–S4 translocates ∼20 Å through the bilayer during the gating cycle (Jiang, Y., A. Lee, J. Chen, V. Ruta, M. Cadene, B.T. Chait, and R. MacKinnon. 2003. Nature. 423:33–41; Jiang, Y., V. Ruta, J. Chen, A. Lee, and R. MacKinnon. 2003. Nature. 423:42–48.; Ruta, V., J. Chen, and R. MacKinnon. 2005. Cell. 123:463–475). We used two methods to test for analogous motions in the Shaker K+ channel, each examining the aqueous exposure of residues near S3. In the first, we employed a pore-blocking maleimide reagent (Blaustein, R.O., P.A. Cole, C. Williams, and C. Miller. 2000. Nat. Struct. Biol. 7:309–311) to probe for state-dependent changes in the chemical reactivity of substituted cysteines; in the second, we tested the state-dependent accessibility of a tethered biotin to external streptavidin (Qiu, X.Q., K.S. Jakes, A. Finkelstein, and S.L. Slatin. 1994. J. Biol. Chem. 269:7483–7488; Slatin, S.L., X.Q. Qiu, K.S. Jakes, and A. Finkelstein. 1994. Nature. 371:158–161). In both types of experiments, residues predicted to lie near the top of S3 did not exhibit any change in aqueous exposure during the gating cycle. This lack of state dependence argues against large-scale movements, either axially or radially, of Shaker's S3–S4 voltage-sensor paddle. PMID:17101817

Unusual Water-mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18

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

Argiriadi, Maria A.; Xiang, Tao; Wu, Chengbin

2009-10-21

The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18 agents are in clinical development, including the recombinant human antibody ABT-325, which is entering trials for autoimmune diseases. Given competing cytokine/receptor and cytokine/receptor decoy interactions, understanding the structural basis for recognition is critical for effective development of anti-cytokine therapies. Here we report three crystal structures: the murine antibody 125-2H Fab fragment bound to human IL-18, at 1.5 {angstrom} resolution; the 125-2H Fab (2.3 {angstrom}); and the ABT-325 Fabmore » (1.5 {angstrom}). These structures, along with human/mouse IL-18 chimera binding data, allow us to make three key observations relevant to the biology and antigenic recognition of IL-18 and related cytokines. First, several IL-18 residues shift dramatically (>10 {angstrom}) upon binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H., Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya, K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat. Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to its interactions with other receptors. Related cytokines may exhibit similar plasticity. Second, ABT-325 and 125-2H differ significantly in combining site character and architecture, thus explaining their ability to bind IL-18 simultaneously at distinct epitopes. These data allow us to define the likely ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both antibodies. Third, given the high 125-2H potency, 10 well ordered water molecules are trapped upon complex formation in a cavity between two IL-18 loops and all six 125-2H complementarity-determining regions. Thus, counterintuitively, tight and specific antibody binding may in some cases be water-mediated.« less

Molecular Determinants and Clinical Implications of Breast Cancer Dormancy

DTIC Science & Technology

2014-12-01

repair mediates resistance of hair follicle bulge stem cells to DNA-damage- induced cell death. Nat Cell Biol 2010; 12: 572–582. 7. Chiruvella KK1...on the role of cellular dormancy in promoting cancer aggressiveness and drug resistance in recurred breast cancer. We aimed to determine the impact...period, we have successfully established a reliable in vitro breast cancer dormancy cell model. Using this model, we tested and confirmed the

Biomineralisation in Mollusc shells

NASA Astrophysics Data System (ADS)

Dauphin, Y.; Cuif, J. P.; Salomé, M.; Williams, C. T.

2009-04-01

The main components of Mollusc shells are carbonate minerals: calcite and aragonite. ACC is present in larval stages. Calcite and aragonite can be secreted simultaneously by the mantle. Despite the small number of varieties, the arrangement of the mineral components is diverse, and dependant upon the taxonomy. They are also associated with organic components much more diverse, the diversity of which reflects the large taxonomic diversity. From TGA analyses, the organic content (water included) is high (>5% in some layers). The biomineralisation process is not a passive precipitation process, but is strongly controlled by the organism. The biological-genetic control is shown by the constancy of the arrangement of the layers, the mineralogy and the microstructure in a given species. Microstructural units (i.e. tablets, prisms etc.) have shapes that do not occur in non-biogenic counterparts. Nacreous tablets, for example, are flattened on their crystallographic c axis, which is normally the axis of maximum growth rate for non-biogenic aragonite. Morever, their inner structure is species-specific: the arrangements of nacreous tablets in Gastropoda - Cephalopoda, and in Bivalvia differ, and the inner arrangement of the nacreous tablets is different in ectocochlear and endocochlear Cephalopoda. The organic-mineral ratios also differ in the various layers of a shell. Differences in chemical composition also demonstrates the biological-genetic control: for example, aragonite has a low Sr content unknown in non-biogenic samples; two aragonitic layers in a shell have different Sr and Mg contents, S is higher in calcitic layers. Decalcification releases soluble (SOM) and insoluble (IOM) organic components. Insoluble components form the main part of the intercrystalline membranes, and contain proteins, polysaccharides and lipids. Soluble phases are present within the crystals and the intercrystalline membranes. These phases are composed of more or less glycosylated proteins and polysaccharides, with a large range of molecular weights. Proteins are rich in acidic aminoacids (aspartic and glutamic acids). Sugars are usually sulphated, and very acidic. Several hundreds of proteins and sugars are present in the SOM. The compositions of IOM and SOM are characteristic for each layer present in a shell. Topographical relationships of mineral and organic components are visible at different scales of observation. SEM images of etched surfaces display the growth line rhythmicity and concordance between adjacent microstructural units. EPMA maps show similar chemical growth lines in various structures. Whatever the taxa, the average thickness of growth lines is about 2-3 µm, indicating an inner biological rhythm, not dependant on the environmental conditions. Such growth lines are observed in deep sea molluscs at depth where diurnal changes in light and temperature are absent. However, the role of the environment is shown by larger periodicities. Sulphur deserves a special interest, because it is associated with the organic matrices. Electrophoretic data have shown that acidic sulphated sugars are abundant in some layers. XANES analyses confirm these results. New microscopic techniques allow us to obtain images at a submicrometer scale. AFM images show that all the microstructural units (i.e. tablets, prisms etc.), calcite or aragonite, are composed of small sub-spherical granules with a diameter typically of about 50 nm. These granules are surrounded by a thin cortex (about 8 nm) of organic and/or amorphous material, and are organo-composite material as shown by phase images. They do not have crystalline shapes, despite the fact that the units they build are often monocrystalline. Molecular biology and genetic studies confirm that the control of the biomineralisation process is exerted at the scale of the whole organism: the expression of genes encoding major shell matrix proteins clearly indicates a regular separation of calcite and aragonite secretory activity. The main control on the structural and compositional features of mollusc shells is genetic. However, environmental influences do exist. Due to the complex structures and composition of these shells, localized analyses must be preferred. The role of the composition and distribution of the organic matrix in fossilisation processes, and any potentially induced alterations is not yet known. Mutvei 1970, Biomineralisation 2, 48. Mutvei 1977, Calc. Tiss. Res. 24, 1. Cuif et al.1980, C. R. Acad. Sc. Paris 290, ser. D: 759. Dauphin & Cuif 1999, Ann. Sci. Nat. 2:73. Dauphin & Denis 2000, Comp. Biochem. Physiol. A126: 367. Dauphin 2001, N. Jb. Geol. Palaont. Mh. 2 : 103. Dauphin 2001, Palaont. Zeit. 75, 1: 113. Levi-Kalisman et al. 2001, J. Struct. Biol. 135:8. Dauphin 2002, Comp. Biochem. Physiol. A132, 3: 577. Dauphin et al. 2003, J. Struct. Biol., 142: 272. Gotliv et al. 2003, Chem. Biochem. 4: 522. Gotliv et al. 2004, ChemBioChem. 6:304. Dauphin et al. 2005, Amer. Mineral. 90: 1748. Nudelman et al. 2006, J. Struct. Biol. 153:176. Takeushi & Endo 2006, mar. Biotech. 8: 52. Dauphin 2008, Anal. Bioanal. Chem. 309: 1659. Cuif et al. 2008, Mineral. Mag. 72, 1: 233. This work has been made possible thanks to the support from ANR-06-BLANC-0233-01 project (BIOCRISTAL).

The Previously Undetected Presence of Culex restuans (Diptera: Culicidae) in Central America, with Notes on Identification

DTIC Science & Technology

1988-01-01

geografica actualizada. Rev. Inv. Salud Publica (Mexico) 33: 11 I - 125. Heinemann, S.J. and J.N. Belkin. 1977. Collection records of the project...Mosquitoes of Middle America” 8. Central America: Belize (BH), Guatemala (GUA), El Salvador ( SAL ), Honduras (HON), Nicaragua (NI, NIC). Mosq. Syst...Culicidae). Ill. Nat. Hist. Surv. Biol. Notes 52, 50 pp. Vargas, L. 1956. Especies y distribucidn de mosquitos mexicanos no anofelinos. Rev. Instit. de

Targeting Common but Complex Proteoglycans on Breast Cancer Cells and Stem Cells Using Evolutionary Refined Malaria Proteins

DTIC Science & Technology

2016-08-01

clearance and infect placental cells, thereby causing pregnancy - associated malaria outbreaks in epidemic regions of the world. Prior to this...recognition and activity. Nat. Chem. Biol. 2, 467–473. Holtan, S.G., Creedon, D.J., Haluska, P., and Markovic, S.N. (2009). Cancer and pregnancy : parallels...falciparum involved in pregnancy -associated malaria. Mol. Microbiol. 49, 179–191. Salanti, A., Dahlbäck, M., Turner, L., Nielsen, M.A., Barfod, L

Role of Rad23 and Dsk2 in Nucleotide Excision Repair and Spindle Pole Body Duplication

DTIC Science & Technology

2007-03-01

proteasome. Mol. Cell, 6, 409–419. 14. Saeki, Y., Saitoh, A., Toh-e, A. & Yokosawa , H. (2002). Ubiquitin-like proteins and Rpn10 play cooperative...Sone, T., Toh-e, A. & Yokosawa , H. (2002). Identification of ubiquitin-like protein-binding sub- units of the 26 S proteasome. Biochem. Biophys. Res...Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat Cell Biol 2002, 4:725-30. 15. Saeki Y, Sone T, Toh-e A, Yokosawa H: Identification of

P38 Mitogen-Activated Protein Kinase in Metastasis Associated With Transforming Growth Factor Beta

DTIC Science & Technology

2005-06-01

36, 2001. Shin I, Bakin AV, Rodeck U, Brunet A, Arteaga CL. TGFbeta enhances epithelial cell survival via Akt - dependent regulation of FKHRLI. Mol Biol... Akt mediates cell-cycle progression by phosphorylation of p27Kip’ at threonine 157 and modulation of its cellular localization. Nat Med 8:1145-1152...stress fibers. Ectopic- expression and siRNA experiments show that Smad3 and Smad4 mediate up-regulation of tropomyosins and stress fiber formation

TECHNICAL REPORT

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

DR. ROBERT SINGER

2007-10-11

Because this DOE grant was abruptly terminated without warning, this group was not able to accomplish the insertion of the biosensor genes into the mouse lines. They have been able to generate some of the mouse lines but have not been able to complete the ones that would give them the model systems that would allow them to investigate metastasis real-time in living tumors at the cellular level. Nonetheless, until the loss of funding, they have made progress in applications of the equipment to biological problems involving RNA and protein movement in living cells. The following products were delivered: (1)more » Imaging of gene expression in living cells and tissues, Singer RH, Lawrence DS, Ovryn B, Condeelis J, J Biomed Optics 10:0514061-0514069, 2005. This paper describes the method for activating single genes within cells and tissues. (2) Single Cell Gene Expression Profiling: Multiplexed Expression Fluorescence in situ Hybridization (FISH): Application to the Analysis of Cultured Cells. Levsky JM, Braut SA, Singer RH, Cell Biology: A Laboratory Handbook Volume 4, eds Celis JE, et al, 121-130. Academic Press, 2005. This paper describes the methodology for single cell expression profiling in tissues. (3) Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1, Huttelmaier S, Zenklusen D, Lederer M, Dictenberg J, Lorenz M, Meng X, Bassell GJ, Condeelis J, Singer RH, Nature 438:512-515, 2005. This paper describes the mechanism by which the translational repressor of actin mRNA ZBP1 can effect regulation of cell motility and metastasis. (4) Visualization of mRNA translation in living cells, Rodriguez AJ, Shenoy SM, Singer RH, Condeelis J, J Cell Biol 175:67-76, 2006. This work describes a method to visualize mRNA translation in single cells. (5) Imaging mRNA movement from transcription sites to translation sites, Rodriguez AJ, Condeelis J, Singer RH, Dictenberg JB, Semin Cell Dev Biol 18:202-208, 2007. This review describes current technology for visualizing mRNA from birth to death. (6) In vivo dynamics of RNA polymerase II transcription, Darzacq X, Shav-Tal Y, de Turris V, Brody Y, Shenoy SM, Phair RD, Singer RH, Nat Struct Mol Biol 14:796-806, 2007. This paper describes methods for visualizing gene transcription in real time and provides a systems modeling approach to understanding polymerase dynamics. (See News & Views 14:788) (7) Nuclear microenvironment in cancer diagnosis and treatment, Pezo RC, Singer RH, J Cell Biochem in press (2007). This work describes the environmental factors acting on the genes directly. (8) The spatial order of transcription in mammalian cells, Levsky JM, Shenoy SM, Chubb JR, Hall CB, Capodieci P, Singer RH, J Cell Biochem in press (2007). This work describes how active genes are spatially distributed throughout the nucleus. (9) ZBP1 Enhances Cell Polarity and Reduces Metastasis, Lapidus K, Wyckoff J, Mouneimne G, Lorenz M, Soon L, Condeelis J and Singer RH, JCS in press (2007). This work describes the role of the RNA binding protein in cell polarity and metastasis.« less

Ca2+ signaling and early embryonic patterning during the blastula and gastrula periods of zebrafish and Xenopus development.

PubMed

Webb, Sarah E; Miller, Andrew L

2006-11-01

It has been proposed that Ca(2+) signaling, in the form of pulses, waves and steady gradients, may play a crucial role in key pattern forming events during early vertebrate development [L.F. Jaffe, Organization of early development by calcium patterns, BioEssays 21 (1999) 657-667; M.J. Berridge, P. Lipp, M.D. Bootman, The versatility and universality of calcium signaling, Nat. Rev. Mol. Cell Biol. 1 (2000) 11-21; S.E. Webb, A.L. Miller, Calcium signalling during embryonic development, Nat. Rev. Mol. Cell Biol. 4 (2003) 539-551]. With reference to the embryos of zebrafish (Danio rerio) and the frog, Xenopus laevis, we review the Ca(2+) signals reported during the Blastula and Gastrula Periods. This developmental window encompasses the major pattern forming events of epiboly, involution, and convergent extension, which result in the establishment of the basic germ layers and body axes [C.B. Kimmel, W.W. Ballard, S.R. Kimmel, B. Ullmann, T.F. Schilling, Stages of embryonic development of the zebrafish, Dev. Dyn. 203 (1995) 253-310]. Data will be presented to support the suggestion that propagating waves (both long and short range) of Ca(2+) release, followed by sequestration, may play a crucial role in: (1) Coordinating cell movements during these pattern forming events and (2) Contributing to the establishment of the basic embryonic axes, as well as (3) Helping to define the morphological boundaries of specific tissue domains and embryonic structures, including future organ anlagen [E. Gilland, A.L. Miller, E. Karplus, R. Baker, S.E. Webb, Imaging of multicellular large-scale rhythmic calcium waves during zebrafish gastrulation, Proc. Natl. Acad. Sci. USA 96 (1999) 157-161; J.B. Wallingford, A.J. Ewald, R.M. Harland, S.E. Fraser, Calcium signaling during convergent extension in Xenopus, Curr. Biol. 11 (2001) 652-661]. The various potential targets of these Ca(2+) transients will also be discussed, as well as how they might integrate with other known pattern forming pathways known to modulate early developmental events (such as the Wnt/Ca(2+)pathway; [T.A. Westfall, B. Hjertos, D.C. Slusarski, Requirement for intracellular calcium modulation in zebrafish dorsal-ventral patterning, Dev. Biol. 259 (2003) 380-391]).

Screening for Ataxia-Telangiectasia Mutations in a Population-Based Sample of Women with Early-Onset Breast Cancer

DTIC Science & Technology

1999-09-01

nuclear phosphoprotein. J Biol Chem 271: skipping of fibrillin-1 gene in Marfan syndrome . Nat Genet 33693-33697 16:328-329 Concannon P, Gatti RA (1997...1989) ATFresno: a phenotype linking ataxia-tel- ilnikova OM, Lenoir GM (1998) A BRCA1 nonsense mu- angiectasia with the Nijmegen breakage syndrome ...effectors. Am J Hum Genet 62:269-277 tions and Ehlers-Danlos syndrome type IV. Am J Hum Genet Hull J, Shackleton S, Harris A (1994) The stop mutation 61:1276

The Role of Ubiquitin E3 Ligase SCF-SKP2 in Prostate Cancer Development

DTIC Science & Technology

2007-02-01

2004; 303:1371-4. 26. Nag A, Bondar T, Shiv S, Raychaudhuri P. The xeroderma pigmentosum group E gene product DDB2 is a specific target of cullin 4A...ubiquitin ligases. Nat Rev Mol Cell Biol 2005; 6:9-20. 2. Nag A, Bondar T, Shiv S, Raychaudhuri P. The xeroderma pigmentosum group E gene product DDB2 is... xeroderma pigmentosum group E patient and the subsequent inability to bind DDB1 (ref. 16). This motif is present in most of the WDR proteins we found (see

The Role of Siah1-Induced Degradation of beta-Catenin in Androgen Receptor Signaling

DTIC Science & Technology

2007-11-01

biological responses to DNA damage: Insights from yeast and p53. Nat. Cell Biol. 3, E277–E286. Winston, J.T., Strack, P., Beer -Romero, P., Chu, C.Y...apoptosis, depending on the cell line tested [3]. The findings suggest that p53-mediated induction of Siah1 expression could play an important role in the...hypothesis that Siah1 is an important mediator of p53’s effects in prostate cancers. If the hypothesis proves to be correct, then the results derived

Postexposure Protection of Guinea Pigs against a Lethal Ebola Virus Challenge is Conferred by RNA Interference

DTIC Science & Technology

2006-06-15

because its suppression should lead to a nearly total loss of all RNA synthesis , but also because of the absence of similar proteins in mammalian cells...protects mice from fulminant hepatitis. Nat Med 2003; 9:347–51. 12. Ge Q, Filip L, Bai A, Nguyen T, Eisen HN, Chen J. Inhibition of influenza virus...human beta interferon gene in simian cells defective in interferon synthesis . Mol Cell Biol 1986; 6:2279–83. 21. Spann KM, Tran KC, Collins PL

Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury

DTIC Science & Technology

2015-03-01

terminus amino acids of amyloid precursor protein (cAPP). cAPP was found in our recent publication in Gene Therapy (2013) to be the most effective...Therapy. 2012;20:275-86 PubMed PMID: 22008911. 7. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing...NatRevMolCell Biol. 2011;12:21-35. 8. Morita T, Sobue K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR

Cross-language Babel structs—making scientific interfaces more efficient

NASA Astrophysics Data System (ADS)

Prantl, Adrian; Ebner, Dietmar; Epperly, Thomas G. W.

2013-01-01

Babel is an open-source language interoperability framework tailored to the needs of high-performance scientific computing. As an integral element of the Common Component Architecture, it is employed in a wide range of scientific applications where it is used to connect components written in different programming languages. In this paper we describe how we extended Babel to support interoperable tuple data types (structs). Structs are a common idiom in (mono-lingual) scientific application programming interfaces (APIs); they are an efficient way to pass tuples of nonuniform data between functions, and are supported natively by most programming languages. Using our extended version of Babel, developers of scientific codes can now pass structs as arguments between functions implemented in any of the supported languages. In C, C++, Fortran 2003/2008 and Chapel, structs can be passed without the overhead of data marshaling or copying, providing language interoperability at minimal cost. Other supported languages are Fortran 77, Fortran 90/95, Java and Python. We will show how we designed a struct implementation that is interoperable with all of the supported languages and present benchmark data to compare the performance of all language bindings, highlighting the differences between languages that offer native struct support and an object-oriented interface with getter/setter methods. A case study shows how structs can help simplify the interfaces of scientific codes significantly.

Distributed Password Cracking

DTIC Science & Technology

2009-12-01

other services for early UNIX systems at Bell labs. In many UNIX based systems, the field added to ‘etc/ passwd ’ file to carry GCOS ID information was...charset, and external. struct options_main { /* Option flags */ opt_flags flags; /* Password files */ struct list_main * passwd ; /* Password file...object PASSWD . It is part of several other data structures. struct PASSWD { int id; char *login; char *passwd_hash; int UID

Structural Perturbations in the Ala → Val Polymorphism of Methylenetetrahydrofolate Reductase: How Binding of Folates May Protect against Inactivation†‡

PubMed Central

Pejchal, Robert; Campbell, Elizabeth; Guenther, Brian D.; Lennon, Brett W.; Matthews, Rowena G.; Ludwig, Martha L.

2006-01-01

In human methylenetetrahydrofolate reductase (MTHFR) the Ala222Val (677C → T) polymorphism encodes a heat-labile gene product that is associated with elevated levels of homocysteine and possibly with risk for cardiovascular disease. Generation of the equivalent Ala to Val mutation in Escherichia coli MTHFR, which is 30% identical to the catalytic domain of the human enzyme, creates a protein with enhanced thermolability. In both human and E. coli MTHFR, the A → V mutation increases the rate of dissociation of FAD, and in both enzymes, loss of FAD is linked to changes in quaternary structure [Yamada, K., Chen, Z., Rozen, R., and Matthews, R. G. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14853–14858; Guenther, B. D., Sheppard, C. A., Tran, P., Rozen, R., Matthews, R. G., and Ludwig, M. L. (1999) Nat. Struct. Biol. 6, 359–365]. Folates have been shown to protect both human and bacterial enzymes from loss of FAD. Despite its effect on affinity for FAD, the A → V mutation is located at the bottom of the (βα)8 barrel of the catalytic domain in a position that does not contact the bound FAD prosthetic group. Here we report the structures of the Ala177Val mutant of E. coli MTHFR and of its complex with the 5,10-dideazafolate analogue, LY309887, and suggest mechanisms by which the mutation may perturb FAD binding. Helix α5, which immediately precedes the loop bearing the mutation, carries several residues that interact with FAD, including Asn168, Arg171, and Lys172. In the structures of the mutant enzyme this helix is displaced, perturbing protein–FAD interactions. In the complex with LY309887, the pterin-like ring of the analogue stacks against the si face of the flavin and is secured by hydrogen bonds to residues Gln183 and Asp120 that adjoin this face. The direct interactions of bound folate with the cofactor provide one mechanism for linkage between binding of FAD and folate binding that could account in part for the protective action of folates. Conformation changes induced by folate binding may also suppress dissociation of FAD. PMID:16605249

The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data

PubMed Central

Berman, Helen; Henrick, Kim; Nakamura, Haruki; Markley, John L.

2007-01-01

The worldwide Protein Data Bank (wwPDB) is the international collaboration that manages the deposition, processing and distribution of the PDB archive. The online PDB archive is a repository for the coordinates and related information for more than 38 000 structures, including proteins, nucleic acids and large macromolecular complexes that have been determined using X-ray crystallography, NMR and electron microscopy techniques. The founding members of the wwPDB are RCSB PDB (USA), MSD-EBI (Europe) and PDBj (Japan) [H.M. Berman, K. Henrick and H. Nakamura (2003) Nature Struct. Biol., 10, 980]. The BMRB group (USA) joined the wwPDB in 2006. The mission of the wwPDB is to maintain a single archive of macromolecular structural data that are freely and publicly available to the global community. Additionally, the wwPDB provides a variety of services to a broad community of users. The wwPDB website at provides information about services provided by the individual member organizations and about projects undertaken by the wwPDB. PMID:17142228

The protein folding network

NASA Astrophysics Data System (ADS)

Rao, Francesco; Caflisch, Amedeo

2004-03-01

Networks are everywhere. The conformation space of a 20-residue antiparallel beta-sheet peptide [1], sampled by molecular dynamics simulations, is mapped to a network. Conformations are nodes of the network, and the transitions between them are links. As previously found for the World-Wide Web as well as for social and biological networks , the conformation space contains highly connected hubs like the native state which is the most populated free energy basin. Furthermore, the network shows a hierarchical modularity [2] which is consistent with the funnel mechanism of folding [3] and is not observed for a random heteropolymer lacking a native state. Here we show that the conformation space network describes the free energy landscape without requiring projections into arbitrarily chosen reaction coordinates. The network analysis provides a basis for understanding the heterogeneity of the folding transition state and the existence of multiple pathways. [1] P. Ferrara and A. Caflisch, Folding simulations of a three-stranded antiparallel beta-sheet peptide, PNAS 97, 10780-10785 (2000). [2] Ravasz, E. and Barabási, A. L. Hierarchical organization in complex networks. Phys. Rev. E 67, 026112 (2003). [3] Dill, K. and Chan, H From Levinthal to pathways to funnels. Nature Struct. Biol. 4, 10-19 (1997)

Interactive Visual Simulation of Communication Systems. Volume 2

DTIC Science & Technology

1988-04-29

struct( int non; ) ARM *PARAMPTR; Itypedef struct float x[8], y [8]; FILE *fp; mnt time; ) STATE, *STATEPTR; *psk8_dem (pparam, size,pstate,pstar) I...i*THETA); pstate-> y ~i]=sin(i*THETA) ; pstate->fp=fopen ( "graf .dat"l,"w"); pstate->time=0; Iif (length output_fifo(o)==maxlength-output_fifo(0...time򒾐) fprintf(pstate->fp,"\

Struct2Net: a web service to predict protein–protein interactions using a structure-based approach

PubMed Central

Singh, Rohit; Park, Daniel; Xu, Jinbo; Hosur, Raghavendra; Berger, Bonnie

2010-01-01

Struct2Net is a web server for predicting interactions between arbitrary protein pairs using a structure-based approach. Prediction of protein–protein interactions (PPIs) is a central area of interest and successful prediction would provide leads for experiments and drug design; however, the experimental coverage of the PPI interactome remains inadequate. We believe that Struct2Net is the first community-wide resource to provide structure-based PPI predictions that go beyond homology modeling. Also, most web-resources for predicting PPIs currently rely on functional genomic data (e.g. GO annotation, gene expression, cellular localization, etc.). Our structure-based approach is independent of such methods and only requires the sequence information of the proteins being queried. The web service allows multiple querying options, aimed at maximizing flexibility. For the most commonly studied organisms (fly, human and yeast), predictions have been pre-computed and can be retrieved almost instantaneously. For proteins from other species, users have the option of getting a quick-but-approximate result (using orthology over pre-computed results) or having a full-blown computation performed. The web service is freely available at http://struct2net.csail.mit.edu. PMID:20513650

Mitotic chromosome condensation in vertebrates

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

Vagnarelli, Paola, E-mail: P.Vagnarelli@ed.ac.uk

2012-07-15

Work from several laboratories over the past 10-15 years has revealed that, within the interphase nucleus, chromosomes are organized into spatially distinct territories [T. Cremer, C. Cremer, Chromosome territories, nuclear architecture and gene regulation in mammalian cells, Nat. Rev. Genet. 2 (2001) 292-301 and T. Cremer, M. Cremer, S. Dietzel, S. Muller, I. Solovei, S. Fakan, Chromosome territories-a functional nuclear landscape, Curr. Opin. Cell Biol. 18 (2006) 307-316]. The overall compaction level and intranuclear location varies as a function of gene density for both entire chromosomes [J.A. Croft, J.M. Bridger, S. Boyle, P. Perry, P. Teague,W.A. Bickmore, Differences in themore » localization and morphology of chromosomes in the human nucleus, J. Cell Biol. 145 (1999) 1119-1131] and specific chromosomal regions [N.L. Mahy, P.E. Perry, S. Gilchrist, R.A. Baldock, W.A. Bickmore, Spatial organization of active and inactive genes and noncoding DNA within chromosome territories, J. Cell Biol. 157 (2002) 579-589] (Fig. 1A, A'). In prophase, when cyclin B activity reaches a high threshold, chromosome condensation occurs followed by Nuclear Envelope Breakdown (NEB) [1]. At this point vertebrate chromosomes appear as compact structures harboring an attachment point for the spindle microtubules physically recognizable as a primary constriction where the two sister chromatids are held together. The transition from an unshaped interphase chromosome to the highly structured mitotic chromosome (compare Figs. 1A and B) has fascinated researchers for several decades now; however a definite picture of how this process is achieved and regulated is not yet in our hands and it will require more investigation to comprehend the complete process. From a biochemical point of view a vertebrate mitotic chromosomes is composed of DNA, histone proteins (60%) and non-histone proteins (40%) [6]. I will discuss below what is known to date on the contribution of these two different classes of proteins and their co-operation in establishing the final mitotic chromosome structure.« less

Forensic Memory Analysis for Apple OS X

DTIC Science & Technology

2012-06-14

x86. Table 5. Template interface fields. Variable Python Type Description template dict template implementing the C stuct interface MBR_NAME str ...dictionary key, variable name for a struct member template[MBR_NAME] tuple dictionary value, a struct member description MBR_TYPE str C type of the...named member OFFSET int offset in bytes for the member SIZE int size in bytes for the member type FIELD str lsof field represented by member

Changes in consensus arylamine N-acetyltransferase (NAT) gene nomenclature

PubMed Central

Hein, David W.; Boukouvala, Sotiria; Grant, Denis M.; Minchin, Rodney F.; Sim, Edith

2008-01-01

Changes in consensus arylamine N-acetyltransferase (NAT) gene nomenclature determined at the 2007 international NAT workshop include: 1) Alleles in all species except mouse and rat are all uppercase. For mouse and rat, the first letter is upper case followed by lower case. 2) The nomenclature system is now species-specific. Thus, NAT2*1 (chicken), NAT2*2 & NAT2*3 (rabbit), Nat2*8 Nat2*9, Nat2*22 & Nat2*23 (mouse), NAT2*15, NAT2*16A & NAT2*16B (Syrian hamster), and NAT2*20, NAT2*21A & NAT2*21B (rat) are retired and renumbered within a species. A species modifier incorporated into the allele designation is written in upper case Roman font, e.g., (MOUSE)Nat1*1 is now the reference Nat1 allele in mouse; and 3) The NAT website also can now be accessed at a webbalias address: http://N-acetyltransferasenomenclature.louisville.edu. New NAT alleles should continue to be submitted to the NAT nomenclature committee for inclusion on the website to ensure proper categorization and to continue consistency in nomenclature. PMID:18334921

Evolution of insect arylalkylamine N-acetyltransferases: Structural evidence from the yellow fever mosquito, Aedes aegypti

PubMed Central

Han, Qian; Robinson, Howard; Ding, Haizhen; Christensen, Bruce M.; Li, Jianyong

2012-01-01

Arylalkylamine N-acetyltransferase (aaNAT) catalyzes the transacetylation from acetyl-CoA to arylalkylamines. aaNATs are involved in sclerotization and neurotransmitter inactivation in insects. Phyletic distribution analysis confirms three clusters of aaNAT-like sequences in insects: typical insect aaNAT, polyamine NAT-like aaNAT, and mosquito unique putative aaNAT (paaNAT). Here we studied three proteins: aaNAT2, aaNAT5b, and paaNAT7, each from a different cluster. aaNAT2, a protein from the typical insect aaNAT cluster, uses histamine as a substrate as well as the previously identified arylalkylamines. aaNAT5b, a protein from polyamine NAT -like aaNAT cluster, uses hydrazine and histamine as substrates. The crystal structure of aaNAT2 was determined using single-wavelength anomalous dispersion methods, and that of native aaNAT2, aaNAT5b and paaNAT7 was detected using molecular replacement techniques. All three aaNAT structures have a common fold core of GCN5-related N-acetyltransferase superfamily proteins, along with a unique structural feature: helix/helices between β3 and β4 strands. Our data provide a start toward a more comprehensive understanding of the structure–function relationship and physiology of aaNATs from the mosquito Aedes aegypti and serve as a reference for studying the aaNAT family of proteins from other insect species. The structures of three different types of aaNATs may provide targets for designing insecticides for use in mosquito control. PMID:22753468

Uncooled EuSbTe3 photodetector highly sensitive from ultraviolet to terahertz frequencies

NASA Astrophysics Data System (ADS)

Niu, Ying Y.; Wu, Dong; Su, Yu Q.; Zhu, Hai; Wang, Biao; Wang, Ying X.; Zhao, Zi R.; Zheng, Ping; Niu, Jia S.; Zhou, Hui B.; Wei, Jian; Wang, Nan L.

2018-01-01

Light probe from Uv to THz is critical in photoelectronics and has great applications ranging from imaging, communication to medicine (Woodward et al 2002 Phys. Med. Biol. 47 3853-63 Pospischil et al 2013 Nat. Photon. 7 892-6 Martyniuk and Rogalski 2003 Prog. Quantum Electron. 27 59-210). However, the room temperature ultrabroadband photodetection across visible down to far-infrared is still challenging. The challenging arises mainly from the lack of suitable photoactive materials. Because that conventional semiconductors, such as silicon, have their photosensitive properties cut off by the bandgap and are transparent to spectrum at long-wavelength infrared side (Ciupa and Rogalski 1997 Opto-Electron. Rev. 5 257-66 Tonouchi 2007 Nat. Photon. 1 97-105 Sizov and Rogalski 2010 Prog. Quantum Electron. 34 278-347 Kinch 2000 J. Electron. Mater. 29 809-17). Comparatively, the dielectrics with very narrow band-gap but maintain the semiconductor-like electrical conduction would have priorities for ultrabroadband photodetection. Here we report on EuSbTe3 is highly sensitive from ultraviolet directly to terahertz (THz) at room temperature. High photoresponsivities 1-8 A W-1 reached in our prototype EuSbTe3 detectors with low noise equivalent power (NEP) recorded, for instances ~150 pW · Hz-1/2 (at λ  =  532 nm) and ~0.6 nW · Hz-1/2 (at λ  =  118.8 µm) respectively. Our results demonstrate a promising system with direct photosensitivity extending well into THz regime at room temperature, shed new light on exploring more sophisticated multi-band photoelectronics.

Catalytic properties and heat stabilities of novel recombinant human N-acetyltransferase 2 allozymes support existence of genetic heterogeneity within the slow acetylator phenotype.

PubMed

Hein, David W; Doll, Mark A

2017-08-01

Human N-acetyltransferase 2 (NAT2) catalyzes the N-acetylation of numerous aromatic amine drugs such as sulfamethazine (SMZ) and hydrazine drugs such as isoniazid (INH). NAT2 also catalyzes the N-acetylation of aromatic amine carcinogens such as 2-aminofluorene and the O- and N,O-acetylation of aromatic amine and heterocyclic amine metabolites. Genetic polymorphism in NAT2 modifies drug efficacy and toxicity as well as cancer risk. Acetyltransferase catalytic activities and heat stability associated with six novel NAT2 haplotypes (NAT2*6C, NAT2*14C, NAT2*14D, NAT2*14E, NAT2*17, and NAT2*18) were compared with that of the reference NAT2*4 haplotype following recombinant expression in Escherichia coli. N-acetyltransferase activities towards SMZ and INH were significantly (p < 0.0001) lower when catalyzed by the novel recombinant human NAT2 allozymes compared to NAT2 4. SMZ and INH N-acetyltransferase activities catalyzed by NAT2 14C and NAT2 14D were significantly lower (p < 0.001) than catalyzed by NAT2 6C and NAT2 14E. N-Acetylation catalyzed by recombinant human NAT2 17 was over several hundred-fold lower than by recombinant NAT2 4 precluding measurement of its kinetic or heat inactivation constants. Similar results were observed for the O-acetylation of N-hydroxy-2-aminofluorene and N-hydroxy-2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine and the intramolecular N,O-acetylation of N-hydroxy-N-acetyl-2-aminofluorene. The apparent V max of the novel recombinant NAT2 allozymes NAT2 6C, NAT2 14C, NAT2 14D, and NAT2 14E towards AF, 4-aminobiphenyl (ABP), and 3,2'-dimethyl-4-aminobiphenyl (DMABP) were each significantly (p < 0.001) lower while their apparent K m values did not differ significantly (p > 0.05) from recombinant NAT2 4. The apparent V max catalyzed by NAT2 14C and NAT2 14D were significantly lower (p < 0.05) than the apparent V max catalyzed by NAT2 6C and NAT2 14E towards AF, ABP, and DMABP. Heat inactivation rate constants for recombinant human NAT2 14C, 14D, 14E, and 18 were significantly (p < 0.05) higher than NAT2 4. These results provide further evidence of genetic heterogeneity within the NAT2 slow acetylator phenotype.

StructRNAfinder: an automated pipeline and web server for RNA families prediction.

PubMed

Arias-Carrasco, Raúl; Vásquez-Morán, Yessenia; Nakaya, Helder I; Maracaja-Coutinho, Vinicius

2018-02-17

The function of many noncoding RNAs (ncRNAs) depend upon their secondary structures. Over the last decades, several methodologies have been developed to predict such structures or to use them to functionally annotate RNAs into RNA families. However, to fully perform this analysis, researchers should utilize multiple tools, which require the constant parsing and processing of several intermediate files. This makes the large-scale prediction and annotation of RNAs a daunting task even to researchers with good computational or bioinformatics skills. We present an automated pipeline named StructRNAfinder that predicts and annotates RNA families in transcript or genome sequences. This single tool not only displays the sequence/structural consensus alignments for each RNA family, according to Rfam database but also provides a taxonomic overview for each assigned functional RNA. Moreover, we implemented a user-friendly web service that allows researchers to upload their own nucleotide sequences in order to perform the whole analysis. Finally, we provided a stand-alone version of StructRNAfinder to be used in large-scale projects. The tool was developed under GNU General Public License (GPLv3) and is freely available at http://structrnafinder.integrativebioinformatics.me . The main advantage of StructRNAfinder relies on the large-scale processing and integrating the data obtained by each tool and database employed along the workflow, of which several files are generated and displayed in user-friendly reports, useful for downstream analyses and data exploration.

National Program for Inspection of Non-Federal Dams. Congamond Lakes North Dike (MA 00072), Connecticut River Basin, Southwick, Massachusetts. Phase I Inspection Report.

DTIC Science & Technology

1980-08-01

erosion resistant surface should be designed and con - structed on the downstream face after trees and trash have been removed. The owner should also...made by the Division of Waterways to con - struct a drop inlet spillway at North Dike in order to provide a more constant iake level. Plans (12 sheets...provide a more constant lake level. Plans (12 sheets) for this pro - * posal were prepared for the Division of Waterways by Robert G. Brown & Associ

PlantNATsDB: a comprehensive database of plant natural antisense transcripts.

PubMed

Chen, Dijun; Yuan, Chunhui; Zhang, Jian; Zhang, Zhao; Bai, Lin; Meng, Yijun; Chen, Ling-Ling; Chen, Ming

2012-01-01

Natural antisense transcripts (NATs), as one type of regulatory RNAs, occur prevalently in plant genomes and play significant roles in physiological and pathological processes. Although their important biological functions have been reported widely, a comprehensive database is lacking up to now. Consequently, we constructed a plant NAT database (PlantNATsDB) involving approximately 2 million NAT pairs in 69 plant species. GO annotation and high-throughput small RNA sequencing data currently available were integrated to investigate the biological function of NATs. PlantNATsDB provides various user-friendly web interfaces to facilitate the presentation of NATs and an integrated, graphical network browser to display the complex networks formed by different NATs. Moreover, a 'Gene Set Analysis' module based on GO annotation was designed to dig out the statistical significantly overrepresented GO categories from the specific NAT network. PlantNATsDB is currently the most comprehensive resource of NATs in the plant kingdom, which can serve as a reference database to investigate the regulatory function of NATs. The PlantNATsDB is freely available at http://bis.zju.edu.cn/pnatdb/.

Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery

PubMed Central

Sim, E; Abuhammad, A; Ryan, A

2014-01-01

Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para-aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site-modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co-administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5-AS from prodrugs including balsalazide. PMID:24467436

Role of N-acetyltransferase 2 acetylation polymorphism in 4, 4'-methylene bis (2-chloroaniline) biotransformation.

PubMed

Hein, David W; Zhang, Xiaoyan; Doll, Mark A

2018-02-01

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the acetylation of arylamine carcinogens. Single nucleotide polymorphisms in the NAT2 coding exon present in NAT2 haplotypes encode allozymes with reduced N-acetyltransferase activity towards the N-acetylation of arylamine carcinogens and the O-acetylation of their N-hydroxylated metabolites. NAT2 acetylator phenotype modifies urinary bladder cancer risk following exposures to arylamine carcinogens such as 4-aminobiphenyl. 4, 4'-methylene bis (2-chloroaniline) (MOCA) is a Group 1 carcinogen for which a role of the NAT2 acetylation polymorphism on cancer risk is unknown. We investigated the role of NAT2 and the genetic acetylation polymorphism on both MOCA N-acetylation and N-hydroxy-MOCA O-acetylation. MOCA N-acetylation exhibited a robust gene dose response in rabbit liver cytosol and in cryopreserved human hepatocytes derived from individuals of rapid, intermediate and slow acetylator NAT2 genotype. MOCA exhibited about 4-fold higher affinity for recombinant human NAT2 than NAT1. Recombinant human NAT2*4 (reference) and 15 variant recombinant human NAT2 allozymes catalyzed both the N-acetylation of MOCA and the O-acetylation of N-hydroxy-MOCA. Human NAT2 5, NAT2 6, NAT2 7 and NAT2 14 allozymes catalyzed MOCA N-acetylation and N-hydroxy-O-acetylation at rates much lower than the reference NAT2 4 allozyme. In conclusion, our results show that NAT2 acetylator genotype has an important role in MOCA metabolism and suggest that risk assessments related to MOCA exposures consider accounting for NAT2 acetylator phenotype in the analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Watching proteins function with time-resolved x-ray crystallography

NASA Astrophysics Data System (ADS)

Šrajer, Vukica; Schmidt, Marius

2017-09-01

Macromolecular crystallography was immensely successful in the last two decades. To a large degree this success resulted from use of powerful third generation synchrotron x-ray sources. An expansive database of more than 100 000 protein structures, of which many were determined at resolution better than 2 Å, is available today. With this achievement, the spotlight in structural biology is shifting from determination of static structures to elucidating dynamic aspects of protein function. A powerful tool for addressing these aspects is time-resolved crystallography, where a genuine biological function is triggered in the crystal with a goal of capturing molecules in action and determining protein kinetics and structures of intermediates (Schmidt et al 2005a Methods Mol. Biol. 305 115-54, Schmidt 2008 Ultrashort Laser Pulses in Biology and Medicine (Berlin: Springer) pp 201-41, Neutze and Moffat 2012 Curr. Opin. Struct. Biol. 22 651-9, Šrajer 2014 The Future of Dynamic Structural Science (Berlin: Springer) pp 237-51). In this approach, short and intense x-ray pulses are used to probe intermediates in real time and at room temperature, in an ongoing reaction that is initiated synchronously and rapidly in the crystal. Time-resolved macromolecular crystallography with 100 ps time resolution at synchrotron x-ray sources is in its mature phase today, particularly for studies of reversible, light-initiated reactions. The advent of the new free electron lasers for hard x-rays (XFELs; 5-20 keV), which provide exceptionally intense, femtosecond x-ray pulses, marks a new frontier for time-resolved crystallography. The exploration of ultra-fast events becomes possible in high-resolution structural detail, on sub-picosecond time scales (Tenboer et al 2014 Science 346 1242-6, Barends et al 2015 Science 350 445-50, Pande et al 2016 Science 352 725-9). We review here state-of-the-art time-resolved crystallographic experiments both at synchrotrons and XFELs. We also outline challenges and further developments necessary to broaden the application of these methods to many important proteins and enzymes of biomedical relevance.

Watching proteins function with time-resolved x-ray crystallography

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

Šrajer, Vukica; Schmidt, Marius

Macromolecular crystallography was immensely successful in the last two decades. To a large degree this success resulted from use of powerful third generation synchrotron x-ray sources. An expansive database of more than 100 000 protein structures, of which many were determined at resolution better than 2 Å, is available today. With this achievement, the spotlight in structural biology is shifting from determination of static structures to elucidating dynamic aspects of protein function. A powerful tool for addressing these aspects is time-resolved crystallography, where a genuine biological function is triggered in the crystal with a goal of capturing molecules in actionmore » and determining protein kinetics and structures of intermediates (Schmidt et al 2005a Methods Mol. Biol. 305 115–54, Schmidt 2008 Ultrashort Laser Pulses in Biology and Medicine (Berlin: Springer) pp 201–41, Neutze and Moffat 2012 Curr. Opin. Struct. Biol. 22 651–9, Šrajer 2014 The Future of Dynamic Structural Science (Berlin: Springer) pp 237–51). In this approach, short and intense x-ray pulses are used to probe intermediates in real time and at room temperature, in an ongoing reaction that is initiated synchronously and rapidly in the crystal. Time-resolved macromolecular crystallography with 100 ps time resolution at synchrotron x-ray sources is in its mature phase today, particularly for studies of reversible, light-initiated reactions. The advent of the new free electron lasers for hard x-rays (XFELs; 5–20 keV), which provide exceptionally intense, femtosecond x-ray pulses, marks a new frontier for time-resolved crystallography. The exploration of ultra-fast events becomes possible in high-resolution structural detail, on sub-picosecond time scales (Tenboer et al 2014 Science 346 1242–6, Barends et al 2015 Science 350 445–50, Pande et al 2016 Science 352 725–9). We review here state-of-the-art time-resolved crystallographic experiments both at synchrotrons and XFELs. We also outline challenges and further developments necessary to broaden the application of these methods to many important proteins and enzymes of biomedical relevance.« less

Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam.

PubMed

Olivera, M; Martínez, C; Gervasini, G; Carrillo, J A; Ramos, S; Benítez, J; García-Martin, E; Agúndez, J A G

2007-01-01

We investigated the role of NAT2 on clonazepam acetylation, using transiently expressed human NAT2 alleles. The NAT25*B and the NAT2*6A variant alleles cause a 20 and 22-fold reduction in the Vmax, respectively. We conclude that NAT2 is responsible for 7-aminoclonazepam acetylation and that NAT2 gene polymorphisms impair such metabolic pathway.

Genetic heterogeneity among slow acetylator N-acetyltransferase 2 phenotypes in cryopreserved human hepatocytes.

PubMed

Doll, Mark A; Hein, David W

2017-07-01

Genetic polymorphisms in human N-acetyltransferase 2 (NAT2) modify the metabolism of numerous drugs and carcinogens. These genetic polymorphisms modify both drug efficacy and toxicity and cancer risk associated with carcinogen exposure. Previous studies have suggested phenotypic heterogeneity among different NAT2 slow acetylator genotypes. NAT2 phenotype was investigated in vitro and in situ in samples of human hepatocytes obtained from various NAT2 slow and intermediate NAT2 acetylator genotypes. NAT2 gene dose response (NAT2*5B/*5B > NAT2*5B/*6A > NAT2*6A/*6A) was observed towards the N-acetylation of the NAT2-specific drug sulfamethazine by human hepatocytes both in vitro and in situ. N-acetylation of 4-aminobiphenyl, an arylamine carcinogen substrate for both N-acetyltransferase 1 and NAT2, showed the same trend both in vitro and in situ although the differences were not significant (p > 0.05). The N-acetylation of the N-acetyltransferase 1-specific substrate p-aminobenzoic acid did not follow this trend. In comparisons of NAT2 intermediate acetylator genotypes, differences in N-acetylation between NAT2*4/*5B and NAT2*4/*6B hepatocytes were not observed in vitro or in situ towards any of these substrates. These results further support phenotypic heterogeneity among NAT2 slow acetylator genotypes, consistent with differential risks of drug failure or toxicity and cancer associated with carcinogen exposure.

Arylamine N-acetyltransferase 1 in situ N-acetylation on CD3+ peripheral blood mononuclear cells correlate with NATb mRNA and NAT1 haplotype.

PubMed

Salazar-González, Raúl A; Turiján-Espinoza, Eneida; Hein, David W; Niño-Moreno, Perla C; Romano-Moreno, Silvia; Milán-Segovia, Rosa C; Portales-Pérez, Diana P

2018-02-01

Human arylamine N-acetyltransferase 1 (NAT1) is responsible for the activation and elimination of xenobiotic compounds and carcinogens. Genetic polymorphisms in NAT1 modify both drug efficacy and toxicity. Previous studies have suggested a role for NAT1 in the development of several diseases. The aim of the present study was to evaluate NAT1 protein expression and in situ N-acetylation capacity in peripheral blood mononuclear cells (PBMC), as well as their possible associations with the expression of NAT1 transcript and NAT1 genotype. We report NAT1 protein, mRNA levels, and N-acetylation in situ activity for PBMC obtained from healthy donors. NAT1-specific protein expression was higher in CD3+ cells than other major immune cell subtypes (CD19 or CD56 cells). N-acetylation of pABA varied markedly among the PBMC of participants, but correlated very significantly with levels of NAT1 transcripts. NAT1*4 subjects showed significantly (p = 0.017) higher apparent pABA V max of 71.3 ± 3.7 versus the NAT1*14B subjects apparent V max of 58.5 ± 2.5 nmoles Ac-pABA/24 h/million cells. Levels of pABA N-acetylation activity at each concentration of substrate evaluated also significantly correlated with NAT1 mRNA levels for all samples (p < 0.0001). This highly significant correlation was maintained for samples with the NAT1*4 (p = 0.002) and NAT1*14B haplotypes (p = 0.0106). These results provide the first documentation that NAT1-catalyzed N-acetylation in PBMC is higher in T cell than in other immune cell subtypes and that individual variation in N-acetylation capacity is dependent upon NAT1 mRNA and NAT1 haplotype.

Functional Effects of Genetic Polymorphisms in the N-acetyltransferase 1 Coding and 3′ Untranslated Regions

PubMed Central

Zhu, Yuanqi; States, J. Christopher; Wang, Yang; Hein, David W.

2011-01-01

BACKGROUND The functional effects of N-acetyltransferase 1 (NAT1) polymorphisms and haplotypes are poorly understood, compromising the validity of associations reported with diseases including birth defects and numerous cancers. METHODS We investigated the effects of genetic polymorphisms within the NAT1 coding region and the 3′-untranslated region (3′-UTR) and their associated haplotypes on N- and O-acetyltransferase catalytic activities, and NAT1 mRNA and protein levels following recombinant expression in COS-1 cells. RESULTS 1088T>A (rs1057126; 3′-UTR) and 1095C>A (rs15561; 3′-UTR) each slightly reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. A 9-base pair (TAATAATAA) deletion between nucleotides 1065-1090 (3′-UTR) reduced NAT1 catalytic activity and NAT1 mRNA and protein levels. In contrast, a 445G>A (rs4987076; V149I), 459G>A (rs4986990; T153T), 640T>G (rs4986783; S214A) coding region haplotype present in NAT1*11 increased NAT1 catalytic activity and NAT1 protein, but not NAT1 mRNA levels. A combination of the 9-base pair (TAATAATAA) deletion and the 445G>A, 459G>A, 640T>G coding region haplotypes, both present in NAT1*11, appeared to neutralize the opposing effects on NAT1 protein and catalytic activity, resulting in levels of NAT1 protein and catalytic activity that did not differ significantly from the NAT1*4 reference. CONCLUSIONS Since 1095C>A (3′-UTR) is the sole polymorphism present in NAT1*3, our data suggests that NAT1*3 is not functionally equivalent to the NAT1*4 reference. Furthermore, our findings provide biological support for reported associations of 1088T>A and 1095C>A polymorphisms with birth defects. PMID:21290563

NATpipe: an integrative pipeline for systematical discovery of natural antisense transcripts (NATs) and phase-distributed nat-siRNAs from de novo assembled transcriptomes

PubMed Central

Yu, Dongliang; Meng, Yijun; Zuo, Ziwei; Xue, Jie; Wang, Huizhong

2016-01-01

Nat-siRNAs (small interfering RNAs originated from natural antisense transcripts) are a class of functional small RNA (sRNA) species discovered in both plants and animals. These siRNAs are highly enriched within the annealed regions of the NAT (natural antisense transcript) pairs. To date, great research efforts have been taken for systematical identification of the NATs in various organisms. However, developing a freely available and easy-to-use program for NAT prediction is strongly demanded by researchers. Here, we proposed an integrative pipeline named NATpipe for systematical discovery of NATs from de novo assembled transcriptomes. By utilizing sRNA sequencing data, the pipeline also allowed users to search for phase-distributed nat-siRNAs within the perfectly annealed regions of the NAT pairs. Additionally, more reliable nat-siRNA loci could be identified based on degradome sequencing data. A case study on the non-model plant Dendrobium officinale was performed to illustrate the utility of NATpipe. Finally, we hope that NATpipe would be a useful tool for NAT prediction, nat-siRNA discovery, and related functional studies. NATpipe is available at www.bioinfolab.cn/NATpipe/NATpipe.zip. PMID:26858106

N-Acetyltransferase 2 (NAT2) polymorphism as a risk modifier of susceptibility to pediatric acute lymphoblastic leukemia.

PubMed

Kamel, Azza M; Ebid, Gamal T A; Moussa, Heba S

2015-08-01

N-Acetyltransferases (NAT) have been known to modify the risk to a variety of solid tumors. However, the role of NAT2 polymorphism in risk susceptibility to childhood acute lymphoblastic leukemia (ALL) is still not well known. We performed a case-control study to determine if the common NAT2 polymorphisms play a role in altering susceptibility to pediatric ALL. DNA of 92 pediatric ALL patients and 312 healthy controls was analyzed for the NAT2 polymorphisms using the PCR-RFLP method. The wild-type NAT2*4 was encountered in 8.6 % of patients versus 11.8 % of controls (P = 0.23). The rapid acetylators NAT2*12 803A>G, AG, GG, and AG/GG were overrepresented in controls (P = 0.0001; odds ratio (OR) 0.22, 0.19, and 0.21 respectively). NAT2*5D 341T>C and NAT2*11A 481C>T were of comparable frequencies. For their combination, NAT2*5A, a slow acetylator, both TCTT and CCCT were overrepresented in patients (P < 0.001; OR 15.8 and 17.9 respectively). NAT2*5B (803A>G, 341T>C, 481C>T) was overrepresented in controls (P < 0.001; OR 0.12). Apparently, 803A>G ameliorated the combined effect of 341T>C and 481C>T. A similar effect was obtained with NAT2*5C (341T>A, 803A>G) (P < 0.0001; OR 0.11). For slow acetylator NAT2*7A 857G>A, GA and GA/AA were overrepresented in patients (P = 0.009 and 0.01; OR 2.74 and 2.72 respectively). NAT2*13 282C>T, NAT2*6B 590G>A, and NAT2*14A 191G>A were of comparable frequencies. NAT2 282C>A in combination with NAT2 857G>A (NAT2*7B) showed a synergistic effect in patients versus controls (P < 0.0001; OR 3.51). In conclusion, NAT2 gene polymorphism(s) with slow acetylator phenotype is generally associated with the risk of development of ALL in children.

NAT2 gene diversity and its evolutionary trajectory in the Americas.

PubMed

Bisso-Machado, R; Ramallo, V; Paixão-Côrtes, V R; Acuña-Alonzo, V; Demarchi, D A; Sandoval, J R S; Granara, A A S; Salzano, F M; Hünemeier, T; Bortolini, M C

2016-11-01

N-acetyltransferase 2 (NAT2) is responsible for metabolizing xenobiotics; NAT2 polymorphisms lead to three phenotypes: rapid, intermediate and slow acetylators. We aimed to investigate NAT2 diversity in Native Americans. NAT2 exon 2 was sequenced for 286 individuals from 21 populations (Native American and American Mestizos). Excluding the basal/rapid haplotype NAT2*4, the most frequent haplotypes are NAT2*5B (35.95%) in hunter-gatherers and NAT2*7B (20.61%) and NAT2*5B (19.08%) in agriculturalists that were related to the slow phenotype. A new haplotype was identified in two Amerindians. Data from the ~44 kb region surrounding NAT2 in 819 individuals from Africa, East-Asia, Europe and America were used in additional analyses. No significant differences in the acetylator NAT2 haplotype and phenotype distributions were found between Native American populations practicing farming and/or herding and those practicing hunting and gathering, probably because of the absence or weakness of selection pressures and presence of demographic and random processes preventing detection of any selection signal.

StructAlign, a Program for Alignment of Structures of DNA-Protein Complexes.

PubMed

Popov, Ya V; Galitsyna, A A; Alexeevski, A V; Karyagina, A S; Spirin, S A

2015-11-01

Comparative analysis of structures of complexes of homologous proteins with DNA is important in the analysis of DNA-protein recognition. Alignment is a necessary stage of the analysis. An alignment is a matching of amino acid residues and nucleotides of one complex to residues and nucleotides of the other. Currently, there are no programs available for aligning structures of DNA-protein complexes. We present the program StructAlign, which should fill this gap. The program inputs a pair of complexes of DNA double helix with proteins and outputs an alignment of DNA chains corresponding to the best spatial fit of the protein chains.

Congenic rats with higher arylamine N-acetyltransferase 2 activity exhibit greater carcinogen-induced mammary tumor susceptibility independent of carcinogen metabolism.

PubMed

Stepp, Marcus W; Doll, Mark A; Samuelson, David J; Sanders, Mary Ann G; States, J Christopher; Hein, David W

2017-03-31

Recent investigations suggest role(s) of human arylamine N-acetyltransferase 1 (NAT1) in breast cancer. Rat NAT2 is orthologous to human NAT1 and the gene products are functional homologs. We conducted in vivo studies using F344.WKY-Nat2 rapid/slow rats, congenic at rat Nat2 for high (rapid) and low (slow) arylamine N-acetyltransferase activity, to assess a possible role for rat NAT2 in mammary tumor susceptibility. Mammary carcinogens, methylnitrosourea (MNU) and 7,12-dimethylbenzanthracene (DMBA) neither of which is metabolized by N-acetyltransferase, were administered to assess mammary tumors. MNU was administered at 3 or 8 weeks of age. DMBA was administered at 8 weeks of age. NAT2 enzymatic activity and endogenous acetyl-coenzyme A (AcCoA) levels were measured in tissue samples and embryonic fibroblasts isolated from the congenic rats. Tumor latency was shorter in rapid NAT2 rats compared to slow NAT2 rats, with statistical significance for MNU administered at 3 and 8 weeks of age (p = 0.009 and 0.050, respectively). Tumor multiplicity and incidence were higher in rapid NAT2 rats compared to slow NAT2 rats administered MNU or DMBA at 8 weeks of age (MNU, p = 0.050 and 0.035; DMBA, p = 0.004 and 0.027, respectively). Recombinant rat rapid-NAT2, as well as tissue samples and embryonic fibroblasts derived from rapid NAT2 rats, catalyzed p-aminobenzoic acid N-acetyl transfer and folate-dependent acetyl-coenzyme A (AcCoA) hydrolysis at higher rates than those derived from rat slow-NAT2. Embryonic fibroblasts isolated from rapid NAT2 rats displayed lower levels of cellular AcCoA than slow NAT2 rats (p < 0.01). A novel role for rat NAT2 in mammary cancer was discovered unrelated to carcinogen metabolism, suggesting a role for human NAT1 in breast cancer.

Arylamine N-acetyltransferase 2 gene polymorphism in an Algerian population.

PubMed

Chelouti, Hiba; Khelil, Malika

2017-09-01

The arylamine N-acetyltransferase 2 (NAT2) is a key enzyme in the biotransformation of xenobiotics. NAT2 gene polymorphisms have been associated with the risk of isoniazid hepatotoxicity and these polymorphisms change among different populations. The objective of this study is to investigate NAT2 polymorphisms in order to predict the prevalence of NAT2 phenotype in an Algerian population. Genotyping of NAT2 was done using a PCR-RFLP method. Haplotype was analysed using the software package PHASE, version 2.0. The major haplotypes were NAT2*5B (23.72%), NAT2*6 A (18.61%), NAT2*4 (14.60%) and NAT2*5 F (10%). The average of the expected slow acetylator phenotype was 53%. Our results suggest that the high frequency of slow acetylator phenotype requires investigation into its possible association with ATDH.

E-MSD: improving data deposition and structure quality.

PubMed

Tagari, M; Tate, J; Swaminathan, G J; Newman, R; Naim, A; Vranken, W; Kapopoulou, A; Hussain, A; Fillon, J; Henrick, K; Velankar, S

2006-01-01

The Macromolecular Structure Database (MSD) (http://www.ebi.ac.uk/msd/) [H. Boutselakis, D. Dimitropoulos, J. Fillon, A. Golovin, K. Henrick, A. Hussain, J. Ionides, M. John, P. A. Keller, E. Krissinel et al. (2003) E-MSD: the European Bioinformatics Institute Macromolecular Structure Database. Nucleic Acids Res., 31, 458-462.] group is one of the three partners in the worldwide Protein DataBank (wwPDB), the consortium entrusted with the collation, maintenance and distribution of the global repository of macromolecular structure data [H. Berman, K. Henrick and H. Nakamura (2003) Announcing the worldwide Protein Data Bank. Nature Struct. Biol., 10, 980.]. Since its inception, the MSD group has worked with partners around the world to improve the quality of PDB data, through a clean up programme that addresses inconsistencies and inaccuracies in the legacy archive. The improvements in data quality in the legacy archive have been achieved largely through the creation of a unified data archive, in the form of a relational database that stores all of the data in the wwPDB. The three partners are working towards improving the tools and methods for the deposition of new data by the community at large. The implementation of the MSD database, together with the parallel development of improved tools and methodologies for data harvesting, validation and archival, has lead to significant improvements in the quality of data that enters the archive. Through this and related projects in the NMR and EM realms the MSD continues to improve the quality of publicly available structural data.

Conformational flexibility of domain III of annexin V: the effect of pH and binding to membrane-water interfaces

NASA Astrophysics Data System (ADS)

Sopkova, Jana; Vincent, Michel; Takahashi, Maza; Lewit-Bentley, Anita; Gallay, Jacques

1999-05-01

Steady-state and time-resolved fluorescence of the single tryptophan residue (W187) of annexin V show that the conformation and the dynamics of domain III are strongly modified upon binding of the protein to negatively charged phospholipid vesicles in the presence of calcium, or upon incorporation into reverse micelles of water/sodium bis(2- ethylhexyl) sulfosuccinate (AOT) in iso-octane. In the protein at neutral pH, W187 is slightly mobile and buried in a hydrophobic pocket. It becomes more mobile and is moved in a more polar environment when the protein interacts with the model membranes. In each condition, the heterogeneity of the fluorescence intensity decay of W187 is likely due to the co- existence of local conformers with different dynamics. A similar change of conformation and dynamics can be provoked by mild acidic pH. This suggests that electrostatic interactions are important for the folding of domain III. An interplay of salt bridges implying charged amino-acid side-chains at the protein surface in domain III can be observed in the crystal structure. Local pH modifications at the membrane surface can therefore be responsible for the observed conformational change. The high flexibility of domain III in the membrane- bound protein suggests moreover that this domain may not be crucial for the interaction of the protein with the membrane, in agreement with recent atomic force microscope results (Reviakine et al., 1998, J. Struct. Biol. 121, 356-362).

Thermodynamic and kinetic characterization of a beta-hairpin peptide in solution: an extended phase space sampling by molecular dynamics simulations in explicit water.

PubMed

Daidone, Isabella; Amadei, Andrea; Di Nola, Alfredo

2005-05-15

The folding of the amyloidogenic H1 peptide MKHMAGAAAAGAVV taken from the syrian hamster prion protein is explored in explicit aqueous solution at 300 K using long time scale all-atom molecular dynamics simulations for a total simulation time of 1.1 mus. The system, initially modeled as an alpha-helix, preferentially adopts a beta-hairpin structure and several unfolding/refolding events are observed, yielding a very short average beta-hairpin folding time of approximately 200 ns. The long time scale accessed by our simulations and the reversibility of the folding allow to properly explore the configurational space of the peptide in solution. The free energy profile, as a function of the principal components (essential eigenvectors) of motion, describing the main conformational transitions, shows the characteristic features of a funneled landscape, with a downhill surface toward the beta-hairpin folded basin. However, the analysis of the peptide thermodynamic stability, reveals that the beta-hairpin in solution is rather unstable. These results are in good agreement with several experimental evidences, according to which the isolated H1 peptide adopts very rapidly in water beta-sheet structure, leading to amyloid fibril precipitates [Nguyen et al., Biochemistry 1995;34:4186-4192; Inouye et al., J Struct Biol 1998;122:247-255]. Moreover, in this article we also characterize the diffusion behavior in conformational space, investigating its relations with folding/unfolding conditions. Copyright 2005 Wiley-Liss, Inc.

Evolutionary transition from biological to social systems via generation of reflexive models of externality.

PubMed

Igamberdiev, Abir U

2017-12-01

Evolutionary transition from biological to social systems corresponds to the emergence of the structure of subject that incorporates the internal image of the external world. This structure, established on the basis of referral of the subject (self) to its symbolic image, acquires a potential to rationally describe the external world through the semiotic structure of human language. It has been modelled in reflexive psychology using the algebra of simple relations (Lefebvre, V.A., J. Soc. Biol. Struct. 10, 129-175, 1987). The model introduces a substantial opposition of the two basic complementary types of reflexion defined as Western (W) and Eastern (E). These types generate opposite models of behavior and opposite organizations of societies. Development of human societies involves the interactions of W and E types not only between the societies but also within one society underlying its homeostasis and dynamics. Invention of new ideas and implementation of new technologies shift the probability pattern of reflexive choices, appearing as internal assessments of the individual agents within a society, and direct changes in the preference of reflexive types. The dynamics of societies and of interactions between societies is based on the interference of opposite reflexive structures and on the establishment of different patterns during such interference. At different times in the history of human civilization these changing patterns resulted in the formation and splitting of large empires, the development and spreading of new technologies, the consecutive periods of wellness and decline. Copyright © 2017 Elsevier Ltd. All rights reserved.

Induction of neuronal axon outgrowth by Shati/Nat8l by energy metabolism in mice cultured neurons.

PubMed

Sumi, Kazuyuki; Uno, Kyosuke; Matsumura, Shohei; Miyamoto, Yoshiaki; Furukawa-Hibi, Yoko; Muramatsu, Shin-Ichi; Nabeshima, Toshitaka; Nitta, Atsumi

2015-09-09

A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens of mice repeatedly treated with methamphetamine (METH). Shati/Nat8l has been reported to inhibit the pharmacological action induced by METH. Shati/Nat8l produces N-acetylaspartate from aspartate and acetyl-CoA. Previously, we reported that overexpression of Shati/Nat8l in nucleus accumbens attenuates the response to METH by N-acetylaspartylglutamate (which is derived from N-acetylaspartate)-mGluR3 signaling in the mice brain. In the present study, to clarify the type of cells that produce Shati/Nat8l, we carried out in-situ hybridization for the detection of Shati/Nat8l mRNA along with immunohistochemical studies using serial sections of mice brain. Shati/Nat8l mRNA was detected in neuronal cells, but not in astrocytes or microglia cells. Next, we investigated the function of Shati/Nat8l in the neuronal cells in mice brain; then, we used an adeno-associated virus vector containing Shati/Nat8l for transfection and overexpression of Shati/Nat8l protein into the primary cultured neurons to investigate the contribution toward the neuronal activity of Shati/Nat8l. Overexpression of Shati/Nat8l in the mice primary cultured neurons induced axonal growth, but not dendrite elongation at day 1.5 (DIV). This finding indicated that Shati/Nat8l contributes toward neuronal development. LY341495, a selective group II mGluRs antagonist, did not abolish this axonal growth, and N-acetylaspartylglutamate itself did not abolish axon outgrowth in the same cultured system. The cultured neurons overexpressing Shati/Nat8l contained high ATP, suggesting that axon outgrowth is dependent on energy metabolism. This study shows that Shati/Nat8l in the neuron may induce axon outgrowth by ATP synthesis and not through mGluR3 signaling.

Wet-Bulb-Globe Temperature Data Report

DTIC Science & Technology

2015-03-01

Hour Min Pressure Dry Nat Wet Globe Dry Nat Wet Globe Dry Nat Wet Globe Wind Cld amt Cld type Obscuration Quest RH Kestrel RH VPSc RH S1 WBGT Q WBGT...Wet Globe Dry Nat Wet Globe Dry Nat Wet Globe Wind Cld amt Cld type Obscuration Quest RH Kestrel RH VPSc RH S1 WBGT Q WBGT K2 WBGT GMT millibars deg F...Dry Nat Wet Globe Dry Nat Wet Globe Wind Cld amt Cld type Obscuration Quest RH Kestrel RH VPSc RH S1 WBGT Q WBGT K2 WBGT GMT millibars deg F deg F deg

Rapid birth-and-death evolution of the xenobiotic metabolizing NAT gene family in vertebrates with evidence of adaptive selection

PubMed Central

2013-01-01

Background The arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics. Considering the temporal changes in the levels and toxicity of environmentally available chemicals, the metabolic function of NATs is likely to be under adaptive evolution to broaden or change substrate specificity over time, making NATs a promising subject for evolutionary analyses. In this study, we trace the molecular evolutionary history of the NAT gene family during the last ~450 million years of vertebrate evolution and define the likely role of gene duplication, gene conversion and positive selection in the evolutionary dynamics of this family. Results A phylogenetic analysis of 77 NAT sequences from 38 vertebrate species retrieved from public genomic databases shows that NATs are phylogenetically unstable genes, characterized by frequent gene duplications and losses even among closely related species, and that concerted evolution only played a minor role in the patterns of sequence divergence. Local signals of positive selection are detected in several lineages, probably reflecting response to changes in xenobiotic exposure. We then put a special emphasis on the study of the last ~85 million years of primate NAT evolution by determining the NAT homologous sequences in 13 additional primate species. Our phylogenetic analysis supports the view that the three human NAT genes emerged from a first duplication event in the common ancestor of Simiiformes, yielding NAT1 and an ancestral NAT gene which in turn, duplicated in the common ancestor of Catarrhini, giving rise to NAT2 and the NATP pseudogene. Our analysis suggests a main role of purifying selection in NAT1 protein evolution, whereas NAT2 was predicted to mostly evolve under positive selection to change its amino acid sequence over time. These findings are consistent with a differential role of the two human isoenzymes and support the involvement of NAT1 in endogenous metabolic pathways. Conclusions This study provides unequivocal evidence that the NAT gene family has evolved under a dynamic process of birth-and-death evolution in vertebrates, consistent with previous observations made in fungi. PMID:23497148

Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods

PubMed Central

Hiragaki, Susumu; Suzuki, Takeshi; Mohamed, Ahmed A. M.; Takeda, Makio

2015-01-01

The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N-acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising. PMID:25918505

Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods.

PubMed

Hiragaki, Susumu; Suzuki, Takeshi; Mohamed, Ahmed A M; Takeda, Makio

2015-01-01

The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N-acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising.

N-acetyltransferase polymorphisms are associated with risk of lymphoma subtypes.

PubMed

Cocco, Pierluigi; Zucca, Mariagrazia; Sanna, Sonia; Satta, Giannina; Nonne, Tinucia; Angelucci, Emanuele; Gabbas, Attilio; Rais, Marco; Malpeli, Giorgio; Campagna, Marcello; Scarpa, Aldo; G Ennas, Maria

2016-06-01

Genes encoding for arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) have been investigated with alternate findings in relation to risk of non-Hodgkin lymphoma (NHL). We tested functional haplotype-based NAT1 and NAT2 gene polymorphisms in relation to risk of lymphoma overall and its major B cell subtypes, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia (CLL). We used allele specific primers and multiplex PCR to detect NAT1 and NAT2 haplotypes in 248 patients with incident lymphoma and 208 population controls. We inferred the NAT1 rapid and slow acetylator and the NAT2 rapid, intermediate or slow acetylator phenotype, based on published functional data on the respective genotypes. Odds ratios and 95% confidence intervals (95% CIs) for lymphoma, B-NHL, DLBCL, FL, CLL, and other B-NHL combined associated with the inferred rapid NAT1 acetylator and with the intermediate and slow NAT2 acetylator phenotypes were estimated with unconditional and polytomous logistic regression analysis, adjusting for age, gender and education. NAT1 rapid acetylators showed a 2.8-fold excess risk (95% CI 1.5-5.2) for lymphoma (all subtypes combined). Risk was highest for CLL and FL, with significant heterogeneity detected across subtypes. Risk also increased with decreasing NAT2 acetylating capacity with no heterogeneity detected across B cell lymphoma subtypes. Risks did not vary by gender. Although poor statistical power was a major limitation in our study, larger studies and pooled analyses are warranted to test whether NAT1 and NAT2 gene polymorphisms might modulate risk of specific lymphoma subtypes through the varying metabolic activity of their products. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Importance of the Evaluation of N-Acetyltransferase Enzyme Activity Prior to 5-Aminosalicylic Acid Medication for Ulcerative Colitis.

PubMed

Matthis, Andrea L; Zhang, Bin; Denson, Lee A; Yacyshyn, Bruce R; Aihara, Eitaro; Montrose, Marshall H

2016-08-01

5-aminosalicylic acid (5-ASA) is a classic anti-inflammatory drug for the treatment of ulcerative colitis. N-acetyltransferase (NAT) enzymes convert 5-ASA to its metabolite N-acetyl-5-ASA, and it is unresolved whether 5-ASA or N-acetyl-5-ASA is the effective therapeutic molecule. We previously demonstrated that colonic production of N-acetyl-5-ASA (NAT activity) is decreased in dextran sulfate sodium-induced colitis. Our hypothesis is that 5-ASA is the therapeutic molecule to improve colitis, with the corollary that altered NAT activity affects drug efficacy. Since varying clinical effectiveness of 5-ASA has been reported, we also ask if NAT activity varies with inflammation in pediatric or adult patients. Acute colonic inflammation was induced in C57BL/6 NAT wild-type (WT) or knockout mice, using 3.5% dextran sulfate sodium (w/v) concurrent with 5-ASA treatment. Adult and pediatric rectosigmoid biopsies were collected from control or patients with ulcerative colitis. Tissue was analyzed for NAT and myeloperoxidase activity. Dextran sulfate sodium-induced colitis was of similar severity in both NAT WT and knockout mice, and NAT activity was significantly decreased in NAT WT mice. In the setting of colitis, 5-ASA significantly restored colon length and decreased myeloperoxidase activity in NAT knockout but not in WT mice. Myeloperoxidase activity negatively correlated with NAT activity in pediatric patients, but correlation was not observed in adult patients. Inflammation decreases NAT activity in the colon of mice and human pediatric patients. Decreased NAT activity enhances the therapeutic effect of 5-ASA in mice. A NAT activity assay could be useful to help predict the efficacy of 5-ASA therapy.

Natural antisense transcripts are significantly involved in regulation of drought stress in maize.

PubMed

Xu, Jie; Wang, Qi; Freeling, Micheal; Zhang, Xuecai; Xu, Yunbi; Mao, Yan; Tang, Xin; Wu, Fengkai; Lan, Hai; Cao, Moju; Rong, Tingzhao; Lisch, Damon; Lu, Yanli

2017-05-19

Natural antisense transcripts (NATs) are a prominent and complex class of regulatory RNAs. Using strand-specific RNA sequencing, we identified 1769 sense and antisense transcript pairs (NAT pairs) in two maize inbreds with different sensitivity to drought, as well as in two derivative recombination inbred lines (RILs). A significantly higher proportion of NATs relative to non-NATs are specifically expressed under water stress (WS). Surprisingly, expression of sense and antisense transcripts produced by NAT pairs is significantly correlated, particularly under WS. We found an unexpected large proportion of NATs with protein coding potential, as estimated by ribosome release scores. Small RNAs significantly accumulate within NAT pairs, with 21 nt smRNA particularly enriched in overlapping regions of these pairs of genes. The abundance of these smRNAs is significantly altered in the leafbladeless1 mutant, suggesting that these genes may be regulated by the tasiRNA pathway. Further, NATs are significantly hypomethylated and include fewer transposable element sequences relative to non-NAT genes. NAT gene regions also exhibit higher levels of H3K36me3, H3K9ac, and H3K4me3, but lower levels of H3K27me3, indicating that NAT gene pairs generally exhibit an open chromatin configuration. Finally, NAT pairs in 368 diverse maize inbreds and 19 segregating populations were specifically enriched for polymorphisms associated with drought tolerance. Taken together, the data highlight the potential impact of that small RNAs and histone modifications have in regulation of NAT expression, and the significance of NATs in response to WS. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Half a decade of mini-pool nucleic acid testing: Cost-effective way for improving blood safety in India

PubMed Central

Chandrashekar, Shivaram

2014-01-01

Background and Objectives: It is well established that Nucleic acid testing (NAT) reduces window phase of transfusion transmissible infections (TTI) and helps improve blood safety. NAT testing can be done individually or in pools. The objectives of this study were to determine the utility, feasibility and cost effectiveness of an in-house minipool-NAT(MP-NAT). Materials and Methods: Blood donors were screened by history, tested by ELISA and sero-negative samples were subjected to an in-house NAT by using reverse transcriptase-polymerase chain reaction (RT-PCR). Testing was done in mini-pools of size eight (8). Positive pools were repeated with individual samples. Results: During the study period of Oct 2005-Sept 2010 (5 years) all blood donors (n=53729) were screened by ELISA. Of which 469 (0.87%) were positive for HIV-1, HBV or HCV. Sero-negative samples (n=53260) were screened by in-house MP-NAT. HIV-NAT yield was 1/53260 (n=1) and HBV NAT yield (n=2) was 1/26630. Conclusion: NAT yield was lower than other India studies possibly due to the lower sero-reactivity amongst our donors. Nevertheless it intercepted 9 lives including the components prepared. The in-house assay met our objective of improving blood safety at nominal cost and showed that it is feasible to set up small molecular biology units in medium-large sized blood banks and deliver blood within 24-48 hours. The utility of NAT (NAT yield) will vary based on the donor population, the type of serological test used, the nature of kit employed and the sensitivity of NAT test used. The limitations of our in-house MP-NAT consisted of stringent sample preparation requirements, with labor and time involved. The benefits of our MP-NAT were that it acted as a second level of check for ELISA tests, was relatively inexpensive compared to ID-NAT and did not need sophisticated equipment. PMID:24678172

A pilot study of the modulation of sirtuins on arylamine N-acetyltransferase 1 and 2 enzymatic activity.

PubMed

Turiján-Espinoza, Eneida; Salazar-González, Rául Alejandro; Uresti-Rivera, Edith Elena; Hernández-Hernández, Gloria Estela; Ortega-Juárez, Montserrat; Milán, Rosa; Portales-Pérez, Diana

2018-03-01

Arylamine N -acetyltransferase (NAT; E.C. 2.3.1.5) enzymes are responsible for the biotransformation of several arylamine and hydrazine drugs by acetylation. In this process, the acetyl group transferred to the acceptor substrate produces NAT deacetylation and, in consequence, it is susceptible of degradation. Sirtuins are protein deacetylases, dependent on nicotine adenine dinucleotide, which perform post-translational modifications on cytosolic proteins. To explore possible sirtuin participation in the enzymatic activity of arylamine NATs, the expression levels of NAT1, NAT2, SIRT1 and SIRT6 in peripheral blood mononuclear cells (PBMC) from healthy subjects were examined by flow cytometry and Western blot. The in situ activity of the sirtuins on NAT enzymatic activity was analyzed by HPLC, in the presence or absence of an agonist (resveratrol) and inhibitor (nicotinamide) of sirtuins. We detected a higher percentage of positive cells for NAT2 in comparison with NAT1, and higher numbers of SIRT1+ cells compared to SIRT6 in lymphocytes. In situ NAT2 activity in the presence of NAM inhibitors was higher than in the presence of its substrate, but not in the presence of resveratrol. In contrast, the activity of NAT1 was not affected by sirtuins. These results showed that NAT2 activity might be modified by sirtuins.

N-Acetyltransferase 2 Genotypes Are Associated With Diisocyanate-Induced Asthma.

PubMed

Yucesoy, Berran; Kissling, Grace E; Johnson, Victor J; Lummus, Zana L; Gautrin, Denyse; Cartier, André; Boulet, Louis-Philippe; Sastre, Joaquin; Quirce, Santiago; Tarlo, Susan M; Cruz, Maria-Jesus; Munoz, Xavier; Luster, Michael I; Bernstein, David I

2015-12-01

To investigate whether genetic variants of N-acetyltransferase (NAT) genes are associated with diisocyanate asthma (DA). The study population consisted of 354 diisocyanate-exposed workers. Genotyping was performed using a 5'-nuclease polymerase chain reaction assay. The NAT2 rs2410556 and NAT2 rs4271002 variants were significantly associated with DA in the univariate analysis. In the first logistic regression model comparing DA+ and asymptomatic worker groups, the rs2410556 (P = 0.004) and rs4271002 (P < 0.001) single nucleotide polymorphisms and the genotype combination, NAT2 rs4271002*NAT1 rs11777998, showed associations with DA risk (P = 0.014). In the second model comparing DA+ and DA- groups, NAT2 rs4271002 variant and the combined genotype, NAT1 rs8190845*NAT2 rs13277605, were significantly associated with DA risk (P = 0.022, P = 0.036, respectively). These findings suggest that variations in the NAT2 gene and their interactions contribute to DA susceptibility.

Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.

PubMed

Wang, Pengcheng; Shehu, Amina I; Lu, Jie; Joshi, Rujuta H; Venkataramanan, Raman; Sugamori, Kim S; Grant, Denis M; Zhong, Xiao-Bo; Ma, Xiaochao

2017-12-01

Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers. Copyright © 2017 Elsevier Inc. All rights reserved.

NATb/NAT1*4 promotes greater arylamine N-acetyltransferase 1 mediated DNA adducts and mutations than NATa/NAT1*4 following exposure to 4-aminobiphenyl

PubMed Central

Millner, Lori M.; Doll, Mark A.; Cai, Jian; States, J. Christopher; Hein, David W.

2011-01-01

N -acetyltransferase 1 (NAT1) is a phase II metabolic enzyme responsible for the biotransformation of aromatic and heterocyclic amine carcinogens such as 4-aminobiphenyl (ABP). NAT1 catalyzes N-acetylation of arylamines as well as the O-acetylation of N-hydroxylated arylamines. O-acetylation leads to the formation of electrophilic intermediates that result in DNA adducts and mutations. NAT1 is transcribed from a major promoter, NATb, and an alternative promoter, NATa, resulting in mRNAs with distinct 5′-untranslated regions (UTR). NATa mRNA is expressed primarily in the kidney, liver, trachea and lung while NATb mRNA has been detected in all tissues studied. To determine if differences in 5′-UTR have functional effect upon NAT1 activity and DNA adducts or mutations following exposure to ABP, pcDNA5/FRT plasmid constructs were prepared for transfection of full length human mRNAs including the 5′-UTR derived from NATa or NATb, the open reading frame, and 888 nucleotides of the 3′-UTR. Following stable transfection of NATb/NAT1*4 or NATa/NAT1*4 into nucleotide excision repair (NER) deficient Chinese hamster ovary cells, N-acetyltransferase activity (in vitro and in situ), mRNA, and protein expression were higher in NATb/NAT1*4 than NATa/NAT1*4 transfected cells (p<0.05). Consistent with NAT1 expression and activity, ABP-induced DNA adducts and hypoxanthine phosphoribosyl transferase mutants were significantly higher (p<0.05) in NATb/NAT1*4 than in NATa/NAT1*4 transfected cells following exposure to ABP. These differences observed between NATa and NATb suggest that the 5′-UTRs are differentially regulated. PMID:21837760

N-acetyltransferase 1*10 genotype in bladder cancer patients.

PubMed

Höhne, Svetlana; Gerullis, Holger; Blaszkewicz, Meinolf; Selinski, Silvia; Hengstler, Jan G; Otto, Thomas; Golka, Klaus

2017-01-01

In a large bladder cancer study in the greater Berlin area with 425 cases and 343 controls, the haplotype N-acetyltransferase 1*10 (NAT1*10) was associated with a decreased bladder cancer risk. In a recently published meta-analysis, results of the studies were found to be inconclusive. Therefore, the aim of this study was to investigate the frequency of NAT1*10 in bladder cancer patients and controls recruited in an area without industries reported to be associated with increased bladder cancer risk. Rs1057126 (1088 T > A) and rs15561 (1095 C > A) were determined in 412 bladder cancer patients and 415 controls without a known history of malignancies. With these two single-nucleotide polymorphisms (SNP), it was possible to distinguish between NAT1*4 (wild type), NAT1*3 (1095 C > A), and NAT1*10 (1088 T > A, 1095C > A). The frequencies of the determined NAT1 haplotypes did not differ markedly between cases and controls: NAT1*4: 74%, NAT1*3: 6%, NAT1*10: 20%. Bladder cancer risk was not significantly modulated by NAT1*10/*10 (OR 1.03, 95% CI 0.71-1.48) but was higher for NAT1*3/*3 genotypes (OR 2.05, 95% CI 1.32-3.21). In contrast to the Berlin study from 2001, data in present study demonstrated that NAT1*10 haplotype was not associated with a significantly decreased bladder cancer risk. This may be due to local effects in the greater Berlin area, particularly at the time of investigation. The findings of the present study are in agreement with observations of a recently published meta-analysis which also showed no relevant impact of NAT1*10 haplotype on bladder cancer risk. The impact of the rare NAT1*3/*3 genotype was significant but this may be attributed to rarity without major practical relevance.

Systemic functional expression of N-acetyltransferase polymorphism in the F344 Nat2 congenic rat

PubMed Central

Hein, David W.; Bendaly, Jean; Neale, Jason R.; Doll, Mark A.

2008-01-01

Rat lines congenic for the rat N-acetyltransferase 2 [(RAT)Nat2] gene were constructed and characterized. F344 (homozygous Nat2 rapid) males were mated to WKY (homozygous Nat2 slow) females to produce heterozygous F1. F1 females were then backcrossed to F344 males. Heterozygous acetylator female progeny from this and each successive backcross were identified by rat Nat2 genotyping and mated with F344 rapid acetylator males. Following ten generations of backcross mating, heterozygous acetylator brother/sister progeny were mated to produce the homozgygous rapid and slow acetylator Nat2 congenic rat lines. p-Aminobenzoic acid (selective for rat NAT2) and 4-aminobiphenyl N-acetyltransferase activities were expressed in all tissues examined (liver, lung, esophagus, stomach, small intestine, colon, pancreas, kidney, skin, leukocytes, and urinary bladder in male and female rats and in breast of female and prostate of male rats). NAT2 expression in rat extrahepatic tissues was much higher than in liver. In each tissue, activities were Nat2-genotype dependent, with highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators, and lowest in homozygous slow acetylators. Sulfamethazine (selective for rat NAT1) N-acetyltransferase activities were observed in all tissues examined in both male and female rats except for breast (females), bladder and leukocytes. In each tissue, the activity was Nat2-genotype independent, with similar levels in homozygous rapid, heterozygous, and homozygous slow acetylators. These congenic rat lines are useful to investigate the role of NAT2 genetic polymorphism in susceptibility to cancers related to arylamine carcinogen exposures. PMID:18799801

Insight into cofactor recognition in arylamine N-acetyltransferase enzymes: structure of Mesorhizobium loti arylamine N-acetyltransferase in complex with coenzyme A.

PubMed

Xu, Ximing; Li de la Sierra-Gallay, Inés; Kubiak, Xavier; Duval, Romain; Chaffotte, Alain F; Dupret, Jean Marie; Haouz, Ahmed; Rodrigues-Lima, Fernando

2015-02-01

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes that catalyze the acetyl-CoA-dependent acetylation of arylamines. To better understand the mode of binding of the cofactor by this family of enzymes, the structure of Mesorhizobium loti NAT1 [(RHILO)NAT1] was determined in complex with CoA. The F42W mutant of (RHILO)NAT1 was used as it is well expressed in Escherichia coli and displays enzymatic properties similar to those of the wild type. The apo and holo structures of (RHILO)NAT1 F42W were solved at 1.8 and 2 Å resolution, respectively. As observed in the Mycobacterium marinum NAT1-CoA complex, in (RHILO)NAT1 CoA binding induces slight structural rearrangements that are mostly confined to certain residues of its `P-loop'. Importantly, it was found that the mode of binding of CoA is highly similar to that of M. marinum NAT1 but different from the modes reported for Bacillus anthracis NAT1 and Homo sapiens NAT2. Therefore, in contrast to previous data, this study shows that different orthologous NATs can bind their cofactors in a similar way, suggesting that the mode of binding CoA in this family of enzymes is less diverse than previously thought. Moreover, it supports the notion that the presence of the `mammalian/eukaryotic insertion loop' in certain NAT enzymes impacts the mode of binding CoA by imposing structural constraints.

Arylamine n-acetyltransferases in eukaryotic microorganisms

USDA-ARS?s Scientific Manuscript database

Microorganisms can survive highly toxic environments through numerous xenobiotic metabolizing enzymes, including arylamine N-acetyltransferases (NATs). NAT genes are present in bacteria, archaea, protists and fungi. In lower taxa of fungi, NAT genes are found in chytridiomycetes. In Dikarya, NAT gen...

Suitability of the HAM-Nat test and TMS module "basic medical-scientific understanding" for medical school selection

PubMed Central

Hissbach, Johanna; Feddersen, Lena; Sehner, Susanne; Hampe, Wolfgang

2012-01-01

Aims: Tests with natural-scientific content are predictive of the success in the first semesters of medical studies. Some universities in the German speaking countries use the ‘Test for medical studies’ (TMS) for student selection. One of its test modules, namely “medical and scientific comprehension”, measures the ability for deductive reasoning. In contrast, the Hamburg Assessment Test for Medicine, Natural Sciences (HAM-Nat) evaluates knowledge in natural sciences. In this study the predictive power of the HAM-Nat test will be compared to that of the NatDenk test, which is similar to the TMS module “medical and scientific comprehension” in content and structure. Methods: 162 medical school beginners volunteered to complete either the HAM-Nat (N=77) or the NatDenk test (N=85) in 2007. Until spring 2011, 84.2% of these successfully completed the first part of the medical state examination in Hamburg. Via different logistic regression models we tested the predictive power of high school grade point average (GPA or “Abiturnote”) and the test results (HAM-Nat and NatDenk) with regard to the study success criterion “first part of the medical state examination passed successfully up to the end of the 7th semester” (Success7Sem). The Odds Ratios (OR) for study success are reported. Results: For both test groups a significant correlation existed between test results and study success (HAM-Nat: OR=2.07; NatDenk: OR=2.58). If both admission criteria are estimated in one model, the main effects (GPA: OR=2.45; test: OR=2.32) and their interaction effect (OR=1.80) are significant in the HAM-Nat test group, whereas in the NatDenk test group only the test result (OR=2.21) significantly contributes to the variance explained. Conclusions: On their own both HAM-Nat and NatDenk have predictive power for study success, but only the HAM-Nat explains additional variance if combined with GPA. The selection according to HAM-Nat and GPA has under the current circumstances of medical school selection (many good applicants and only a limited number of available spaces) the highest predictive power of all models. PMID:23255967

Studies on N-Acetyltransferase (NAT2) Genotype Relationships in Emiratis: Confirmation of the Existence of Phenotype Variation among Slow Acetylators.

PubMed

Al-Ahmad, Mohammad M; Amir, Naheed; Dhanasekaran, Subramanian; John, Anne; Abdulrazzaq, Yousef M; Ali, Bassam R; Bastaki, Salim

2017-09-01

Individuals with slow N-acetylation phenotype often experience toxicity from drugs such as isoniazid, sulfonamides, procainamide, and hydralazine, whereas rapid acetylators may not respond to these medications. The highly polymorphic N-acetyltransferase 2 enzyme encoded by the NAT2 gene is one of the N-acetylators in humans with a clear impact on the metabolism of a significant number of important drugs. However, there are limited studies on N-acetylation phenotypes and NAT2 genotypes among Emiratis, and thus this study was carried out to fill this gap. Five hundred seventy-six Emirati subjects were asked to consume a soft drink containing caffeine (a nontoxic and reliable probe for predicting the acetylation phenotype) and then provide a buccal swab along with a spot urine sample. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotype of each individual. Phenotyping was carried out by analyzing the caffeine metabolites using high-performance liquid chromatography (HPLC) analysis. We found that 78.5%, 19.1%, and 2.4% of the Emirati subjects were slow, intermediate, and rapid acetylators, respectively. In addition, we found that 77.4% of the subjects were homozygous or heterozygous for two nonreference alleles, whereas 18.4% and 4.2% were heterozygous or homozygous for the reference allele (NAT2*4), respectively. The most common genotypes found were NAT2*5B/*7B, NAT2*5B/*6A, NAT2*7B/*14B, and NAT2*4/*5B, with frequencies of 0.255, 0.135, 0.105, and 0.09, respectively. The degree of phenotype/genotype concordance was 96.2%. The NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, and NAT2*5A/*5B genotypes were found to be associated with the lowest 5-acetylamino-6-formylamino-3-methyluracil/1-methylxanthine (AFMU/1X) ratios. There is a high percentage of slow acetylators among Emiratis, which correlates with the presence of nonreference alleles for the NAT2 gene. Individuals who carried NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, or NAT2*5A/*5B genotypes might be at higher risk of toxicity with some drugs and some diseases compared to others, as these genotypes are associated with the slowest acetylation status. © 2017 John Wiley & Sons Ltd/University College London.

Recent progress in N-acetyltransferase research: 7th international workshop on N-acetyltransferases (NAT): workshop report.

PubMed

Lichter, Jutta; Golka, Klaus; Sim, Edith; Blömeke, Brunhilde

2017-07-01

The 7th International Workshop on N-Acetyltransferases (NAT), held from 18 to 20 June 2016, was hosted by Brunhilde Blömeke and her team at the Trier University (Germany). The workshop addressed important aspects and latest advancements in the fields of NAT enzymes, endogenous functions of NATs, NAT gene nomenclature, genetic polymorphisms, and their associations with diseases as well as their use in diagnosis. Representatives from the leading teams performing research on NATs presented their excellent work, discussed the latest results, and created new ideas in the field of N-acetyltransferase research.

Environmental Adaptations Improve Everyday Action in Schizophrenia.

PubMed

Kessler, Rachel K; Rhodes, Emma; Giovannetti, Tania

2015-05-01

Cognitive functioning, particularly executive functioning, is a strong predictor of functional outcomes in people with schizophrenia. Cognitive remediation has been shown to improve specific cognitive processes, but adjunctive interventions are required for meaningful gains in adaptive functioning, particularly in people with chronic illness. This study examined whether (and how) environmental adaptations, used without training, may circumvent cognitive difficulties and facilitate everyday task performance in individuals with chronic schizophrenia. Forty-two individuals with chronic schizophrenia/schizoaffective disorder were administered cognitive measures and two versions of the Naturalistic Action Test (NAT)-a standard version (ST-NAT), and a user-centered version (UC-NAT) that incorporated environmental adaptations designed to facilitate task performance. The NAT conditions were counterbalanced across participants. Analyses compared performance between the NAT versions and examined the cognitive correlates of each NAT condition. Individuals with schizophrenia made fewer errors on the UC-NAT as compared to the ST-NAT; this between-group difference was significant for all error types. Compared to the ST-NAT, the UC-NAT performance was not significantly associated with an executive function measure of planning. Environmental adaptations may be implemented without extensive training to improve everyday action in individuals with chronic schizophrenia. Environmental adaptations that reduce planning demands may be most effective in this population.

Cis-Natural Antisense Transcripts Are Mainly Co-expressed with Their Sense Transcripts and Primarily Related to Energy Metabolic Pathways during Muscle Development.

PubMed

Zhao, Yunxia; Hou, Ye; Zhao, Changzhi; Liu, Fei; Luan, Yu; Jing, Lu; Li, Xinyun; Zhu, Mengjin; Zhao, Shuhong

2016-01-01

Cis-natural antisense transcripts (cis-NATs) are a new class of RNAs identified in various species. However, the biological functions of cis-NATs are largely unknown. In this study, we investigated the transcriptional characteristics and functions of cis-NATs in the muscle tissue of lean Landrace and indigenous fatty Lantang pigs. In total, 3,306 cis-NATs of 2,469 annotated genes were identified in the muscle tissue of pigs. More than 1,300 cis-NATs correlated with their sense genes at the transcriptional level, and approximately 80% of them were co-expressed in the two breeds. Furthermore, over 1,200 differentially expressed cis-NATs were identified during muscle development. Function annotation showed that the cis-NATs participated in muscle development mainly by co-expressing with genes involved in energy metabolic pathways, including citrate cycle (TCA cycle), glycolysis or gluconeogenesis, mitochondrial activation and so on. Moreover, these cis-NATs and their sense genes abruptly increased at the transition from the late fetal stages to the early postnatal stages and then decreased along with muscle development. In conclusion, the cis-NATs in the muscle tissue of pigs were identified and determined to be mainly co-expressed with their sense genes. The co-expressed cis-NATs and their sense gene were primarily related to energy metabolic pathways during muscle development in pigs. Our results offered novel evidence on the roles of cis-NATs during the muscle development of pigs.

Codominant Expression of N-Acetylation and O-Acetylation Activities Catalyzed by N-Acetyltransferase 2 in Human Hepatocytes

PubMed Central

Doll, Mark A.; Zang, Yu; Moeller, Timothy

2010-01-01

Human populations exhibit genetic polymorphism in N-acetylation capacity, catalyzed by N-acetyltransferase 2 (NAT2). We investigated the relationship between NAT2 acetylator genotype and phenotype in cryopreserved human hepatocytes. NAT2 genotypes determined in 256 human samples were assigned as rapid (two rapid alleles), intermediate (one rapid and one slow allele), or slow (two slow alleles) acetylator phenotypes based on functional characterization of the NAT2 alleles reported previously in recombinant expression systems. A robust and significant relationship was observed between deduced NAT2 phenotype (rapid, intermediate, or slow) and N-acetyltransferase activity toward sulfamethazine (p < 0.0001) and 4-aminobiphenyl (p < 0.0001) and for O-acetyltransferase-catalyzed metabolic activation of N-hydroxy-4-aminobiphenyl (p < 0.0001), N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (p < 0.01), and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (p < 0.0001). NAT2-specific protein levels also significantly associated with the rapid, intermediate, and slow NAT2 acetylator phenotypes (p < 0.0001). As a negative control, p-aminobenzoic acid (an N-acetyltransferase 1-selective substrate) N-acetyltransferase activities from the same samples did not correlate with the three NAT2 acetylator phenotypes (p > 0.05). These results clearly document codominant expression of human NAT2 alleles resulting in rapid, intermediate, and slow acetylator phenotypes. The three phenotypes reflect levels of NAT2 protein catalyzing both N- and O-acetylation. Our results suggest a significant role of NAT2 acetylation polymorphism in arylamine-induced cancers and are consistent with differential cancer risk and/or drug efficacy/toxicity in intermediate compared with rapid or slow NAT2 acetylator phenotypes. PMID:20430842

Arylamine N-Acetyltransferases in Mycobacteria

PubMed Central

Sim, Edith; Sandy, James; Evangelopoulos, Dimitrios; Fullam, Elizabeth; Bhakta, Sanjib; Westwood, Isaac; Krylova, Anna; Lack, Nathan; Noble, Martin

2008-01-01

Polymorphic Human arylamine N-acetyltransferase (NAT2) inactivates the anti-tubercular drug isoniazid by acetyltransfer from acetylCoA. There are active NAT proteins encoded by homologous genes in mycobacteria including M. tuberculosis, M. bovis BCG, M. smegmatis and M. marinum. Crystallographic structures of NATs from M. smegmatis and M. marinum, as native enzymes and with isoniazid bound share a similar fold with the first NAT structure, Salmonella typhimurium NAT. There are three approximately equal domains and an active site essential catalytic triad of cysteine, histidine and aspartate in the first two domains. An acetyl group from acetylCoA is transferred to cysteine and then to the acetyl acceptor e.g. isoniazid. M. marinum NAT binds CoA in a more open mode compared with CoA binding to human NAT2. The structure of mycobacterial NAT may promote its role in synthesis of cell wall lipids, identified through gene deletion studies. NAT protein is essential for survival of M. bovis BCG in macrophage as are the proteins encoded by other genes in the same gene cluster (hsaA-D). HsaA-D degrade cholesterol, essential for mycobacterial survival inside macrophage. Nat expression remains to be fully understood but is co-ordinated with hsaA-D and other stress response genes in mycobacteria. Amide synthase genes in the streptomyces are also nat homologues. The amide synthases are predicted to catalyse intramolecular amide bond formation and creation of cyclic molecules, e.g. geldanamycin. Lack of conservation of the CoA binding cleft residues of M. marinum NAT suggests the amide synthase reaction mechanism does not involve a soluble CoA intermediate during amide formation and ring closure. PMID:18680471

Genetic and small molecule inhibition of arylamine N-acetyltransferase 1 reduces anchorage-independent growth in human breast cancer cell line MDA-MB-231.

PubMed

Stepp, Marcus W; Doll, Mark A; Carlisle, Samantha M; States, J Christopher; Hein, David W

2018-04-01

Arylamine N-acetyltransferase 1 (NAT1) expression is reported to affect proliferation, invasiveness, and growth of cancer cells. MDA-MB-231 breast cancer cells were engineered such that NAT1 expression was elevated or suppressed, or treated with a small molecule inhibitor of NAT1. The MDA-MB-231 human breast cancer cell lines were engineered with a scrambled shRNA, a NAT1 specific shRNA or a NAT1 overexpression cassette stably integrated into a single flippase recognition target (FRT) site facilitating incorporation of these different genetic elements into the same genomic location. NAT1-specific shRNA reduced NAT1 activity in vitro by 39%, increased endogenous acetyl coenzyme A levels by 35%, and reduced anchorage-independent growth (sevenfold) without significant effects on cell morphology, growth rates, anchorage-dependent colony formation, or invasiveness compared to the scrambled shRNA cell line. Despite 12-fold overexpression of NAT1 activity in the NAT1 overexpression cassette transfected MDA-MB-231 cell line, doubling time, anchorage-dependent cell growth, anchorage-independent cell growth, and relative invasiveness were not changed significantly when compared to the scrambled shRNA cell line. A small molecule (5E)-[5-(4-hydroxy-3,5-diiodobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (5-HDST) was 25-fold more selective towards the inhibition of recombinant human NAT1 than N-acetyltransferase 2. Incubation of MDA-MB-231 cell line with 5-HDST resulted in 60% reduction in NAT1 activity and significant decreases in cell growth, anchorage-dependent growth, and anchorage-independent growth. In summary, inhibition of NAT1 activity by either shRNA or 5-HDST reduced anchorage-independent growth in the MDA-MB-231 human breast cancer cell line. These findings suggest that human NAT1 could serve as a target for the prevention and/or treatment of breast cancer. © 2018 Wiley Periodicals, Inc.

Xenobiotic-metabolizing enzymes in Bacillus anthracis: molecular and functional analysis of a truncated arylamine N-acetyltransferase isozyme.

PubMed

Kubiak, Xavier; Duval, Romain; Pluvinage, Benjamin; Chaffotte, Alain F; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2017-07-01

The arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that play an important role in the detoxification and/or bioactivation of arylamine drugs and xenobiotics. In bacteria, NATs may contribute to the resistance against antibiotics such as isoniazid or sulfamides through their acetylation, which makes this enzyme family a possible drug target. Bacillus anthracis, a bacterial species of clinical significance, expresses three NAT isozymes with distinct structural and enzymatic properties, including an inactive isozyme ((BACAN)NAT3). (BACAN)NAT3 features both a non-canonical Glu residue in its catalytic triad and a truncated C-terminus domain. However, the role these unusual characteristics play in the lack of activity of the (BACAN)NAT3 isozyme remains unclear. Protein engineering, recombinant expression, enzymatic analyses with aromatic amine substrates and phylogenetic analysis approaches were conducted. The deletion of guanine 580 (G580) in the nat3 gene was shown to be responsible for the expression of a truncated (BACAN)NAT3 isozyme. Artificial re-introduction of G580 in the nat3 gene led to a functional enzyme able to acetylate several arylamine drugs displaying structural characteristics comparable with its functional Bacillus cereus homologue ((BACCR)NAT3). Phylogenetic analysis of the nat3 gene in the B. cereus group further indicated that nat3 may constitute a pseudogene of the B. anthracis species. The existence of NATs with distinct properties and evolution in Bacillus species may account for their adaptation to their diverse chemical environments. A better understanding of these isozymes is of importance for their possible use as drug targets. This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc. © 2016 The British Pharmacological Society.

A pilot study on screening blood donors with individual-donation nucleic acid testing in China

PubMed Central

Dong, Jie; Wu, Yaling; Zhu, Hong; Li, Gan; Lv, Mengen; Wu, Daxiao; Li, Xiaotao; Zhu, Faming; Lv, Hangjun

2014-01-01

Background Nucleic acid amplification testing (NAT) is not yet obligatory in China for blood donor screening and the risk of enzyme immunoassay (EIA)-negative, NAT-reactive donations in Chinese blood donors has rarely been reported. The aim of this study was to screen a population of Chinese blood donors using a triplex individual-donation (ID)-NAT assay and assess the safety benefits of implementing NAT. Materials and methods Between 1st August, 2010 and 31st December, 2011 all donations at a Chinese blood centre were screened individually using the Procleix® Ultrio® assay, a multiplex NAT assay for the detection of hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) RNA and human immunodeficiency virus-1 (HIV-1) RNA. All donations were also screened for HBsAg, anti-HIV and anti-HCV using two different EIA for each marker. Samples with discordant results between NAT and EIA were further tested with an alternative NAT assay (Cobas® TaqMan®). Potential yield cases (serologically negative/NAT-reactive donors) were further evaluated when possible. Results During the study period a total of 178,447 donations were screened by NAT and EIA, among which 169 HBV NAT yield cases (0.095%) were detected. No N AT yield cases were found for HIV-1 or HCV. For the HBV NAT yield cases, follow-up results showed that 11 (6.51%) were probable or confirmed HBV window period infections, 5 (2.96%) were chronic HBV carriers and 153 (90.53%) were probable or confirmed occult HBV infections. There was a statistically significant difference between the NAT-positive rates for first-time vs repeat donations (0.472% vs 0.146%, respectively; P<0.001). Discussion Our data demonstrate that the potential HBV yield rate was 1:1,056 for blood donations in the Zhejiang province of China. Implementation of NAT will provide a significant increment in safety relative to serological screening alone. PMID:24333061

N-acetyltransferase 2 activity and folate levels

PubMed Central

Cao, Wen; Strnatka, Diana; McQueen, Charlene A.; Hunter, Robert J.; Erickson, Robert P.

2010-01-01

Aims To determine whether increased N-acetyltransferase (NAT) activity might have a toxic effect during development and an influence on folate levels since previous work has shown that only low levels of exogenous NAT can be achieved in constitutionally transgenic mice (Cao, et al, 2005) Main Methods A human NAT1 tet-inducible construct was used that would not be expressed until the inducer was delivered. Human NAT1 cDNA was cloned into pTRE2 and injected into mouse oocytes. Two transgenic lines were crossed to mouse line TgN(rtTahCMV)4Uh containing the CMV promoted “teton.”Measurements of red blood cell folate levels in inbred strains of mice were performed. Key findings Only low levels of human NAT1 could be achieved in kidney (highly responsive in other studies) whether the inducer, doxycycline, was given by gavage or in drinking water.An inverse correlation of folate levels with Nat2 enzyme activity was found. Significance Since increasing NAT1 activity decrease folate in at least one tissue, the detrimental effect of expression of human NAT1 in combination with endogenous mouse Nat2 may be a consequence of increased catabolism of folate. PMID:19932120

Gene cloning and characterization of arylamine N-acetyltransferase from Bacillus cereus strain 10-L-2.

PubMed

Takenaka, Shinji; Cheng, Minyi; Mulyono; Koshiya, Atsushi; Murakami, Shuichiro; Aoki, Kenji

2009-01-01

Bacillus cereus strain 10-L-2 synthesizes two arylamine N-acetyltransferases (Nat-a and Nat-b) with broad substrate specificities toward aniline and its derivatives. In southern blot analysis using probes encoding the NH2-terminus of Nat-b and a conserved region of N-acetyltransferases, digested total DNA of strain 10-L-2 showed one positive band. We cloned and sequenced the gene encoding Nat-b. The NH2-terminal amino acid sequence predicted from the open reading frame (768 base pairs) corresponded to that of purified Nat-b. The cloned Nat-b gene was expressed in Escherichia coli. The expressed enzyme (BcNAT) from the recombinant strain was partially purified and characterized. Nat-b from strain 10-L-2 and BcNAT from the recombinant strain were slightly different from each others in substrate specificity and thermo-stability. We examined the biotransformations of 2-aminophenols and phenylenediamines by the whole cells of the recombinant strain. The cells converted these compounds into their corresponding acetanilides. Only one amino group of phenylenediamines was acetylated. The cells utilized 4-nitroacetanilide as an acetyl donor instead of acetyl-CoA. 4-Aminoacetanilide was produced and 4-nitroaniline was released almost stoichiometrically.

Proton and deuteron induced reactions on natGa: Experimental and calculated excitation functions

NASA Astrophysics Data System (ADS)

Hermanne, A.; Adam-Rebeles, R.; Tárkányi, F.; Takács, S.; Ditrói, F.

2015-09-01

Cross-sections for reactions on natGa, induced by protons (up to 65 MeV) and deuterons (up to 50 MeV), producing γ-emitting radionuclides with half-lives longer than 1 h were measured in a stacked-foil irradiation using thin Ga-Ni alloy (70-30%) targets electroplated on Cu or Au backings. Excitation functions for generation of 68,69Ge, 66,67,68,72Ga and 65,69mZn on natGa are discussed, relative to the monitor reactions natAl(d,x)24,22Na, natAl(p,x)24,22Na, natCu(p,x)62Zn and natNi(p,x)57Ni. The results are compared to our earlier measurements, the scarce literature values and to the results of the code TALYS 1.6 (online database TENDL-2014).

Comparative investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and higher eukaryotes. The role of NATs in fungal biology has only recently been investigated. The NAT1 gene of Gibberella moniliformis was the first NAT cloned and characterized from fun...

Phylogenetic and biological investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and eukaryotic organisms. The role of NATs in fungal biology has only recently been investigated. The NAT1 (FDB2) gene of Fusarium verticillioides was the first NAT cloned and character...

Experimental study of the energy dependence of the total cross section for the 6He + natSi and 9Li + natSi reactions

NASA Astrophysics Data System (ADS)

Sobolev, Yu. G.; Penionzhkevich, Yu. E.; Aznabaev, D.; Zemlyanaya, E. V.; Ivanov, M. P.; Kabdrakhimova, G. D.; Kabyshev, A. M.; Knyazev, A. G.; Kugler, A.; Lashmanov, N. A.; Lukyanov, K. V.; Maj, A.; Maslov, V. A.; Mendibayev, K.; Skobelev, N. K.; Slepnev, R. S.; Smirnov, V. V.; Testov, D.

2017-11-01

New experimental measurements of the total reaction cross sections for the 6He + natSi and 9Li + natSi processes in the energy range of 5 to 40 A MeV are presented. A modified transmission method based on high-efficiency detection of prompt n-γ radiation has been used in the experiment. A bump is observed for the first time in the energy dependence σR( E) at E ˜ 10-30 A MeV for the 9Li + natSi reaction, and existence of the bump in σR( E) at E ˜ 10-20 A MeV first observed in the standard transmission experiments is experimentally confirmed for the 6He + natSi reaction. Theoretical analysis of the measured 6He + natSi and 9Li + natSi reaction cross sections is performed within the microscopic double folding model. Disagreement is observed between the experimental and theoretical cross sections in the region of the bump at the energies of 10 to 20 A MeV, which requires further study.

Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1.

PubMed

Egleton, James E; Thinnes, Cyrille C; Seden, Peter T; Laurieri, Nicola; Lee, Siu Po; Hadavizadeh, Kate S; Measures, Angelina R; Jones, Alan M; Thompson, Sam; Varney, Amy; Wynne, Graham M; Ryan, Ali; Sim, Edith; Russell, Angela J

2014-06-01

A naphthoquinone inhibitor of human arylamine N-acetyltransferase 1 (hNAT1), a potential cancer biomarker and therapeutic target, has been reported which undergoes a distinctive concomitant color change from red to blue upon binding to the enzyme. Here we describe the use of in silico modeling alongside structure-activity relationship studies to advance the hit compound towards a potential probe to quantify hNAT1 levels in tissues. Derivatives with both a fifty-fold higher potency against hNAT1 and a two-fold greater absorption coefficient compared to the initial hit have been synthesized; these compounds retain specificity for hNAT1 and its murine homologue mNat2 over the isoenzyme hNAT2. A relationship between pKa, inhibitor potency and colorimetric properties has also been uncovered. The high potency of representative examples against hNAT1 in ZR-75-1 cell extracts also paves the way for the development of inhibitors with improved intrinsic sensitivity which could enable detection of hNAT1 in tissue samples and potentially act as tools for elucidating the unknown role hNAT1 plays in ER+ breast cancer; this could in turn lead to a therapeutic use for such inhibitors. Copyright © 2014. Published by Elsevier Ltd.

Effectiveness of a flow-based device using riboflavin photochemistry in damaging blood-borne viral nucleic acids.

PubMed

Zhu, Liguo; Tong, Hongli; Wang, Shufang; Yu, Yang; Liu, Zhong; Li, Changqing; Wang, Deqing

2018-05-03

Effectiveness of a flow-based treatment device using riboflavin photochemistry was demonstrated by cytopathic effect method using indicator viruses. However, inactivation efficacy against real blood-borne viruses needs to be evaluated, especially at nucleic acid level. Special plasma samples with varying concentrations of blood-borne virus were selected using a strict blood selection procedure and were treated with device treatment (DT). Nucleic acid test (NAT) using polymerase chain reaction fluorescence method was used to detect virus copies. The NAT value of 4325 in plasma with high Hepatitis B Virus (HBV) concentrations decreased to 1330 with DT. After 100-fold dilution, the NAT value was below the NAT detection limits with DT compared with 23.0 that without DT. The NAT value of 61.9 in plasma with medium HBV concentrations decreased to 37.8 with DT, and after 10-fold dilution, the NAT value was below the NAT detection limits with DT compared with below 20 that without DT. The Ct values of plasma with low concentrations of blood-borne viruses were below the NAT detection limits with DT. There was a dose effect with DT which was effective in blood-borne viruses damaging nucleic acids to a level below the NAT detection limits. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional effects of single nucleotide polymorphisms in the coding region of human N-acetyltransferase 1

PubMed Central

Zhu, Yuanqi; Hein, David W.

2007-01-01

Genetic variants of human N-acetyltransferase 1 (NAT1) are associated with cancer and birth defects. N- and O-acetyltransferase catalytic activities, Michaelis-Menten kinetic constants (Km & Vmax), and steady state expression levels of NAT1-specific mRNA and protein were determined for the reference NAT1*4 and variant human NAT1 haplotypes possessing single nucleotide polymorphisms (SNPs) in the open reading frame. Although none of the SNPs caused a significant effect on steady state levels of NAT1-specific mRNA, C97T(R33stop), C190T(R64W), C559T (R187stop) and A752T(D251V) each reduced NAT1 protein level and/or N- and O-acetyltransferase catalytic activities to levels below detection. G560A(R187Q) substantially reduced NAT1 protein level and catalytic activities and increased substrate Km. The G445A(V149I), G459A(synonymous) and T640G(S214A) haplotype present in NAT1*11 significantly (p<0.05) increased NAT1 protein level and catalytic activity. Neither T21G(synonymous), T402C(synonymous), A613G(M205V), T777C(synonymous), G781A(E261K), or A787G(I263V) significantly affected Km, catalytic activity, mRNA or protein level. These results suggest heterogeneity among slow NAT1 acetylator phenotypes. PMID:17909564

4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype–Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats

PubMed Central

Jefferson, Felicia A.; Xiao, Gong H.; Hein, David W.

2009-01-01

Aromatic and heterocyclic amine carcinogens present in the diet and in cigarette smoke induce breast tumors in rats. N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) enzymes have important roles in their metabolic activation and deactivation. Human epidemiological studies suggest that genetic polymorphisms in NAT1 and/or NAT2 modify breast cancer risk in women exposed to these carcinogens. p-Aminobenzoic acid (selective for rat NAT2) and sulfamethazine (SMZ; selective for rat NAT1) N-acetyltransferase catalytic activities were both expressed in primary cultures of rat mammary epithelial cells. PABA, 2-aminofluorene, and 4-aminobiphenyl N-acetyltransferase and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine and N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline O-acetyltransferase activities were two- to threefold higher in mammary epithelial cell cultures from rapid than slow acetylator rats. In contrast, SMZ (a rat NAT1-selective substrate) N-acetyltransferase activity did not differ between rapid and slow acetylators. Rat mammary cells cultured in the medium supplemented 24 h with 10μM ABP showed downregulation in the N-and O-acetylation of all substrates tested except for the NAT1-selective substrate SMZ. This downregulation was comparable in rapid and slow NAT2 acetylators. These studies clearly show NAT2 acetylator genotype–dependent N- and O-acetylation of aromatic and heterocyclic amine carcinogens in rat mammary epithelial cell cultures to be subject to downregulation by the arylamine carcinogen ABP. PMID:18842621

FUNCTIONAL CHARACTERIZATION OF THE A411T (L137F) and G364A (D122N) GENETIC POLYMORPHISMS IN HUMAN N-ACETYLTRANSFERASE 2

PubMed Central

Zang, Yu; Zhao, Shuang; Doll, Mark A.; States, J Christopher; Hein, David W.

2007-01-01

Human N-acetyltransferase 2 (NAT2) genetic polymorphisms may modify drug efficacy and toxicity and individual cancer susceptibility from carcinogen exposure. A411T (L137F) and G364A (D122N) are two single nucleotide polymorphisms (SNPs) that coexist with other SNPs in human NAT2 alleles NAT2*5I and NAT2*12D, respectively. Cloning and expression in COS-1 cells showed that both A411T and G364A reduced NAT2 immunoreactive protein to an undetectable level without causing changes in mRNA level. Missense mutants displayed different effects on sulfamethazine N-acetylation activity for both L137 (wild-type: 70.2±5.2; L137F: 1.34±0.03; L137W: non-detectable; L137I: 34.2±2.0; L137G: 0.52±0.04 nmol/min/mg) and D122 (wildtype: 70.2±5.2; D122R: non-detectable; D122Q: non-detectable; D122E: 1.72±0.24 nmol/min/mg). To further test our hypothesis that A411T (L137F) and G364A (D122N) accelerate protein degradation, various NAT2 alleles were cloned and expressed in E. coli, which does not possess the ubiquitin-mediated degradation pathway. In contrast to the expression in mammalian cells, recombinant NAT2 possessing either of these two SNPs showed no reduction in immunoreactive NAT2 level when expressed in E. coli. These findings suggest that both A411T (L137F) and G364A (D122N) enhance NAT2 degradation, resulting in reduced NAT2 protein and catalytic activity for NAT2 5I and NAT2 12D. PMID:17264801

N-Acetyltransferase-2 Genotypes Among Patients with Rheumatoid Arthritis Attending Jordan University Hospital

PubMed Central

Oqal, Muna K.; Mustafa, Khader N.

2012-01-01

Aim: To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). Methods: The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. Results: The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184–0.298) for NAT2*4, 0.449 (95% CI 0.383–0.515) for NAT2*5, 0.273 (95% CI 0.214–0.332) for NAT2*6, and 0.037 (95% CI 0.012–0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. Conclusion: The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification. PMID:22731637

The Shift From Sentinel Lymph Node Biopsy Performed Either Before or After Neoadjuvant Systemic Therapy in the Clinical Negative Nodes of Breast Cancer Patients. Results, and the Advantages and Disadvantages of Both Procedures.

PubMed

Fernandez-Gonzalez, Sergi; Falo, Catalina; Pla, Maria Jesus; Pernas, Sonia; Bajen, Maite; Soler, Teresa; Ortega, Raul; Quetglas, Cecilia; Perez-Martin, Xavier; Fernandez Montoli, Maria Eulalia; Campos, Miriam; Varela-Rodriguez, Mar; Ponce, Jordi; Garcia-Tejedor, Amparo

2018-02-01

In patients with breast cancer who are candidates for neoadjuvant therapy (NAT), the timing of when to perform sentinel lymph node biopsy (SLNB) remains under discussion. The aim of this study was to compare the advantages and disadvantages of SLNB performed before and after NAT. One hundred seventy-two patients, T1c to T3 and N0 (clinically and according to ultrasound) candidates for NAT were included. We compared the outcomes of 2 groups: (1) 122 patients of whom SLNB was performed before NAT (pre-NAT) from December 2006 to April 2014; and (2) 50 patients with SLNB performed after NAT (post-NAT) from May 2014 to July 2016. Both groups were homogeneous in baseline patient characteristics. The SLNB was positive in 50 patients [41.7%] (33 macrometastases [66%] and 17 micrometastases [34%]) versus 6 patients [12%] (5 macrometastases [83.3%] and 1 micrometastases [16.7%]) in pre- and post-NAT groups, respectively. The lymphadenectomy was performed in 34 patients [28.3%] versus 4 patients [8%], with an odds ratio of 3.48 (95% confidence interval, 1.3-9.3). The recurrences in the pre-NAT group after a median follow-up of 62 months were 12 systemic, 2 local and systemic, and none axillary. In the post-NAT group were no recurrences after a median follow-up of 16 months. Finally, SLNB after NAT reduces the delay in starting NAT from 24 to 14 days (medians; P < .001) and the identification of the SLNB was in 122 patients [100%] versus 49 patients [98%]. SLNB performed after NAT significantly reduces the rate of lymphadenectomies without any increase in recurrences at early follow-up. Furthermore, it allows systemic treatment to be started earlier without interfering in the SLNB identification rate. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of HCV and HIV-1 antibody negative infections in Scottish and Northern Ireland blood donations by nucleic acid amplification testing.

PubMed

Jarvis, L M; Dow, B C; Cleland, A; Davidson, F; Lycett, C; Morris, K; Webb, B; Jordan, A; Petrik, J

2005-10-01

To reduce the risk of transfusion-transmissible viruses entering the blood supply, the nucleic acid amplification testing (NAT) was implemented to screen Scottish and Northern Irish blood donations in minipools. After 5 years of NAT for hepatitis C virus (HCV) and 2 years for human immunodeficiency virus-1 (HIV-1), the yield of serologically negative, nucleic acid positive 'window donations' and cost-benefit of NAT is under review. When the Scottish National Blood Transfusion Service (SNBTS) implemented NAT in 1999, a fully automated 'black box' system was not available. Therefore, an 'in-house' assimilated NAT assay was developed, validated and implemented. The system is flexible and allows testing for additional viral markers to be introduced with relative ease. The HCV and HIV NAT assays have 95% detection levels of 7.25 IU/ml and 39.8 IU/ml, respectively, as determined by probit analysis. One HCV (1 in 1.9 million) and one HIV (1 in 0.77 million) window donation have been detected in 5 and 2 years, respectively, of NAT. The SNBTS NAT assays are robust and have performed consistently over the last 5 years. The design of the in-house system allowed HIV NAT to be added in 2003 at a relatively small additional cost per sample, although for both assays, the royalty fee far exceeds the cost of the test itself. Clearly NAT has a benefit in improving the safety of the blood supply although the risks of transfusion-transmitted viral infections, as reported in the Serious Hazards of Transfusion (SHOT) report, are extremely low. Also, in UK the yield of HCV antibody negative, NAT positive donations is far lower than predicted although the early detection of an HIV window period donation and the increase of HIV in the blood donor and general populations may provide a stronger case for HIV NAT. SUMMARY SENTENCE: The yield of HCV and HIV NAT in UK is significantly less than that anticipated from statistical models.

Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition.

PubMed

Cocaign, Angélique; Kubiak, Xavier; Xu, Ximing; Garnier, Guillaume; Li de la Sierra-Gallay, Inès; Chi-Bui, Linh; Dairou, Julien; Busi, Florent; Abuhammad, Areej; Haouz, Ahmed; Dupret, Jean Marie; Herrmann, Jean Louis; Rodrigues-Lima, Fernando

2014-11-01

Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

75 FR 22814 - Guidance for Industry: Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-30

... Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral... Industry: Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1 (HIV-1) and Hepatitis C Virus... Acid Test (NAT) and Hepatitis C Virus (HCV) NAT, on testing individual samples or pooled samples from...

Analysis of protein function in clinical C. albicans isolates

PubMed Central

Gerami-Nejad, Maryam; Forche, Anja; McClellan, Mark; Berman, Judith

2012-01-01

Clinical isolates are prototrophic and hence are not amenable to genetic manipulation using nutritional markers. Here we describe a new set of plasmids carrying the NAT1 (nourseothricin) drug resistance marker (Shen et al., 2005) that can be used both in clinical isolates and in laboratory strains. We constructed novel plasmids containing HA-NAT1 or MYC-NAT1 cassettes to facilitate PCR-mediated construction of strains with C-terminal epitope-tagged proteins and a NAT1-pMet3-GFP plasmid to enable conditional expression of proteins with or without the green fluorescent protein fused at the N-terminus. Furthermore, for proteins that require both the endogenous N- and C-termini for function, we have constructed a GF-NAT1-FP cassette carrying truncated alleles that facilitate insertion of an intact, single copy of GFP internal to the coding sequence. In addition, GFP-NAT1, RFP-NAT1, and M-Cherry-NAT1 plasmids were constructed expressing two differently labeled gene products for the study of protein co-expression and co-localization in vivo. Together, these vectors provide a useful set of genetic tools for studying diverse aspects of gene function in C. albicans clinical as well as laboratory strains. PMID:22777821

Crystal Structure of the Golgi-Associated Human Nα-Acetyltransferase 60 Reveals the Molecular Determinants for Substrate-Specific Acetylation.

PubMed

Støve, Svein Isungset; Magin, Robert S; Foyn, Håvard; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas

2016-07-06

N-Terminal acetylation is a common and important protein modification catalyzed by N-terminal acetyltransferases (NATs). Six human NATs (NatA-NatF) contain one catalytic subunit each, Naa10 to Naa60, respectively. In contrast to the ribosome-associated NatA to NatE, NatF/Naa60 specifically associates with Golgi membranes and acetylates transmembrane proteins. To gain insight into the molecular basis for the function of Naa60, we developed an Naa60 bisubstrate CoA-peptide conjugate inhibitor, determined its X-ray structure when bound to CoA and inhibitor, and carried out biochemical experiments. We show that Naa60 adapts an overall fold similar to that of the catalytic subunits of ribosome-associated NATs, but with the addition of two novel elongated loops that play important roles in substrate-specific binding. One of these loops mediates a dimer to monomer transition upon substrate-specific binding. Naa60 employs a catalytic mechanism most similar to Naa50. Collectively, these data reveal the molecular basis for Naa60-specific acetyltransferase activity with implications for its Golgi-specific functions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Paper-based sample-to-answer molecular diagnostic platform for point-of-care diagnostics.

PubMed

Choi, Jane Ru; Tang, Ruihua; Wang, ShuQi; Wan Abas, Wan Abu Bakar; Pingguan-Murphy, Belinda; Xu, Feng

2015-12-15

Nucleic acid testing (NAT), as a molecular diagnostic technique, including nucleic acid extraction, amplification and detection, plays a fundamental role in medical diagnosis for timely medical treatment. However, current NAT technologies require relatively high-end instrumentation, skilled personnel, and are time-consuming. These drawbacks mean conventional NAT becomes impractical in many resource-limited disease-endemic settings, leading to an urgent need to develop a fast and portable NAT diagnostic tool. Paper-based devices are typically robust, cost-effective and user-friendly, holding a great potential for NAT at the point of care. In view of the escalating demand for the low cost diagnostic devices, we highlight the beneficial use of paper as a platform for NAT, the current state of its development, and the existing challenges preventing its widespread use. We suggest a strategy involving integrating all three steps of NAT into one single paper-based sample-to-answer diagnostic device for rapid medical diagnostics in the near future. Copyright © 2015 Elsevier B.V. All rights reserved.

Preventing disease transmission by deceased tissue donors by testing blood for viral nucleic acid.

PubMed

Strong, D Michael; Nelson, Karen; Pierce, Marge; Stramer, Susan L

2005-01-01

Nucleic acid testing (NAT) has reduced the risk of transmitting infectious disease through blood transfusion. Currently NAT for HIV-1 and HCV are FDA licensed and performed by nearly all blood collection facilities, but HBV NAT is performed under an investigational study protocol. Residual risk estimates indicate that NAT could potentially reduce disease transmission through transplanted tissue. However, tissue donor samples obtained post-mortem have the potential to produce an invalid NAT result due to inhibition of amplification reactions by hemolysis and other factors. The studies reported here summarize the development of protocols to allow NAT of deceased donor samples with reduced rates of invalid results. Using these protocols, inventories from two tissue centers were tested with greater than 99% of samples producing a valid test result.

A Crucial Role for Host APCs in the Induction of Donor CD4+CD25+ Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease

PubMed Central

Tawara, Isao; Shlomchik, Warren D.; Jones, Angela; Zou, Weiping; Nieves, Evelyn; Liu, Chen; Toubai, Tomomi; Duran-Struuck, Raimon; Sun, Yaping; Clouthier, Shawn G.; Evers, Rebecca; Lowler, Kathleen P.; Levy, Robert B.; Reddy, Pavan

2010-01-01

Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385–389 and Copelan. 2006. N Engl J Med. 354: 1813–1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent and severe of which is the development of graft-versus-host disease (GVHD) (Copelan. 2006. N Engl J Med. 354: 1813–1826 and Blazar and Murphy. 2005. Philos Trans R Soc Lond B Biol Sci. 360: 1747–1767). Alloreactive donor T cells are critical for causing GVHD (Fowler. 2006. Crit Rev Oncol Hematol. 57: 225–244 and Ferrara and Reddy. 2006. Semin Hematol. 43: 3–10), whereas recent data demonstrated a significant role for the naturally occurring thymic-derived donor CD4+CD25+Foxp3+ regulatory T cells (Tregs) (Bluestone and Abbas. 2003. Nat Rev Immunol. 3: 253–257 and Shevach. 2006. Immunity. 25: 195–201) in suppressing experimental GVHD after bone marrow transplantation (Blazar and Taylor. 2005. Biol Blood Marrow Transpl. 11: 46–49 and Joffe and van Meerwijk. 2006. Semin Immunol. 18: 128–135). Host APCs are required for induction of GVHD by the conventional donor T cells. However, it is not known whether they are also obligatory for donor Treg-mediated suppression of GVHD. Using multiple clinically relevant MHC-matched and -mismatched murine models of GVHD, we investigated the role of host APCs in the suppression of GVHD by donor Tregs. We found that alloantigen expression by the host APCs is necessary and sufficient for induction of GVHD protection by donor Tregs. This requirement was independent of their effect on the maintenance of Treg numbers and the production of IL-10 or IDO by the host APCs. PMID:20810991

Comparison of receptor affinity of natSc-DOTA-TATE versus natGa-DOTA-TATE.

PubMed

Koumarianou, Eftychia; Pawlak, Dariusz; Korsak, Agnieszka; Mikolajczak, Renata

2011-01-01

44Sc as a positron emitter can be an interesting alternative to 68Ga (T½=67.71 min) due to its longer half-life (T½=3.97 h). Moreover, the b-emitter 47Sc can be used for therapy when attached to the same biomolecule vectors. DOTA as a chelating agent has been proven suitable for the radiolabelling of peptides recognising tumour cell receptors in vivo with M3+ radiometals. DOTA-derivatized peptides have been successfully labelled with 90Y and 177Lu for therapy, and with 68Ga for PET imaging. However, published data on 44Sc-labelled DOTA-biomolecules as potential PET radiotracers are still very limited. The aim of this study was to compare the affinity of natGa- and natSc-labelled DOTA-TATE to somatostatin receptors subtype 2 expressed in rat pancreatic cancer cell line AR42J. The cold complexes of DOTA-TATE with natGa and natSc were synthesized and identified by HPLC and MS analysis and evaluated in vitro for competitive binding to cancer cell line AR42J expressing somatostatin receptors subtype 2 (sstr2). The IC50 values calculated from the displacement curve of {125I-Tyr11}-SST-14 were: 0.20±0.18, 0.70±0.20, 0.64±0.22 and 0.67±0.12 for natGa-DOTA-TATE, natSc-DOTA-TATE, DOTA-TATE, and {Tyr11}-SST-14 complexes, respectively, with the affinity lowering in the decreasing order: natGa-DOTA-TATE>DOTA-TATE>Tyr11-SST-14>natSc-DOTA-TATE. The binding affinity of natGa-DOTA-TATE appeared higher than that of natSc-DOTA-TATE. Further in vitro and in vivo studies are needed to verify the influence of the chelated metal on the affinity and uptake of the respective radiolabelled compounds. This information might be crucial when the in vivo applications of peptides labelled with 68Ga and 44Sc for PET, as well as the use of 47Sc for radiotherapy are considered.

Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes

PubMed Central

Hein, David W; Doll, Mark A

2012-01-01

Aim Humans exhibit genetic polymorphism in NAT2 resulting in rapid, intermediate and slow acetylator phenotypes. Over 65 NAT2 variants possessing one or more SNPs in the 870-bp NAT2 coding region have been reported. The seven most frequent SNPs are rs1801279 (191G>A), rs1041983 (282C>T), rs1801280 (341T>C), rs1799929 (481C>T), rs1799930 (590G>A), rs1208 (803A>G) and rs1799931 (857G>A). The majority of studies investigate the NAT2 genotype assay for three SNPs: 481C>T, 590G>A and 857G>A. A tag-SNP (rs1495741) recently identified in a genome-wide association study has also been proposed as a biomarker for the NAT2 phenotype. Materials & methods Sulfamethazine N-acetyltransferase catalytic activities were measured in cryopreserved human hepatocytes from a convenience sample of individuals in the USA with an ethnic frequency similar to the 2010 US population census. These activities were segregated by the tag-SNP rs1495741 and each of the seven SNPs described above. We assessed the accuracy of the tag-SNP and various two-, three-, four- and seven-SNP genotyping panels for their ability to accurately infer NAT2 phenotype. Results The accuracy of the various NAT2 SNP genotype panels to infer NAT2 phenotype were as follows: seven-SNP: 98.4%; tag-SNP: 77.7%; two-SNP: 96.1%; three-SNP: 92.2%; and four-SNP: 98.4%. Conclusion A NAT2 four-SNP genotype panel of rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A) and rs1799931 (857G>A) infers NAT2 acetylator phenotype with high accuracy, and is recommended over the tag-, two-, three- and (for economy of scale) the seven-SNP genotyping panels, particularly in populations of non-European ancestry. PMID:22092036

N-acetyltransferase genotypes and the pharmacokinetics and tolerability of para-aminosalicylic acid in patients with drug-resistant pulmonary tuberculosis.

PubMed

Sy, Sherwin K B; de Kock, Lizanne; Diacon, Andreas H; Werely, Cedric J; Xia, Huiming; Rosenkranz, Bernd; van der Merwe, Lize; Donald, Peter R

2015-07-01

The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, -17, -48, and -27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells.

PubMed

Sugiyama, Hayami; Takahashi, Kazutoshi; Yamamoto, Takuya; Iwasaki, Mio; Narita, Megumi; Nakamura, Masahiro; Rand, Tim A; Nakagawa, Masato; Watanabe, Akira; Yamanaka, Shinya

2017-01-10

Novel APOBEC1 target 1 (Nat1) (also known as "p97," "Dap5," and "Eif4g2") is a ubiquitously expressed cytoplasmic protein that is homologous to the C-terminal two thirds of eukaryotic translation initiation factor 4G (Eif4g1). We previously showed that Nat1-null mouse embryonic stem cells (mES cells) are resistant to differentiation. In the current study, we found that NAT1 and eIF4G1 share many binding proteins, such as the eukaryotic translation initiation factors eIF3 and eIF4A and ribosomal proteins. However, NAT1 did not bind to eIF4E or poly(A)-binding proteins, which are critical for cap-dependent translation initiation. In contrast, compared with eIF4G1, NAT1 preferentially interacted with eIF2, fragile X mental retardation proteins (FMR), and related proteins and especially with members of the proline-rich and coiled-coil-containing protein 2 (PRRC2) family. We also found that Nat1-null mES cells possess a transcriptional profile similar, although not identical, to the ground state, which is established in wild-type mES cells when treated with inhibitors of the ERK and glycogen synthase kinase 3 (GSK3) signaling pathways. In Nat1-null mES cells, the ERK pathway is suppressed even without inhibitors. Ribosome profiling revealed that translation of mitogen-activated protein kinase kinase kinase 3 (Map3k3) and son of sevenless homolog 1 (Sos1) is suppressed in the absence of Nat1 Forced expression of Map3k3 induced differentiation of Nat1-null mES cells. These data collectively show that Nat1 is involved in the translation of proteins that are required for cell differentiation.

Piperidinols That Show Anti-Tubercular Activity as Inhibitors of Arylamine N-Acetyltransferase: An Essential Enzyme for Mycobacterial Survival Inside Macrophages

PubMed Central

Abuhammad, Areej; Fullam, Elizabeth; Lowe, Edward D.; Staunton, David; Kawamura, Akane; Westwood, Isaac M.; Bhakta, Sanjib; Garner, Alun Christopher; Wilson, David L.; Seden, Peter T.; Davies, Stephen G.; Russell, Angela J.; Garman, Elspeth F.; Sim, Edith

2012-01-01

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3–16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs. PMID:23285185

N-acetyltransferase (nat) is a critical conjunct of photoperiodism between the circadian system and endocrine axis in Antheraea pernyi.

PubMed

Mohamed, Ahmed A M; Wang, Qiushi; Bembenek, Jadwiga; Ichihara, Naoyuki; Hiragaki, Susumu; Suzuki, Takeshi; Takeda, Makio

2014-01-01

Since its discovery in 1923, the biology of photoperiodism remains a mystery in many ways. We sought the link connecting the circadian system to an endocrine switch, using Antheraea pernyi. PER-, CLK- and CYC-ir were co-expressed in two pairs of dorsolateral neurons of the protocerebrum, suggesting that these are the circadian neurons that also express melatonin-, NAT- and HIOMT-ir. The results suggest that a melatonin pathway is present in the circadian neurons. Melatonin receptor (MT2 or MEL-1B-R)-ir in PTTH-ir neurons juxtaposing clock neurons suggests that melatonin gates PTTH release. RIA showed a melatonin rhythm with a peak four hours after lights off in adult brain both under LD16:8 (LD) and LD12:12 (SD), and both the peak and the baseline levels were higher under LD than SD, suggesting a photoperiodic influence. When pupae in diapause were exposed to 10 cycles of LD, or stored at 4 °C for 4 months under constant darkness, an increase of NAT activity was observed when PTTH released ecdysone. DNA sequence upstream of nat contained E-boxes to which CYC/CLK could bind, and nat transcription was turned off by clk or cyc dsRNA. dsRNA(NAT) caused dysfunction of photoperiodism. dsRNA(PER) upregulated nat transcription as anticipated, based on findings in the Drosophila melanogaster circadian system. Transcription of nat, cyc and clk peaked at ZT12. RIA showed that dsRNA(NAT) decreased melatonin while dsRNA(PER) increased melatonin. Thus nat, a clock controlled gene, is the critical link between the circadian clock and endocrine switch. MT-binding may release PTTH, resulting in termination of diapause. This study thus examined all of the basic functional units from the clock: a photoperiodic counter as an accumulator of mRNA(NAT), to endocrine switch for photoperiodism in A. pernyi showing this system is self-complete without additional device especially for photoperiodism.

N-Acetyltransferase 2 (NAT2) genetic variation and the susceptibility to noncardiac gastric adenocarcinoma in Taiwan.

PubMed

Chang, Chih-Hao; Huang, Yi-Shin; Perng, Chin-Lin; Lin, Han-Chieh

2016-03-01

N-Acetyltransferase (NAT) is an important enzyme with the capacity to metabolize carcinogenic aromatic amines. However, it remains controversial whether the encoded functional NAT2 genetic polymorphism is related to the risk of gastric adenocarcinoma (GA). The aim of this study was to evaluate the association between NAT2 genetic variation and gastric adenocarcinoma (GA), with special reference to the gastric noncardiac adenocarcinoma (GNA). Peripheral white blood cell DNA from 368 GA patients and 368 age- and sex-matched controls were genotyped for NAT2 by a polymerase chain reaction method. The lifestyle habits of the participants were assessed using a semiquantitative food-frequency questionnaire. NAT2 genotype, interaction with lifestyle habits, and the risk of GA and GNA were analyzed by logistic regression. GA patients were more likely to have a smoking habit, ate more salted foods, and consumed more well-done meat than the controls. There was no association between the NAT2 genotypes and susceptibility to GA. However, if patients with gastric cardiac adenocarcinoma (GCA; n = 42) were excluded, the NAT2 slow acetylators (without rapid acetylator allele) had a higher risk of GA than intermediate and rapid acetylators (odds ratio = 1.53; 95% confidence interval, 1.05-2.23, p = 0.027). In addition, there was a synergic effect of NAT2 slow acetylator and well-done meat intake to the development of GNA (odds ratio = 3.83; 95% confidence interval, 1.68-8.76, p = 0.001). NAT2 slow acetylators have a higher risk of GNA than intermediate and rapid acetylators have in a Taiwanese population. The intake of well-done meat, an additive to the acetylator status, may contribute to the incidence of gastric carcinogenesis. Copyright © 2015. Published by Elsevier Taiwan LLC.

Cost projections for implementation of safety interventions to prevent transfusion-transmitted Zika virus infection in the United States

PubMed Central

Ellingson, Katherine D.; Sapiano, Mathew R.P.; Haass, Kathryn A.; Savinkina, Alexandra A.; Baker, Misha L.; Henry, Richard A.; Berger, James J.; Kuehnert, Matthew J.; Basavaraju, Sridhar V.

2017-01-01

BACKGROUND In August 2016, the Food and Drug Administration advised US blood centers to screen all whole blood and apheresis donations for Zika virus (ZIKV) with an individual-donor nucleic acid test (ID-NAT) or to use approved pathogen reduction technology (PRT). The cost of implementing this guidance nationally has not been assessed. STUDY DESIGN AND METHODS Scenarios were constructed to characterize approaches to ZIKV screening, including universal ID-NAT, risk-based seasonal allowance of minipool (MP) NAT by state, and universal MP-NAT. Data from the 2015 National Blood Collection and Utilization Survey (NBCUS) were used to characterize the number of donations nationally and by state. For each scenario, the estimated cost per donor ($3–$9 for MP-NAT, $7–$13 for ID-NAT) was multiplied by the estimated number of relevant donations from the NBCUS. Cost of PRT was calculated by multiplying the cost per unit ($50–$125) by the number of units approved for PRT. Prediction intervals for costs were generated using Monte Carlo simulation methods. RESULTS Screening all donations in the 50 states and DC for ZIKV by ID-NAT would cost $137 million (95% confidence interval [CI], $109–$167) annually. Allowing seasonal MP-NAT in states with lower ZIKV risk could reduce NAT screening costs by 18% to 25%. Application of PRT to all platelet (PLT) and plasma units would cost $213 million (95% CI, $156–$304). CONCLUSION Universal ID-NAT screening for ZIKV will cost US blood centers more than $100 million annually. The high cost of PRT for apheresis PLTs and plasma could be mitigated if, once validated, testing for transfusion transmissible pathogens could be eliminated. PMID:28591470

Rapid and sensitive approach to simultaneous detection of genomes of hepatitis A, B, C, D and E viruses.

PubMed

Kodani, Maja; Mixson-Hayden, Tonya; Drobeniuc, Jan; Kamili, Saleem

2014-10-01

Five viruses have been etiologically associated with viral hepatitis. Nucleic acid testing (NAT) remains the gold standard for diagnosis of viremic stages of infection. NAT methodologies have been developed for all hepatitis viruses; however, a NAT-based assay that can simultaneously detect all five viruses is not available. We designed TaqMan card-based assays for detection of HAV RNA, HBV DNA, HCV RNA, HDV RNA and HEV RNA. The performances of individual assays were evaluated on TaqMan Array Cards (TAC) for detecting five viral genomes simultaneously. Sensitivity and specificity were determined by testing 329 NAT-tested clinical specimens. All NAT-positive samples for HCV (n = 32), HDV (n = 28) and HEV (n = 14) were also found positive in TAC (sensitivity, 100%). Forty-three of 46 HAV-NAT positive samples were also positive in TAC (sensitivity, 94%), while 36 of 39 HBV-NAT positive samples were positive (sensitivity, 92%). No false-positives were detected for HBV (n = 32), HCV (n = 36), HDV (n = 30), and HEV (n = 31) NAT-negative samples (specificity 100%), while 38 of 41 HAV-NAT negative samples were negative by TAC (specificity 93%). TAC assay was concordant with corresponding individual NATs for hepatitis A-E viral genomes and can be used for their detection simultaneously. The TAC assay has potential for use in hepatitis surveillance, for screening of donor specimens and in outbreak situations. Wider availability of TAC-ready assays may allow for customized assays, for improving acute jaundice surveillance and for other purposes for which there is need to identify multiple pathogens rapidly. Published by Elsevier B.V.

Interaction between Red Meat Intake and NAT2 Genotype in Increasing the Risk of Colorectal Cancer in Japanese and African Americans

PubMed Central

Wang, Hansong; Iwasaki, Motoki; Haiman, Christopher A.; Kono, Suminori; Wilkens, Lynne R.; Keku, Temitope O.; Berndt, Sonja I.; Tsugane, Shoichiro; Le Marchand, Loïc

2015-01-01

Heterocyclic aromatic amines formed in cooked meat may be an underlying mechanism for the red meat-colorectal cancer (CRC) association. These compounds require bioactivaction by N-acetyltransferase 2 (NAT2). An interaction effect between red meat consumption and NAT2 in increasing CRC risk has been inconsistently reported in whites. We investigated this interaction in two populations in which the high-activity rapid NAT2 phenotype is 10- and 2-fold more common than in whites. We meta-analyzed four studies of Japanese (2,217 cases, 3,788 controls) and three studies of African Americans (527 cases, 4,527 controls). NAT2 phenotype was inferred from an optimized seven-SNP genotyping panel. Processed and total red meat intakes were associated with an increased CRC risk in Japanese and in both ethnic groups combined (P’s ≤ 0.002). We observed an interaction between processed meat intake and NAT2 in Japanese (P = 0.04), African Americans (P = 0.02), and in both groups combined (P = 0.006). The association of processed meat with CRC was strongest among individuals with the rapid NAT2 phenotype (combined analysis, OR for highest vs. lowest quartile: 1.62, 95% CI: 1.28–2.05; Ptrend = 8.0×10−5), intermediate among those with the intermediate NAT2 phenotype (1.29, 95% CI: 1.05–1.59; Ptrend = 0.05) and null among those with the slow phenotype (Ptrend = 0.45). A similar interaction was found for NAT2 and total red meat (Pinteraction = 0.03). Our findings support a role for NAT2 in modifying the association between red meat consumption and CRC in Japanese and African Americans. PMID:26683305

Antarctic NAT PSC Belt of June 2003: Observational Validation of the Mountain Wave Seeding Hypothesis

NASA Technical Reports Server (NTRS)

Eckermann, S. D.; Hoffmann, L.; Hoepfner, M.; Wu, D. L.; Alexander, M. J.

2009-01-01

Satellite observations of polar stratospheric clouds (PSCs) over Antarctica in June 2003 revealed small nitric acid trihydrate (NAT) particles forming suddenly along the vortex edge. Models suggest the trigger was mountain waves over the Antarctic Peninsula (AP) forming ice for NAT nucleation. We test this hypothesis by analyzing perturbations in stratospheric radiances from the Atmospheric Infrared Sounder (AIRS). AIRS data show mountain waves over the AP on 10-14 June, with no resolved wave activity before or after. Peak wave temperature amplitudes derived from independent 40 hPa channels all return values of 10-12 K, in agreement with values used to model this NAT event. These observations support a NAT wake from a small region of mountain wave activity over the AP as the source of this circumpolar NAT outbreak.

NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules

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

Shen, Qi; Zheng, Xingzheng; McNutt, Michael A.

2009-06-10

The midbody is a structural organelle formed in late phase mitosis which is responsible for completion of cytokinesis. Although various kinds of proteins have been found to distribute or immigrate to this organelle, their functions have still not been completely worked out. In this study, we demonstrated that NAT10 (N-acetyltransferase 10, NAT10) is not only predominantly distributed in the nucleolus in interphase, but is also concentrated in the mitotic midbody during telophase. The domain in N-terminal residues 549-834 of NAT10 specifically mediated its subcellular localization. Treatment with genotoxic agents or irradiation increased concentration of NAT10 in both the nucleolus andmore » midbody. Moreover, DNA damage induced increase of NAT10 in the midbody apparently accompanied by in situ elevation of the level of acetylated {alpha}-tubulin, suggesting that it plays a role in maintaining or enhancing stability of {alpha}-tubulin. The depletion of NAT10 induced defects in nucleolar assembly, cytokinesis and decreased acetylated {alpha}-tubulin, leading to G2/M cell cycle arrest or delay of mitotic exit. In addition, over-expression of NAT10 was found in a variety of soft tissue sarcomas, and correlated with tumor histological grading. These results indicate that NAT10 may play an important role in cell division through facilitating reformation of the nucleolus and midbody in the late phase of cell mitosis, and stabilization of microtubules.« less

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.

PubMed

Knowles, Joshua W; Xie, Weijia; Zhang, Zhongyang; Chennamsetty, Indumathi; Chennemsetty, Indumathi; Assimes, Themistocles L; Paananen, Jussi; Hansson, Ola; Pankow, James; Goodarzi, Mark O; Carcamo-Orive, Ivan; Morris, Andrew P; Chen, Yii-Der I; Mäkinen, Ville-Petteri; Ganna, Andrea; Mahajan, Anubha; Guo, Xiuqing; Abbasi, Fahim; Greenawalt, Danielle M; Lum, Pek; Molony, Cliona; Lind, Lars; Lindgren, Cecilia; Raffel, Leslie J; Tsao, Philip S; Schadt, Eric E; Rotter, Jerome I; Sinaiko, Alan; Reaven, Gerald; Yang, Xia; Hsiung, Chao A; Groop, Leif; Cordell, Heather J; Laakso, Markku; Hao, Ke; Ingelsson, Erik; Frayling, Timothy M; Weedon, Michael N; Walker, Mark; Quertermous, Thomas

2015-04-01

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

Nucleic Acid Amplification Test For Detection Of West Nile Virus Infection In Pakistani Blood Donors.

PubMed

Niazi, Saifullah Khan; Alam, Maqbool; Yazdani, Muhammad Sajid; Ghani, Eijaz; Rathore, Muhammad Ali

2017-01-01

The study was planned to determine the presence of West Nile Virus (WNV) infection in Pakistani blood donors, using Nucleic Acid Amplification Test (NAT). The blood donors for study were selected on the basis of the standard questionnaire and routine screening results. Six donors were pooled using an automated pipettor and NAT for WNV was performed on Roche Cobas s 201 NAT system. The reactive pools were resolved in Individual Donation-NAT (ID-NAT) format and a sample from FFP bags of reactive donations was retrieved. NAT was again performed on retrieved plasma bag (RPB) sample to confirm the reactive donations. The donors were also recalled and interviewed about history of illness related to recent WNV infection. After serological screening of 1929 donors during the study period, 1860 donors were selected for NAT test for WNV detection. The mean age of the donors was 28±8.77 (range: 18-57 years). 1847 (99.3%) donors were male and 13 (0.7%) were female. NAT for WNV identified six initially reactive pools (0.32%). On follow-up testing with RPB samples, 4 donors (0.21%) were found confirmed reactive for WNV RNA (NAT yield of 1 in 465 blood donors). WNV is a threat to safety of blood products in Pakistan. A screening strategy can be implemented after a large-scale study and financial considerations. One of the reduced cost screening strategies is seasonal screening of blood donors for WNV, with pooling of samples.

In vitro effects of 5-hydroxytryptophan, indoleamines and leptin on arylalkylamine N-acetyltransferase (AA-NAT) activity in pineal organ of the fish, Clarias gariepinus (Burchell, 1822) during different phases of the breeding cycle.

PubMed

Gupta, B B P; Yanthan, L; Singh, Ksh Manisana

2010-08-01

Arylalkylamine N-acetyltransferase (AA-NAT) is the rate-limiting enzyme of melatonin biosynthetic pathway. In vitro effects of 5-hydroxytryptophan (5-HTP) and indoleamines (serotonin, N-acetylserotonin and melatonin) were studied on AA-NAT activity in the pineal organ of the fish, C. gariepinus during different phases of its annual breeding cycle. Further, in vitro effects of leptin on AA-NAT activity in the pineal organ were studied in fed and fasted fishes during summer and winter seasons. Treatments with 5-HTP and indoleamines invariably stimulated pineal AA-NAT activity in a dose-dependent manner during all the phases. However, leptin increased AA-NAT activity in a dose-dependent manner only in the pineal organ of the fed fishes, but not of the fasted fishes irrespective of the seasons.

Plakins in development and disease.

PubMed

Sonnenberg, Arnoud; Liem, Ronald K H

2007-06-10

Plakins are large multi-domain molecules that have various functions to link cytoskeletal elements together and to connect them to junctional complexes. Plakins were first identified in epithelial cells where they were found to connect the intermediate filaments to desmosomes and hemidesmosomes [Ruhrberg, C., and Watt, F.M. (1997). The plakin family: versatile organizers of cytoskeletal architecture. Curr Opin Genet Dev 7, 392-397.]. They were subsequently found to be important for the integrity of muscle cells. Most recently, they have been found in the nervous system, where their functions appear to be more complex, including cross-linking of microtubules (MTs) and actin filaments [Leung, C.L., Zheng, M., Prater, S.M., and Liem, R.K. (2001). The BPAG1 locus: Alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neurons and muscles. J Cell Biol 154, 691-697., Leung, C.L., Sun, D., Zheng, M., Knowles, D.R., and Liem, R.K. (1999). Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. J Cell Biol 147, 1275-1286.]. These plakins have also indicated their relationship to the spectrin superfamily of proteins and the plakins appear to be evolutionarily related to the spectrins, but have diverged to perform different specialized functions. In invertebrates, a single plakin is present in both Drosophila melanogaster and Caenorhabditis elegans, which resemble the more complex plakins found in mammals [Roper, K., Gregory, S.L., and Brown, N.H. (2002). The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families. J Cell Sci 115, 4215-4225.]. In contrast, there are seven plakins found in mammals and most of them have alternatively spliced forms leading to a very complex group of proteins with potential tissue specific functions [Jefferson, J.J., Leung, C.L., and Liem, R.K. (2004). Plakins: goliaths that link cell junctions and the cytoskeleton. Nat Rev Mol Cell Biol 5, 542-553.]. In this review, we will first describe the plakins, desmoplakin, plectin, envoplakin and periplakin and then describe two other mammalian plakins, Bullous pemphigoid antigen 1 (BPAG1) and microtubule actin cross-linking factor 1 (MACF1), that are expressed in multiple isoforms in different tissues. We will also describe the relationship of these two proteins to the invertebrate plakins, shortstop (shot) in Drosophila and VAB-10 in C. elegans. Finally, we will describe an unusual mammalian plakin, called epiplakin.

Excitation function of alpha-particle-induced reactions on natNi from threshold to 44 MeV

NASA Astrophysics Data System (ADS)

Uddin, M. S.; Kim, K. S.; Nadeem, M.; Sudár, S.; Kim, G. N.

2017-05-01

Excitation functions of the natNi(α,x)62,63,65Zn, natNi(α,x)56,57Ni and natNi(α,x)56,57,58m+gCo reactions were measured from the respective thresholds to 44MeV using the stacked-foil activation technique. The tests for the beam characterization are described. The radioactivity was measured using HPGe γ-ray detectors. Theoretical calculations on α-particles-induced reactions on natNi were performed using the nuclear model code TALYS-1.8. A few results are new, the others strengthen the database. Our experimental data were compared with results of nuclear model calculations and described the reaction mechanism.

Beyond detection: biological physics informing progression and treatment of cancer Beyond detection: biological physics informing progression and treatment of cancer

NASA Astrophysics Data System (ADS)

Newman, T. J.; Thompson, A. M.

2012-12-01

The full text of the Preface is given in the PDF file. References [1] Kaur P et al 2012 Phys. Biol. 9 065001 [2] Lobikin M et al 2012 Phys. Biol. 9 065002 [3] Tanner K 2012 Phys. Biol. 9 065003 [4] Liu S V et al 2012 Phys. Biol. 9 065004 [5] Liao D et al 2012 Phys. Biol. 9 065005 [6] Liao D et al 2012 Phys. Biol. 9 065006 [7] Orlando P A et al 2012 Phys. Biol. 9 065007

Diverse point mutations in the human gene for polymorphic N-acetyltransferase

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

Vatsis, K.P.; Martell, K.J.; Weber, W.W.

1991-07-15

Classification of humans as rapid or slow acetylators is based on hereditary differences in rates of N-acetylation of therapeutic and carcinogenic agents, but N-acetylation of certain arylamine drugs displays no genetic variation. Two highly homologous human genes for N-acetyltransferase NAT1 and NAT2, presumably code for the genetically invariant and variant NAT proteins, respectively. In the present investigation, 1.9-kilobase human genomic EcoRI fragments encoding NAT2 were generated by the polymerase chain reaction with liver and leukocyte DNA from seven subjects phenotyped as homozygous and heterozygous acetylators. Direct sequencing revealed multiple point mutations in the coding region of two distinct NAT2 variants.more » One of these was derived from leukocytes of a slow acetylator and was distinguished by a silent mutation (coden 94) and a separate G {r arrow} A transition (position 590) leading to replacement of Arg-197 by Gln; the mutated guanine was part of a CpG dinucleotide and a Taq I site. The second NAT2 variant originated from liver with low N-acetylation activity. It was characterized by three nucleotide transitions giving rise to a silent mutation (codon 161), accompanied by obliteration of the sole Kpn I site, and two amino acid substitutions. The results show conclusively that the genetically variant NAT is encoded by NAT2.« less

Priority needs and wisdom strategy for blood transfusion safety in developing low-resource countries.

PubMed

Abdelrazik, Abeer Mohamed; Ezzat Ahmed, Ghada M

2016-02-01

To evaluate the implementation of alternative safety measures that reduce the risk of transfusion transmissible infections as an affordable measure in low resource countries. It is still difficult in developing countries with limited resources to mandate nucleic acid testing due to its high cost. Although NAT reduces the window period of infection, the developing countries are still in need of an efficient and effective transfusion programme before implementing the complex high cost NAT. Two thousand eight hundred eighty sero-negative first-time and repeat donations from Fayoum University Hospital blood bank were individually analysed by NAT for HIV, HBV and HCV. Only discriminatory-positive NAT were classified comparing the non-remunerated and family replacement donations. Significant discriminatory-positive differences were observed for HBV NAT results, 2 remunerated donations compared to 0 non-remunerated sero-negative donations. The discriminatory positive differences were also significant for HCV NAT results, 4 remunerated donations compared to 1 non-remunerated sero-negative donation. No sero-negative, discriminatory-positive NAT HIV case was found. Seven out of 8 discriminatory positive cases were from first time donations. In order to ensure blood safety, the recruitment and retention of voluntary, non-remunerated repeat donors should be a major commitment for low resource countries in which NAT implementation is costly and not feasible. Copyright © 2016 Elsevier Ltd. All rights reserved.

Measurement of activation cross sections of alpha particle induced reactions on iridium up to an energy of 50 MeV.

PubMed

Takács, S; Ditrói, F; Szűcs, Z; Aikawa, M; Haba, H; Komori, Y; Saito, M

2018-06-01

Cross sections of alpha particle induced nuclear reactions on iridium were investigated using a 51.2-MeV alpha particle beam. The standard stacked-foil target technique and the activation method were applied. The activity of the reaction products was assessed without chemical separation using high resolution gamma-ray spectrometry. Excitation functions for production of gold, platinum and iridium isotopes ( 196m2 Au, 196m,g Au, 195m,g Au, 194 Au, 193 m,g Au, 192 Au, 191m,g Au, 191 Pt, 195m Pt, 194g Ir, 194m Ir, 192g Ir, 190g Ir and 189 Ir) were determined and compared with available earlier measured experimental data and results of theoretical calculations using TALYS code system. Cross section data were reported for the first time for the nat Ir(α,x) 196m2 Au, nat Ir(α,x) 196m,g Au, nat Ir(α,x) 191 Pt, nat Ir(α,x) 195m Pt, nat Ir(α,x) 194g Ir, nat Ir(α,x) 194m Ir, nat Ir(α,x) 190g Ir and nat Ir(α,x) 189 Ir processes. A possible production route for 195m Pt, the potentially important radionuclide in nuclear medicine, is discussed. Copyright © 2018 Elsevier Ltd. All rights reserved.

NAT1/DAP5/p97 and Atypical Translational Control in the Drosophila Circadian Oscillator

PubMed Central

Bradley, Sean; Narayanan, Siddhartha; Rosbash, Michael

2012-01-01

Circadian rhythms are driven by gene expression feedback loops in metazoans. Based on the success of genetic screens for circadian mutants in Drosophila melanogaster, we undertook a targeted RNAi screen to study the impact of translation control genes on circadian locomotor activity rhythms in flies. Knockdown of vital translation factors in timeless protein-positive circadian neurons caused a range of effects including lethality. Knockdown of the atypical translation factor NAT1 had the strongest effect and lengthened circadian period. It also dramatically reduced PER protein levels in pigment dispersing factor (PDF) neurons. BELLE (BEL) protein was also reduced by the NAT1 knockdown, presumably reflecting a role of NAT1 in belle mRNA translation. belle and NAT1 are also targets of the key circadian transcription factor Clock (CLK). Further evidence for a role of NAT1 is that inhibition of the target of rapamycin (TOR) kinase increased oscillator activity in cultured wings, which is absent under conditions of NAT1 knockdown. Moreover, the per 5′- and 3′-UTRs may function together to facilitate cap-independent translation under conditions of TOR inhibition. We suggest that NAT1 and cap-independent translation are important for per mRNA translation, which is also important for the circadian oscillator. A circadian translation program may be especially important in fly pacemaker cells. PMID:22904033

N-acetyltransferase 1 and 2 polymorphisms and risk of diabetes mellitus type 2 in a Saudi population.

PubMed

Al-Shaqha, Waleed M; Alkharfy, Khalid M; Al-Daghri, Nasser M; Mohammed, Abdul Khader

2015-01-01

There have been inconsistent reports on N-acetyltransferase (NAT) gene polymorphism in type 2 diabetes mellitus (T2DM), and data is particularly limited in the Arab population. Therefore, the main objective of this study was to identify whether the genetic polymorphisms of NAT1 and NAT2 play a role in susceptibility to T2DM in the Saudi population. A population-based, prospective genetic association case-control study on a Saudi population. Whole blood, anthropometric measurements and biochemistry data were collected from 369 Saudi individuals (186 T2DM patients and 183 healthy controls). DNA was isolated from the blood. Polymorphism of NAT1 and NAT2 SNPs [NAT2*7B, rs1041983(C > T); NAT2*7, rs1799931(G > A); NAT2*6A, rs1799930(G > A); NAT2*5A, rs1799929(C > T); and NAT1*11A, rs4986988(C > T)] were evaluated by allelic discrimination using real-time PCR. Subjects with T2DM had a significantly increased body mass index (BMI), waist circumference, sys.tolic and diastolic blood pressure, glucose, triglycerides, and LDL-cholesterol compared with healthy controls (P < .05). The rs1799931(G > A) genotype was detected in the control population but not in the T2DM population (P < .001). The wild type (G) allele frequency was higher in T2DM than controls (P=.038). The mutant allele (A) in rs1799931(G > A) had a protective effect for T2DM (OR 0.32, 95% CI 0.16-0.62; P=.001). Regression analysis showed that BMI, systolic BP and triglycerides are potential risk factors for T2DM. The genotypes as well as the individual alleles of rs1799931(G > A) differed significantly be.tween the case and control populations. The variation in the data reported so far suggest that polymorphism of the NAT gene may vary among different geographical areas. Environmental or dietary factors may also contribute to disease manifestation.

North Atlantic (NAT) aided inertial navigation system simulation volume I. : technical results

DOT National Transportation Integrated Search

1973-07-01

Current air traffic operations over the North ATlantic (NAT) and the application of hybrid navigation systems to obtain more accurate performance on these NAT routes are reviewed. A digital computer simulation program (NATNAV - North ATlantic NAVigat...

Simulations of the Vertical Redistribution of HNO3 by NAT or NAD PSCs: The Sensitivity to the Number of Cloud Particles Formed and the Cloud Lifetime

NASA Technical Reports Server (NTRS)

Jensen, Eric J.; Tabazadeh, Azadeh; Drdla, Katja; Toon, Owen B.; Gore, Warren J. (Technical Monitor)

2000-01-01

Recent satellite and in situ measurements have indicated that limited denitrification can occur in the Arctic stratosphere. In situ measurements from the SOLVE campaign indicate polar stratospheric clouds (PSCs) composed of small numbers (about 3 x 10^ -4 cm^-3) of 10-20 micron particles (probably NAT or NAD). These observations raise the issue of whether low number density NAT PSCs can substantially denitrify the air with reasonable cloud lifetimes. In this study, we use a one dimensional cloud model to investigate the verticle redistribution of HNO3 by NAT/NAD PSCs. The cloud formation is driven by a temperature oscillation which drops the temperature below the NAT/NAD formation threshold (about 195 K) for a few days. We assume that a small fraction of the available aerosols act as NAT nuclei when the saturation ratio of HNO3 over NAT(NAD) exceeds 10(l.5). The result is a cloud between about 16 and 20 km in the model, with NAT/NAD particle effective radii as large as about 10 microns (in agreement with the SOLVE data). We find that for typical cloud lifetimes of 2-3 days or less, the net depletion of HNO3 is no more than 1-2 ppbv, regardless of the NAT or NAD particle number density. Repeated passes of the air column through the cold pool build up the denitrification to 3-4 ppbv, and the cloud altitude steadily decreases due to the downward transport of nitric acid. Increasing the cloud lifetime results in considerably more effective denitrification, even with very low cloud particle number densities. As expected, the degree of denitrification by NAT clouds is much larger than that by NAD Clouds. Significant denitrification by NAD Clouds is only possible if the cloud lifetime is several days or more. The clouds also cause a local maximum HNO3 mixing ratio at cloud base where the cloud particles sublimate.

Treatment of Rats with Apocynin Has Considerable Inhibitory Effects on Arylamine N-Acetyltransferase Activity in the Liver.

PubMed

Francis, Sheena; Laurieri, Nicola; Nwokocha, Chukwuemeka; Delgoda, Rupika

2016-05-31

The effect of apocynin on the activity of arylamine N-acetyltransferases (NATs) in excised liver samples was examined using eighteen Sprague-Dawley rats. Three groups of six animals each were fed a normal diet alone or a treatment of 50 or 100 mg/kg/day of apocynin via gavages for eight (8) weeks. Chronic in vivo administration of apocynin led to significant (p < 0.001) reduction of in vitro liver NAT activity up to 93% as compared with untreated rats (18.80 ± 2.10 μmols p-anisidine/min/μg liver protein). In vitro exposure of untreated liver homogenates to apocynin led to a dose-dependent inhibition of NAT activity with IC50 = 0.69 ± 0.02 mM. In silico modelling of apocynin tautomers and radical species into human NAT crystal structures supported the hypothesis that thiol functionalities in NAT enzymes may be crucial in apocynin binding. The involvement of human NAT enzymes in different pathological conditions, such as cancer, has encouraged the research for selective NAT inhibitors in both humans and animal models with possible chemopreventive properties.

Occult HBV infection in HIV-infected adults and evaluation of pooled NAT for HBV.

PubMed

Dinesha, T R; Boobalan, J; Sivamalar, S; Subashini, D; Solomon, S S; Murugavel, K G; Balakrishnan, P; Smith, D M; Saravanan, S

2018-06-01

The study aimed to determine the prevalence of occult hepatitis B virus infection among HIV-infected persons and to evaluate the use of a pooling strategy to detect occult HBV infection in the setting of HIV infection. Five hundred and two HIV-positive individuals were tested for HBV, occult HBV and hepatitis C and D with serologic and nucleic acid testing (NAT). We also evaluated a pooled NAT strategy for screening occult HBV infection among the HIV-positive individuals. The prevalence of HBV infection among HIV-positive individuals was 32 (6.4%), and occult HBV prevalence was 10%. The pooling HBV NAT had a sensitivity of 66.7% and specificity of 100%, compared to HBV DNA NAT of individual samples. In conclusion, this study found a high prevalence of occult HBV infection among our HIV-infected population. We also demonstrated that pooled HBV NAT is highly specific, moderately sensitive and cost-effective. As conventional HBV viral load assays are expensive in resource-limited settings such as India, pooled HBV DNA NAT might be a good way for detecting occult HBV infection and will reduce HBV-associated complications. © 2018 John Wiley & Sons Ltd.

Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic Islets Desensitized to Sulfonylureas

PubMed Central

Wang, Shuya; Dunning, Beth E.

2001-01-01

Chronic exposure of pancreatic islets to sulfonylureas (SUs) is known to impair the ability of islets to respond to subsequent acute stimulation by SUs or glucose. Nateglinide (NAT) is a novel insulinotropic agent with a primarily site of action at β-cell KATP channels, which is common to the structurally diverse drugs like repaglinide (REP) and the SUs. Earlier studies on the kinetics, glucosedependence and sensitivity to metabolic inhibitors of the interaction between NAT and KATP channels suggested a distinct signaling pathways with NAT compared to REP, glyburide (GLY) or glimepiride (GLI). To obtain further evidence for this concept, the present study compared the insulin secretion in vitro from rat islets stimulated acutely by NAT, GLY, GLI or REP at equipotent concentrations during 1-hr static incubation following overnight treatment with GLY or tolbutamide (TOL). The islets fully retained the responsiveness to NAT stimulation after prolonged pretreatment with both SUs, while their acute response to REP, GLY, and GLI was markedly attenuated, confirming the desensitization of islets. The insulinotropic efficacy of NAT in islets desensitized to SUs may result from a distinct receptor/effector mechanism, which contributes to the unique pharmacological profile of NAT. PMID:12369729

Impact of stratospheric aircraft on calculations of nitric acid trihydrate cloud surface area densities using NMC temperatures and 2D model constituent distributions

NASA Technical Reports Server (NTRS)

Considine, David B.; Douglass, Anne R.

1994-01-01

A parameterization of NAT (nitric acid trihydrate) clouds is developed for use in 2D models of the stratosphere. The parameterization uses model distributions of HNO3 and H2O to determine critical temperatures for NAT formation as a function of latitude and pressure. National Meteorological Center temperature fields are then used to determine monthly temperature frequency distributions, also as a function of latitude and pressure. The fractions of these distributions which fall below the critical temperatures for NAT formation are then used to determine the NAT cloud surface area density for each location in the model grid. By specifying heterogeneous reaction rates as functions of the surface area density, it is then possible to assess the effects of the NAT clouds on model constituent distributions. We also consider the increase in the NAT cloud formation in the presence of a fleet of stratospheric aircraft. The stratospheric aircraft NO(x) and H2O perturbations result in increased HNO3 as well as H2O. This increases the probability of NAT formation substantially, especially if it is assumed that the aircraft perturbations are confined to a corridor region.

Modeling Conformational Transitions and Energetics of Ligand Binding with the Glutamate Receptor Ligand Binding Domain

NASA Astrophysics Data System (ADS)

Kurnikova, Maria

2009-03-01

Understanding of protein motion and energetics of conformational transitions is crucial to understanding protein function. The glutamate receptor ligand binding domain (GluR2 S1S2) is a two lobe protein, which binds ligand at the interface of two lobes and undergoes conformational transition. The cleft closure conformational transition of S1S2 has been implicated in gating of the ion channel formed by the transmembrane domain of the receptor. In this study we present a composite multi-faceted theoretical analysis of the detailed mechanism of this conformational transition based on rigid cluster decomposition of the protein structure [1] and identifying hydrogen bonds that are responsible for stabilizing the closed conformation [2]. Free energy of the protein reorganization upon ligand binding was calculated using combined Thermodynamic Integration (TI) and Umbrella Sampling (US) simulations [3]. Ligand -- protein interactions in the binding cleft were analyzed using Molecular Dynamics, continuum electrostatics and QM/MM models [4]. All model calculations compare well with corresponding experimental measurements. [4pt] [1] Protein Flexibility using Constraints from Molecular Dynamics Simulations T. Mamonova, B. Hespenheide, R. Straub, M. F. Thorpe, M. G. Kurnikova , Phys. Biol., 2, S137 (2005)[0pt] [2] Theoretical Study of the Glutamate Receptor Ligand Binding Domain Flexibility and Conformational Reorganization T. Mamonova, K. Speranskiy, and M. Kurnikova , Prot.: Struct., Func., Bioinf., 73,656 (2008)[0pt] [3] Energetics of the cleft closing transition and glutamate binding in the Glutamate Receptor ligand Binding Domain T. Mamonova, M. Yonkunas, and M. Kurnikova Biochemistry 47, 11077 (2008)[0pt] [4] On the Binding Determinants of the Glutamate Agonist with the Glutamate Receptor Ligand Binding Domain K. Speranskiy and M. Kurnikova Biochemistry 44, 11208 (2005)

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

Montemayor, Eric J.; Didychuk, Allison L.; Liao, Honghong

U6 small nuclear RNA (snRNA) is a key component of the active site of the spliceosome, a large ribonucleoprotein complex that catalyzes the splicing of precursor messenger RNA. Prior to its incorporation into the spliceosome, U6 is bound by the protein Prp24, which facilitates unwinding of the U6 internal stem-loop (ISL) so that it can pair with U4 snRNA. A previously reported crystal structure of the `core' of the U6 small nuclear ribonucleoprotein (snRNP) contained an ISL-stabilized A62G mutant of U6 bound to all four RNA-recognition motif (RRM) domains of Prp24 [Montemayoret al.(2014),Nature Struct. Mol. Biol.21, 544–551]. The structure revealedmore » a novel topology containing interlocked rings of protein and RNA that was not predicted by prior biochemical and genetic data. Here, the crystal structure of the U6 snRNP core with a wild-type ISL is reported. This complex crystallized in a new space group, apparently owing in part to the presence of an intramolecular cross-link in RRM1 that was not observed in the previously reported U6-A62G structure. The structure exhibits the same protein–RNA interface and maintains the unique interlocked topology. However, the orientation of the wild-type ISL is altered relative to the A62G mutant structure, suggesting inherent structural dynamics that may facilitate its pairing with U4. Consistent with their similar architectures in the crystalline state, the wild-type and A62G variants of U6 exhibit similar Prp24-binding affinities and electrophoretic mobilities when analyzed by gel-shift assay.« less

Role of Increased n-acetylaspartate Levels in Cancer

PubMed Central

Zand, Behrouz; Previs, Rebecca A.; Zacharias, Niki M.; Rupaimoole, Rajesha; Mitamura, Takashi; Nagaraja, Archana Sidalaghatta; Guindani, Michele; Dalton, Heather J.; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Hu, Wei; Pecot, Chad V.; Ivan, Cristina; Wu, Sherry Y.; McCullough, Christopher R.; Gharpure, Kshipra M.; Shoshan, Einav; Pradeep, Sunila; Mangala, Lingegowda S.; Rodriguez-Aguayo, Cristian; Wang, Ying; Nick, Alpa M.; Davies, Michael A.; Armaiz-Pena, Guillermo; Liu, Jinsong; Lutgendorf, Susan K.; Baggerly, Keith A.; Eli, Menashe Bar; Lopez-Berestein, Gabriel; Nagrath, Deepak; Bhattacharya, Pratip K.

2016-01-01

Background: The clinical and biological effects of metabolic alterations in cancer are not fully understood. Methods: In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.cbioportal.org/public-portal/). Using NAT8L siRNA, molecular techniques and histological analysis, we determined cancer cell viability, proliferation, apoptosis, and tumor growth in in vitro and in vivo (n = 6–10 mice/group) settings. Data were analyzed with the Student’s t test and Kaplan-Meier analysis. Statistical tests were two-sided. Results: Patients with high levels of tumoral NAA and its biosynthetic enzyme, aspartate N-acetyltransferase (NAT8L), had worse overall survival than patients with low levels of NAA and NAT8L. The overall survival duration of patients with higher-than-median NAA levels (3.6 years) was lower than that of patients with lower-than-median NAA levels (5.1 years, P = .03). High NAT8L gene expression in other cancers (melanoma, renal cell, breast, colon, and uterine cancers) was associated with worse overall survival. NAT8L silencing reduced cancer cell viability (HEYA8: control siRNA 90.61%±2.53, NAT8L siRNA 39.43%±3.00, P < .001; A2780: control siRNA 90.59%±2.53, NAT8L siRNA 7.44%±1.71, P < .001) and proliferation (HEYA8: control siRNA 74.83%±0.92, NAT8L siRNA 55.70%±1.54, P < .001; A2780: control siRNA 50.17%±4.13, NAT8L siRNA 26.52%±3.70, P < .001), which was rescued by addition of NAA. In orthotopic mouse models (ovarian cancer and melanoma), NAT8L silencing reduced tumor growth statistically significantly (A2780: control siRNA 0.52 g±0.15, NAT8L siRNA 0.08 g±0.17, P < .001; HEYA8: control siRNA 0.79 g±0.42, NAT8L siRNA 0.24 g±0.18, P = .008, A375-SM: control siRNA 0.55 g±0.22, NAT8L siRNA 0.21 g±0.17g, P = .001). NAT8L silencing downregulated the anti-apoptotic pathway, which was mediated through FOXM1. Conclusion: These findings indicate that the NAA pathway has a prominent role in promoting tumor growth and represents a valuable target for anticancer therapy. Altered energy metabolism is a hallmark of cancer (1). Proliferating cancer cells have much greater metabolic requirements than nonproliferating differentiated cells (2,3). Moreover, altered cancer metabolism elevates unique metabolic intermediates, which can promote cancer survival and progression (4,5). Furthermore, emerging evidence suggests that proliferating cancer cells exploit alternative metabolic pathways to meet their high demand for energy and to accumulate biomass (6–8). PMID:26819345

N-Acetyltransferase Polymorphism and Risk of Colorectal Adenoma and Cancer: A Pooled Analysis of Variations from 59 Studies

PubMed Central

Wang, Xiaoxue; Chen, Yizhi; Li, Rong; Zhang, Ying; Luo, Rongcheng

2012-01-01

Background There have been an increasing number of studies with evidence suggesting that the N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2) genotypes may be implicated in the development of colorectal cancer (CRC) and colorectal adenoma (CRA). So far the published data on this association has remained controversial, however. We performed a meta-analysis of case-cohort and case-control studies using a subset of the published data, with an aim to derive a better understanding of the underlying relationship. Methods/Principal Findings A literature search was performed using Medline database for relevant studies published through October 31, 2011. A total of 39 publications were selected for this meta-analysis, including 11,724 cases and 16,215 controls for CRC, and 3,701 cases and 5,149 controls for CRA. In our pooled analysis of all these studies, the results of our meta-analysis suggested that the NAT1 genotype was not significantly associated with an elevated CRC risk (OR 0.99, 95% CI 0.91–1.07). We also found that individuals with the rapid NAT2 genotype did have an elevated risk of CRC (OR 1.07, 95% CI 1.01–1.13). There was no evidence for an association between the NAT1 and 2 rapid genotype and an elevated CRA risk (NAT1: OR 1.14, 95% CI 0.99–1.29; NAT2: OR 0.94, 95% CI 0.86–1.03). Conclusion This meta-analysis suggests that individuals with NAT2 genotype had an elevated risk of CRC. There was no evidence for the association between NAT1 and 2 rapid genotype and CRA risk. PMID:22905173

In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy.

PubMed

Sorensen, Annette; Mairs, Robert J; Braidwood, Lynne; Joyce, Craig; Conner, Joe; Pimlott, Sally; Brown, Moira; Boyd, Marie

2012-04-01

Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled (131)I-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of (131)I-MIBG. Administration of HSV1716/NAT and (131)I-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.

Project Level Performance Database for Rigid Pavements in Texas, II

DOT National Transportation Integrated Search

2011-08-01

Over the years, the Texas Department of Transportation (TxDOT) has built a number of CRCP (continuously reinforced : concrete pavement) experimental sections to investigate the effects of design, materials, and construction variables on CRCP : struct...

Rapid identification of the NAT2 genotype in tuberculosis patients by multicolor melting curve analysis.

PubMed

Hu, Yanjie; Chen, Suting; Yu, Xia; Dai, Guangming; Dong, Lingling; Li, Yunxu; Zhao, Liping; Huang, Hairong

2016-07-01

NAT2 genotype is an indicator for isoniazid dosage adjusting for tuberculosis treatment. Multicolor melting curve analysis (MMCA) was evaluated as a potential method for NAT2 genotyping. 352 blood samples were analyzed by MMCA kit (Zeesan Biotech Co., Xiamen, China) targeting NAT2 SNPs at T341C, C481T, G590A and G857A, and direct sequencing was used as control. The sensitivity, specificity and accuracy of the MMCA assay for rapid NAT2 genotype detection were 97.9, 99.6 and 99.1% respectively, whereas for intermediate genotypes the values were 99.5, 98.7 and 99.1%, respectively, and for slow genotypes the values were 100% for the three aspects. The 24 saliva and blood for the control samples were also successfully analyzed using the MMCA assay, both produced uniform outcomes. The MMCA assay described in our study is very promising for the efficient determination of NAT2 genotype, and can facilitate the personalized dosing of isoniazid.

Strategies to identify natural antisense transcripts.

PubMed

Sun, Yulong; Li, Dijie; Zhang, Ru; Peng, Shang; Zhang, Ge; Yang, Tuanmin; Qian, Airong

2017-01-01

Natural antisense transcripts, originally considered as transcriptional noises arising from so-called "junk DNA″, are recently recognized as important modulators for gene regulation. They are prevalent in nearly all realms of life and have been found to modulate gene expression positively or negatively. By affecting almost all stages of gene expression range from pre-transcriptional, transcriptional and post-transcriptional to translation, NATs are fundamentally involved in various biological processes. However, compared to increasing huge data from transcriptional analysis especially high-throughput sequencing technologies (such as RNA-seq), limited functional NATs (around 70) are so far reported, which hinder our advanced comprehensive understanding for this field. Hence, efficient strategies for identifying NATs are urgently desired. In this review, we discussed the current strategies for identifying NATs, with a focus on the advantages, disadvantages, and applications of methods isolating functional NATs. Moreover, publicly available databases for NATs were also discussed. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Arylamine N-acetyltransferase activity in bronchial epithelial cells and its inhibition by cellular oxidants

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

Dairou, Julien; Petit, Emile; Ragunathan, Nilusha

2009-05-01

Bronchial epithelial cells express xenobiotic-metabolizing enzymes (XMEs) that are involved in the biotransformation of inhaled toxic compounds. The activities of these XMEs in the lung may modulate respiratory toxicity and have been linked to several diseases of the airways. Arylamine N-acetyltransferases (NAT) are conjugating XMEs that play a key role in the biotransformation of aromatic amine pollutants such as the tobacco-smoke carcinogens 4-aminobiphenyl (4-ABP) and {beta}-naphthylamine ({beta}-NA). We show here that functional human NAT1 or its murine counterpart Nat2 are present in different lung epithelial cells i.e. Clara cells, type II alveolar cells and bronchial epithelial cells, thus indicating thatmore » inhaled aromatic amines may undergo NAT-dependent biotransformation in lung epithelium. Exposure of these cells to pathophysiologically relevant amounts of oxidants known to contribute to lung dysfunction, such as H{sub 2}O{sub 2} or peroxynitrite, was found to impair the NAT1/Nat2-dependent cellular biotransformation of aromatic amines. Genetic and non genetic impairment of intracellular NAT enzyme activities has been suggested to compromise the important detoxification pathway of aromatic amine N-acetylation and subsequently to contribute to an exacerbation of untoward effects of these pollutants on health. Our study suggests that oxidative/nitroxidative stress in lung epithelial cells, due to air pollution and/or inflammation, could contribute to local and/or systemic dysfunctions through the alteration of the functions of pulmonary NAT enzymes.« less

Genetic Variation at the N-acetyltransferase (NAT) Genes in Global Populations

EPA Science Inventory

Functional variability at the N-acetyltransferase (NAT) genes is associated with adverse drug reactions and cancer susceptibility in humans. Previous studies of small sets of ethnic groups have indicated that the NAT genes have high levels of amino acid variation that differ in f...

Evaluation of hybrid slurry resulting from the introduction of additives to mineral slurry.

DOT National Transportation Integrated Search

2011-09-01

Drilled shaft construction often requires the use of drill slurry to maintain borehole stability during excavation : and concreting. Florida Department of Transportation (FDOT) specifications require the use of mineral slurry : for all primary struct...

Assessment of limestone blended cements for transportation applications : final report.

DOT National Transportation Integrated Search

2017-09-01

This research assessed the applicability of Type IL cements satisfying AASHTO M 240 specifications for use in transportation applications in place of Type I/II cements which satisfy AASHTO M 85 specifications for construction of transportation struct...

Large-scale laboratory observations of wave forces on a highway bridge superstructure.

DOT National Transportation Integrated Search

2011-10-01

The experimental setup and data are presented for a laboratory experiment conducted to examine realistic wave forcing on a highway bridge : superstructure. The experiments measure wave conditions along with the resulting forces, pressures, and struct...

77 FR 9681 - Federal Property Suitable as Facilities To Assist the Homeless

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-17

... Property-Duk Property Olympic Nat'l Park Clallam WA 98326 Landholding Agency: Interior Property Number.../environmental elements Lake Quinault Lapham Olympic Nat'l Park Quinault WA 98575 Landholding Agency: Interior.../environmental elements House 574-Ozettee Ranger Resid Olympic Nat'l Park Clallam WA 98326 Landholding Agency...

No Association Between Variant N-acetyltransferase Genes, Cigarette Smoking and Prostate Cancer Susceptibility Among Men of African Descent

PubMed Central

Kidd, La Creis Renee; VanCleave, Tiva T.; Doll, Mark A.; Srivastava, Daya S.; Thacker, Brandon; Komolafe, Oyeyemi; Pihur, Vasyl; Brock, Guy N.; Hein, David W.

2011-01-01

Objective We evaluated the individual and combination effects of NAT1, NAT2 and tobacco smoking in a case-control study of 219 incident prostate cancer (PCa) cases and 555 disease-free men. Methods Allelic discriminations for 15 NAT1 and NAT2 loci were detected in germ-line DNA samples using Taqman polymerase chain reaction (PCR) assays. Single gene, gene-gene and gene-smoking interactions were analyzed using logistic regression models and multi-factor dimensionality reduction (MDR) adjusted for age and subpopulation stratification. MDR involves a rigorous algorithm that has ample statistical power to assess and visualize gene-gene and gene-environment interactions using relatively small samples sizes (i.e., 200 cases and 200 controls). Results Despite the relatively high prevalence of NAT1*10/*10 (40.1%), NAT2 slow (30.6%), and NAT2 very slow acetylator genotypes (10.1%) among our study participants, these putative risk factors did not individually or jointly increase PCa risk among all subjects or a subset analysis restricted to tobacco smokers. Conclusion Our data do not support the use of N-acetyltransferase genetic susceptibilities as PCa risk factors among men of African descent; however, subsequent studies in larger sample populations are needed to confirm this finding. PMID:21709725

Aromatic amine metabolism: immunochemical relationships of N-acetyltransferase and N,O-acyltransferase

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

Land, S.; Allaben, W.T.; King, C.M.

1986-05-01

Mutagenic and carcinogenic aromatic amines are acetylated in most organisms. Acetyl CoA and arylhydroxamic acids can serve as acetyl donors for N-Acetylation of amines to yield stable amides, or by O-acetylation of hydroxylamine derivatives to produce reactive metabolites that can react covalently with nucleic acid. Polyclonal antibodies against rat arylhydroxamic acid, N,O-acyltransferase (AHAT) have been compared for their abilities to react with this enzyme and the acetyl CoA-dependent N-acetyltransferase (NAT) of the rat, rabbit, hamster, mouse and human. Liver cytosols were treated with increasing quantities of antibodies from immune or control rabbits. Immune complexes were removed by treatment with proteinmore » A-Sepharose before assay of nucleic acid adduct formation by AHAT activation of N-hydroxy-2-acetylaminofluorene and the acetylation of 2-aminofluorene by NAT. Both rat activities, the AHAT of the hamster and the NAT of the mouse and human were removed by this treatment. No decrease in NAT activity of hamster, or of either rabbit cytosol activity was observed. Neither mouse nor human liver has appreciable AHAT activity. These data support the idea that AHAT and NAT of rat, AHAT of hamster and NAT of mouse and human liver are immunochemically related, but that NAT of the hamster is an immunochemically distinct peptide.« less

Insights into the O-Acetylation Reaction of Hydroxylated Heterocyclic Amines by Human Arylamine N-Acetyltransferases: A Computational Study

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

Lau, E Y; Felton, J S; Lightstone, F C

2006-06-06

A computational study was performed to better understand the differences between human arylamine N-acetyltransferase (NAT) 1 and 2. Homology models were constructed from available crystal structures and comparisons of the active site residues 125, 127, and 129 for these two enzymes provide insight into observed substrate differences. The NAT2 model provided a basis for understanding how some of the common mutations may affect the structure of the protein. Molecular dynamics simulations of the human NAT models and the template structure (NAT from Mycobacterium smegmatis) were performed and showed the models to be stable and reasonable. Docking studies of hydroxylated heterocyclicmore » amines in the models of NAT1 and NAT2 probed the differences exhibited by these two proteins with mutagenic agents. The hydroxylated heterocyclic amines were only able to fit into the NAT2 active site, and an alternative binding site by the P-loop was found using our models and will be discussed. Additionally, quantum mechanical calculations were performed to study the O-acetylation reaction of the hydroxylated heterocyclic amines N-OH MeIQx and N-OH PhIP. This study has given us insight into why there are substrate differences among isoenzymes and explains some of the polymorphic activity differences.« less

Structure of Mesorhizobium loti arylamine N-acetyltransferase 1

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

Holton, Simon J.; Dairou, Julien; Sandy, James

2005-01-01

The crystal structure of a M. loti arylamine N-acetyltransferase 1 has been determined at 2.0 Å resolution. The arylamine N-acetyltransferase (NAT) enzymes have been found in a broad range of both eukaryotic and prokaryotic organisms. The NAT enzymes catalyse the transfer of an acetyl group from acetyl Co-enzyme A onto the terminal nitrogen of a range of arylamine, hydrazine and arylhydrazine compounds. Recently, several NAT structures have been reported from different prokaryotic sources including Salmonella typhimurium, Mycobacterium smegmatis and Pseudomonas aeruginosa. Bioinformatics analysis of the Mesorhizobium loti genome revealed two NAT paralogues, the first example of multiple NAT isoenzymes inmore » a eubacterial organism. The M. loti NAT 1 enzyme was recombinantly expressed and purified for X-ray crystallographic studies. The purified enzyme was crystallized in 0.5 M Ca(OAc){sub 2}, 16% PEG 3350, 0.1 M Tris–HCl pH 8.5 using the sitting-drop vapour-diffusion method. A data set diffracting to 2.0 Å was collected from a single crystal at 100 K. The crystal belongs to the orthorhombic spacegroup P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 53.2, b = 97.3, c = 114.3 Å. The structure was refined to a final free-R factor of 24.8%. The structure reveals that despite low sequence homology, M. loti NAT1 shares the common fold as reported in previous NAT structures and exhibits the same catalytic triad of residues (Cys-His-Asp) in the active site.« less

Heterogeneous Formation of Polar Stratospheric Clouds- Part 1: Nucleation of Nitric Acid Trihydrate (NAT)

NASA Technical Reports Server (NTRS)

Hoyle, C. R.; Engel, I.; Luo, B. P.; Pitts, M. C.; Poole, L. R.; Grooss, J.-U.; Peter, T.

2013-01-01

Satellite-based observations during the Arctic winter of 2009/2010 provide firm evidence that, in contrast to the current understanding, the nucleation of nitric acid trihydrate (NAT) in the polar stratosphere does not only occur on preexisting ice particles. In order to explain the NAT clouds observed over the Arctic in mid-December 2009, a heterogeneous nucleation mechanism is required, occurring via immersion freezing on the surface of solid particles, likely of meteoritic origin. For the first time, a detailed microphysical modelling of this NAT formation pathway has been carried out. Heterogeneous NAT formation was calculated along more than sixty thousand trajectories, ending at Cloud Aerosol Lidar with Orthogonal Polarization (CALIOP) observation points. Comparing the optical properties of the modelled NAT with these observations enabled a thorough validation of a newly developed NAT nucleation parameterisation, which has been built into the Zurich Optical and Microphysical box Model (ZOMM). The parameterisation is based on active site theory, is simple to implement in models and provides substantial advantages over previous approaches which involved a constant rate of NAT nucleation in a given volume of air. It is shown that the new method is capable of reproducing observed polar stratospheric clouds (PSCs) very well, despite the varied conditions experienced by air parcels travelling along the different trajectories. In a companion paper, ZOMM is applied to a later period of the winter, when ice PSCs are also present, and it is shown that the observed PSCs are also represented extremely well under these conditions.

Comparative genomic, phylogenetic, and functional investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and higher eukaryotes. The role of NATs in fungal biology has only recently been investigated (Glenn and Bacon, 2009; Glenn et al., 2010). The NAT1 gene of Gibberella moniliformis was the...

The human serotonin N-acetyltransferase (EC 2.3.1.87) gene (AANAT): Structure, chromosomal localization, and tissue expression

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

Coon, S.L.; Bernard, M.; Roseboom, P.H.

Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT, HGMW-approved symbol AANAT;EC 2.3.1.87) is the penultimate enzyme in melatonin synthesis and controls the night/day rhythm in melatonin production in the vertebrate pineal gland. We have found that the human AA-NAT gene spans {approx}2.5 kb, contains four exons, and is located at chromosome 17q25. The open reading frame encodes a 23.2-kDa protein that is {approx}80% identical to sheep and rat AA-NAT. The AA-NAT transcript ({approx}1 kb) is highly abundant in the pineal gland and is expressed at lower levels in the retina and in the Y79 retinoblastoma cell line. AA-NAT mRNA is also detectable atmore » low levels in several brain regions and the pituitary gland, but not in several peripheral tissues examined. Brain and pituitary AA-NAT could modulate serotonin-dependent aspects of human behavior and pituitary function. 31 refs., 5 figs.« less

Asymmetric localization of natural antisense RNA of neuropeptide sensorin in Aplysia sensory neurons during aging and activity.

PubMed

Kadakkuzha, Beena M; Liu, Xin-An; Narvaez, Maria; Kaye, Alexandra; Akhmedov, Komolitdin; Puthanveettil, Sathyanarayanan V

2014-01-01

Despite the advances in our understanding of transcriptome, regulation and function of its non-coding components continue to be poorly understood. Here we searched for natural antisense transcript for sensorin (NAT-SRN), a neuropeptide expressed in the presynaptic sensory neurons of gill-withdrawal reflex of the marine snail Aplysia californica. Sensorin (SRN) has a key role in learning and long-term memory storage in Aplysia. We have now identified NAT-SRN in the central nervous system (CNS) and have confirmed its expression by northern blotting and fluorescent RNA in situ hybridization. Quantitative analysis of NAT-SRN in micro-dissected cell bodies and processes of sensory neurons suggest that NAT-SRN is present in the distal neuronal processes along with sense transcripts. Importantly, aging is associated with reduction in levels of NAT-SRN in sensory neuron processes. Furthermore, we find that forskolin, an activator of CREB signaling, differentially alters the distribution of SRN and NAT-SRN. These studies reveal novel insights into physiological regulation of natural antisense RNAs.

FAA computer security : concerns remain due to personnel and other continuing weaknesses

DOT National Transportation Integrated Search

2000-08-01

FAA has a history of computer security weaknesses in a number of areas, including its physical security management at facilities that house air traffic control (ATC) systems, systems security for both operational and future systems, management struct...

Performance analysis for wireless networks: an analytical approach by multifarious Sym Teredo.

PubMed

Punithavathani, D Shalini; Radley, Sheryl

2014-01-01

IPv4-IPv6 transition rolls out numerous challenges to the world of Internet as the Internet is drifting from IPv4 to IPv6. IETF recommends few transition techniques which includes dual stack and translation and tunneling. By means of tunneling the IPv6 packets over IPv4 UDP, Teredo maintains IPv4/IPv6 dual stack node in isolated IPv4 networks behindhand network address translation (NAT). However, the proposed tunneling protocol works with the symmetric and asymmetric NATs. In order to make a Teredo support several symmetric NATs along with several asymmetric NATs, we propose multifarious Sym Teredo (MTS), which is an extension of Teredo with a capability of navigating through several symmetric NATs. The work preserves the Teredo architecture and also offers a backward compatibility with the original Teredo protocol.

Performance Analysis for Wireless Networks: An Analytical Approach by Multifarious Sym Teredo

PubMed Central

Punithavathani, D. Shalini; Radley, Sheryl

2014-01-01

IPv4-IPv6 transition rolls out numerous challenges to the world of Internet as the Internet is drifting from IPv4 to IPv6. IETF recommends few transition techniques which includes dual stack and translation and tunneling. By means of tunneling the IPv6 packets over IPv4 UDP, Teredo maintains IPv4/IPv6 dual stack node in isolated IPv4 networks behindhand network address translation (NAT). However, the proposed tunneling protocol works with the symmetric and asymmetric NATs. In order to make a Teredo support several symmetric NATs along with several asymmetric NATs, we propose multifarious Sym Teredo (MTS), which is an extension of Teredo with a capability of navigating through several symmetric NATs. The work preserves the Teredo architecture and also offers a backward compatibility with the original Teredo protocol. PMID:25506611

Reliability of a science admission test (HAM-Nat) at Hamburg medical school.

PubMed

Hissbach, Johanna; Klusmann, Dietrich; Hampe, Wolfgang

2011-01-01

The University Hospital in Hamburg (UKE) started to develop a test of knowledge in natural sciences for admission to medical school in 2005 (Hamburger Auswahlverfahren für Medizinische Studiengänge, Naturwissenschaftsteil, HAM-Nat). This study is a step towards establishing the HAM-Nat. We are investigating parallel forms reliability, the effect of a crash course in chemistry on test results, and correlations of HAM-Nat test results with a test of scientific reasoning (similar to a subtest of the "Test for Medical Studies", TMS). 316 first-year students participated in the study in 2007. They completed different versions of the HAM-Nat test which consisted of items that had already been used (HN2006) and new items (HN2007). Four weeks later half of the participants were tested on the HN2007 version of the HAM-Nat again, while the other half completed the test of scientific reasoning. Within this four week interval students were offered a five day chemistry course. Parallel forms reliability for four different test versions ranged from r(tt)=.53 to r(tt)=.67. The retest reliabilities of the HN2007 halves were r(tt)=.54 and r(tt )=.61. Correlations of the two HAM-Nat versions with the test of scientific reasoning were r=.34 und r=.21. The crash course in chemistry had no effect on HAM-Nat scores. The results suggest that further versions of the test of natural sciences will not easily conform to the standards of internal consistency, parallel-forms reliability and retest reliability. Much care has to be taken in order to assemble items which could be used interchangeably for the construction of new test versions. The test of scientific reasoning and the HAM-Nat are tapping different constructs. Participation in a chemistry course did not improve students' achievement, probably because the content of the course was not coordinated with the test and many students lacked of motivation to do well in the second test.

Reliability of a science admission test (HAM-Nat) at Hamburg medical school

PubMed Central

Hissbach, Johanna; Klusmann, Dietrich; Hampe, Wolfgang

2011-01-01

Objective: The University Hospital in Hamburg (UKE) started to develop a test of knowledge in natural sciences for admission to medical school in 2005 (Hamburger Auswahlverfahren für Medizinische Studiengänge, Naturwissenschaftsteil, HAM-Nat). This study is a step towards establishing the HAM-Nat. We are investigating parallel forms reliability, the effect of a crash course in chemistry on test results, and correlations of HAM-Nat test results with a test of scientific reasoning (similar to a subtest of the "Test for Medical Studies", TMS). Methods: 316 first-year students participated in the study in 2007. They completed different versions of the HAM-Nat test which consisted of items that had already been used (HN2006) and new items (HN2007). Four weeks later half of the participants were tested on the HN2007 version of the HAM-Nat again, while the other half completed the test of scientific reasoning. Within this four week interval students were offered a five day chemistry course. Results: Parallel forms reliability for four different test versions ranged from rtt=.53 to rtt=.67. The retest reliabilities of the HN2007 halves were rtt=.54 and rtt =.61. Correlations of the two HAM-Nat versions with the test of scientific reasoning were r=.34 und r=.21. The crash course in chemistry had no effect on HAM-Nat scores. Conclusions: The results suggest that further versions of the test of natural sciences will not easily conform to the standards of internal consistency, parallel-forms reliability and retest reliability. Much care has to be taken in order to assemble items which could be used interchangeably for the construction of new test versions. The test of scientific reasoning and the HAM-Nat are tapping different constructs. Participation in a chemistry course did not improve students’ achievement, probably because the content of the course was not coordinated with the test and many students lacked of motivation to do well in the second test. PMID:21866246

Comparison of CYP1A2 and NAT2 Phenotypes between Black and White Smokers

PubMed Central

Muscat, Joshua E.; Pittman, Brian; Kleinman, Wayne; Lazarus, Philip; Stellman, Steven D.; Richie, John P.

2008-01-01

The lower incidence rate of transitional cell carcinoma of the urinary bladder in blacks than in whites may be due to racial differences in the catalytic activity of enzymes that metabolize carcinogenic arylamines in tobacco smoke. To examine this, we compared cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 activities (NAT2) in black and white smokers using urinary caffeine metabolites as a probe for enzyme activity in a community-based study of 165 black and 183 white cigarette smokers. The paraxanthine (1,7-dimethylxanthine, 17X)/caffeine (trimethylxanthine, 137X) ratio or [17X + 1,7-dimethyluric acid (17U)]/137X ratio was used as an indicator of CYP1A2 activity. The 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine (1X) ratio indicated NAT2 activity. The odds ratio for the slow NAT2 phenotype associated with black race was 0.4; 95% confidence intervals 0.2–0.7. The putative combined low risk phenotype (slow CYP1A2/rapid NAT2) was more common in blacks than in whites (25% vs. 15%, P<0.02). There were no significant racial differences in slow and rapid CYP1A2 phenotypes, and in the combined slow NAT2/rapid CYP1A2 phenotype. Age, education, cigarette smoking amount, body mass index, GSTM1 and GSTM3 genotypes were unrelated to CYP1A2 and NAT2 activity. Intake of cruciferous vegetables (primarily broccoli), red meat, carrots, grapefruit and onions predicted CYP1A2 activity either for all subjects or in race-specific analyses. Carrot and grapefruit consumption was related to NAT2 activity. Collectively, these results indicated that phenotypic differences in NAT2 alone or in combination with CYP1A2 might help explain the higher incidence rates of transitional cell bladder cancer in whites. PMID:18703023

The results of nucleic acid testing in remunerated and non-remunerated blood donors in Lithuania

PubMed Central

Kalibatas, Vytenis; Kalibatienė, Lina

2014-01-01

Background In Lithuania, governmentally covered remuneration for whole blood donations prevails. Donors may choose to accept or reject the remuneration. The purpose of this study was to compare the rate of nucleic acid testing (NAT) discriminatory-positive markers for human immunodeficiency virus-1 (HIV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) in seronegative, first-time and repeat, remunerated and non-remunerated donations at the National Blood Centre in Lithuania during the period from 2005 to 2010. Materials and methods All seronegative whole blood and blood component donations were individually analysed by NAT for HIV-1, HBV and HCV. Only discriminatory-positive NAT were classified. The prevalence of discriminatory-positive NAT per 100,000 donations in the donor groups and the odds ratios comparing the remunerated and non-remunerated donations were determined. Results Significant differences were observed for HBV NAT results: 47.42 and 26.29 per 100,000 remunerated first-time and repeat donations, respectively, compared to 10.6 and 3.58 per 100,000 non-remunerated first-time and repeat, seronegative donations, respectively. The differences were also significant for HCV NAT results: 47.42 and 51.99 for remunerated first-time and repeat donations, respectively, compared to 2.12 and 0 per 100,000 non-remunerated first-time and repeat, seronegative donations, respectively. No seronegative, discriminatory-positive NAT HIV case was found. The odds of discriminatory HBV and HCV NAT positive results were statistically significantly higher for both first-time and repeat remunerated donations compared to first-time and repeat non-remunerated donations. Discussion First-time and repeat remunerated seronegative donations were associated with a statistically significantly higher prevalence and odds for discriminatory-positive HBV and HCV NAT results compared to first-time and repeat non-remunerated donations at the National Blood Centre in Lithuania. PMID:24120587

Structural Evaluation of 5,5'-Bis(naphth-2-yl)-2,2'-bithiophene in Organic Field-Effect Transistors with n-Octadecyltrichlorosilane Coated SiO2 Gate Dielectric.

PubMed

Lauritzen, Andreas E; Torkkeli, Mika; Bikondoa, Oier; Linnet, Jes; Tavares, Luciana; Kjelstrup-Hansen, Jakob; Knaapila, Matti

2018-05-25

We report on the structure and morphology of 5,5'-bis(naphth-2-yl)-2,2'-bithiophene (NaT2) films in bottom-contact organic field-effect transistors (OFETs) with octadecyltrichlorosilane (OTS) coated SiO 2 gate dielectric, characterized by atomic force microscopy (AFM), grazing-incidence X-ray diffraction (GIXRD), and electrical transport measurements. Three types of devices were investigated with the NaT2 thin-film deposited either on (1) pristine SiO 2 (corresponding to higher surface energy, 47 mJ/m 2 ) or on OTS deposited on SiO 2 under (2) anhydrous or (3) humid conditions (corresponding to lower surface energies, 20-25 mJ/m 2 ). NaT2 films grown on pristine SiO 2 form nearly featureless three-dimensional islands. NaT2 films grown on OTS/SiO 2 deposited under anhydrous conditions form staggered pyramid islands where the interlayer spacing corresponds to the size of the NaT2 unit cell. At the same time, the grain size measured by AFM increases from hundreds of nanometers to micrometers and the crystal size measured by GIXRD from 30 nm to more than 100 nm. NaT2 on OTS/SiO 2 deposited under humid conditions also promotes staggered pyramids but with smaller crystals 30-80 nm. The NaT2 unit cell parameters in OFETs differ 1-2% from those in bulk. Carrier mobilities tend to be higher for NaT2 layers on SiO 2 (2-3 × 10 -4 cm 2 /(V s)) compared to NaT2 on OTS (2 × 10 -5 -1 × 10 -4 cm 2 /(V s)). An applied voltage does not influence the unit cell parameters when probed by GIXRD in operando.

Clinical Outcomes in International Federation of Gynecology and Obstetrics Stage IA Endometrial Cancer With Myometrial Invasion Treated With or Without Postoperative Vaginal Brachytherapy

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

Diavolitsis, V.; Rademaker, A.; Lurain, J.

2012-10-01

Purpose: To assess the clinical outcomes of patients with Stage IA endometrial cancer with myometrial invasion treated with postoperative vaginal brachytherapy (VBT) with those who received no adjuvant therapy (NAT). Methods and Materials: All patients treated with hysterectomy for endometrial cancer at Northwestern Memorial Hospital between 1978 and 2005 were identified. Those patients with Stage IA disease with myometrial invasion who were treated with VBT alone or NAT were identified and included in the present analysis. Results: Of 252 patients with Stage IA endometrial cancer with superficial (<50%) myometrial invasion who met the inclusion criteria, 169 underwent VBT and 83more » received NAT. The median follow-up in the VBT and NAT groups was 103 and 61 months, respectively. In the VBT group, 56.8% had Grade 1, 37.9% had Grade 2, and 5.3% had Grade 3 tumors. In the NAT group, 75.9%, 20.5%, and 3.6% had Grade 1, 2, and 3 tumors, respectively. Lymphatic or vascular space invasion was noted in 12.4% of the VBT patients and 5.6% of the NAT patients. The 5-year overall survival rate was 95.5%. The 5-year recurrence-free survival rate was 92.4% for all patients, 94.4% for the VBT group, and 87.4% for the NAT group (p = NS). Of the 169 VBT patients and 83 NAT patients, 8 (4.7%) and 6 (7.2%) developed recurrent disease. One vaginal recurrence occurred in the VBT group (0.6%) and three in the NAT group (3.8%). Recurrences developed 2-102 months after surgical treatment. Two of the four vaginal recurrences were salvaged. No Grade 3 or higher acute or late radiation toxicity was noted. Conclusions: The use of postoperative VBT in patients with Stage I endometrial cancer with <50% myometrial invasion yielded excellent vaginal disease control and disease-free survival, with minimal toxicity.« less

Single Fluorescent Molecules as Nano-Illuminators for Biological Structure and Function

NASA Astrophysics Data System (ADS)

Moerner, W. E.

2011-03-01

Since the first optical detection and spectroscopy of a single molecule in a solid (Phys. Rev. Lett. {62}, 2535 (1989)), much has been learned about the ability of single molecules to probe local nanoenvironments and individual behavior in biological and nonbiological materials in the absence of ensemble averaging that can obscure heterogeneity. Because each single fluorophore acts a light source roughly 1 nm in size, microscopic imaging of individual fluorophores leads naturally to superlocalization, or determination of the position of the molecule with precision beyond the optical diffraction limit, simply by digitization of the point-spread function from the single emitter. For example, the shape of single filaments in a living cell can be extracted simply by allowing a single molecule to move through the filament (PNAS {103}, 10929 (2006)). The addition of photoinduced control of single-molecule emission allows imaging beyond the diffraction limit (super-resolution) and a new array of acronyms (PALM, STORM, F-PALM etc.) and advances have appeared. We have used the native blinking and switching of a common yellow-emitting variant of green fluorescent protein (EYFP) reported more than a decade ago (Nature {388}, 355 (1997)) to achieve sub-40 nm super-resolution imaging of several protein structures in the bacterium Caulobacter crescentus: the quasi-helix of the actin-like protein MreB (Nat. Meth. {5}, 947 (2008)), the cellular distribution of the DNA binding protein HU (submitted), and the recently discovered division spindle composed of ParA filaments (Nat. Cell Biol. {12}, 791 (2010)). Even with these advances, better emitters would provide more photons and improved resolution, and a new photoactivatable small-molecule emitter has recently been synthesized and targeted to specific structures in living cells to provide super-resolution images (JACS {132}, 15099 (2010)). Finally, a new optical method for extracting three-dimensional position information based on a double-helix point spread function enables quantitative tracking of single mRNA particles in living yeast cells with 15 ms time resolution and 25-50 nm spatial precision (PNAS {107}, 17864 (2010)). These examples illustrate the power of single-molecule optical imaging in extracting new structural and functional information in living cells.

Evaluation of the Procleix Ultrio Elite Assay and the Panther-System for Individual NAT Screening of Blood, Hematopoietic Stem Cell, Tissue and Organ Donors.

PubMed

Heim, Albert

2016-05-01

The performance of the multiplex Procleix Ultrio Elite assay as individual donor nucleic acid test (ID-NAT) for the detection of HIV-1, HIV-2, HCV, and HBV was evaluated in a retrospective, single center study. ID-NAT results of 21,181 blood donors, 984 tissue donors, 293 hematopoietic stem cell donors and 4 organ donors were reviewed in synopsis with results of serological screening and additional discriminatory and repetitive NAT in case of positive donors. Specificity of the initial Procleix Ultrio Elite assay was 99.98% and after discriminatory testing 100.00%. Initially invalid results were observed in 75 of 21,181 blood donors (0.35%) but 16 of 984 tissue donors (1.62%, p < 0.001) which included non-heart-beating ('cadaveric') donors. All these had valid negative ID-NAT results after repeated testing or testing of 1:5 diluted specimens in case of tissue donors. Occult hepatitis B (defined here as HBV DNAemia without HBsAg detection) was demonstrated by ID-NAT in two anti-HBc-positive tissue donors and suspected in two other tissue donors, where a definite diagnosis was not achieved due to the insufficient sample volumes available. The Procleix Ultrio Elite assay proved to be specific, robust and rapid. Therefore, routine ID-NAT may also be feasible for organ and granulocyte donors.

Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specialized acetyl coenzyme A metabolism in the CNS.

PubMed

Ariyannur, Prasanth S; Moffett, John R; Manickam, Pachiappan; Pattabiraman, Nagarajan; Arun, Peethambaran; Nitta, Atsumi; Nabeshima, Toshitaka; Madhavarao, Chikkathur N; Namboodiri, Aryan M A

2010-06-04

N-acetylaspartate (NAA) is a concentrated, neuron-specific brain metabolite routinely used as a magnetic resonance spectroscopy marker for brain injury and disease. Despite decades of research, the functional roles of NAA remain unclear. Biochemical investigations over several decades have associated NAA with myelin lipid synthesis and energy metabolism. However, studies have been hampered by an inability to identify the gene for the NAA biosynthetic enzyme aspartate N-acetyltransferase (Asp-NAT). A very recent report has identified Nat8l as the gene encoding Asp-NAT and confirmed that the only child diagnosed with a lack of NAA on brain magnetic resonance spectrograms has a 19-bp deletion in this gene. Based on in vitro Nat8l expression studies the researchers concluded that many previous biochemical investigations have been technically flawed and that NAA may not be associated with brain energy or lipid metabolism. In studies done concurrently in our laboratory we have demonstrated via cloning, expression, specificity for acetylation of aspartate, responsiveness to methamphetamine treatment, molecular modeling and comparative immunolocalization that NAT8L is the NAA biosynthetic enzyme Asp-NAT. We conclude that NAA is a major storage and transport form of acetyl coenzyme A specific to the nervous system, thus linking it to both lipid synthesis and energy metabolism. Published by Elsevier B.V.

Proper regulation of a sperm-specific cis-nat-siRNA is essential for double fertilization in Arabidopsis

USDA-ARS?s Scientific Manuscript database

/Cis/-nat-siRNAs are a recently characterized class of small regulatory RNAs that are widespread in eukaryotes. Despite their abundance the importance of their regulatory activity is largely unknown. The only functional role for eukaryotic /cis/-nat-siRNAs that has been described to date is in envir...

Heterogeneous kinetics of H2O, HNO3 and HCl on HNO3 hydrates (α-NAT, β-NAT, NAD) in the range 175-200 K

NASA Astrophysics Data System (ADS)

Iannarelli, Riccardo; Rossi, Michel J.

2016-09-01

Experiments on the title compounds have been performed using a multidiagnostic stirred-flow reactor (SFR) in which the gas phase as well as the condensed phase has been simultaneously investigated under stratospheric temperatures in the range 175-200 K. Wall interactions of the title compounds have been taken into account using Langmuir adsorption isotherms in order to close the mass balance between deposited and desorbed (recovered) compounds. Thin solid films at 1 µm typical thickness have been used as a proxy for atmospheric ice particles and have been deposited on a Si window of the cryostat, with the optical element being the only cold point in the deposition chamber. Fourier transform infrared (FTIR) absorption spectroscopy in transmission as well as partial and total pressure measurement using residual gas mass spectrometry (MS) and sensitive pressure gauges have been employed in order to monitor growth and evaporation processes as a function of temperature using both pulsed and continuous gas admission and monitoring under SFR conditions. Thin solid H2O ice films were used as the starting point throughout, with the initial spontaneous formation of α-NAT (nitric acid trihydrate) followed by the gradual transformation of α- to β-NAT at T > 185 K. Nitric acid dihydrate (NAD) was spontaneously formed at somewhat larger partial pressures of HNO3 deposited on pure H2O ice. In contrast to published reports, the formation of α-NAT proceeded without prior formation of an amorphous HNO3 / H2O layer and always resulted in β-NAT. For α- and β-NAT, the temperature-dependent accommodation coefficient α(H2O) and α(HNO3), the evaporation flux Jev(H2O) and Jev(HNO3) and the resulting saturation vapor pressure Peq(H2O) and Peq(HNO3) were measured and compared to binary phase diagrams of HNO3 / H2O in order to afford a thermochemical check of the kinetic parameters. The resulting kinetic and thermodynamic parameters of activation energies for evaporation (Eev) and standard heats of evaporation ΔHev0 of H2O and HNO3 for α- and β-NAT, respectively, led to an estimate for the relative standard enthalpy difference between α- and β-NAT of -6.0 ± 20 kJ mol-1 in favor of β-NAT, as expected, despite a significantly larger value of Eev for HNO3 in α-NAT. This in turn implies a substantial activation energy for HNO3 accommodation in α- compared to β-NAT where Eacc(HNO3) is essentially zero. The kinetic (α(HCl), Jev(HCl)) and thermodynamic (Peq(HCl)) parameters of HCl-doped α- and β-NAT have been determined under the assumption that HCl adsorption did not significantly affect α(H2O) and α(HNO3) as well as the evaporation flux Jev(H2O). Jev(HCl) and Peq(HCl) on both α- and β-NAT are larger than the corresponding values for HNO3 across the investigated temperature range but significantly smaller than the values for pure H2O ice at T < 200 K.

Effective Sealing and Monitoring of Small Movement Expansion Joints in Connecticut Bridges

DOT National Transportation Integrated Search

2017-03-01

One in nine bridges in the United States is rated as structurally deficient by the 2013 Infrastructure Report Card published by the American Society of Civil Engineers. One of the primary degradation factors that contribute to compromising the struct...

A review of federal and Minnesota laws on pedestrian, bicycle, and non-motorized transportation.

DOT National Transportation Integrated Search

2013-10-01

Minnesotas transportation system supports the movement and travel of people, vehicles, and freight : through a wide range of land-, water-, and air-based modes of transportation.21 This multimodal transportation system exists within a legal struct...

N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

PubMed

Adole, Prashant S; Kharbanda, Parampreet S; Sharma, Sadhna

2016-05-01

Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines

PubMed Central

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-01-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. PMID:25627111

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines.

PubMed

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-04-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Brachial artery endothelial function is stable across a menstrual and oral contraceptive pill cycle, but lower in premenopausal women than age-matched men.

PubMed

Shenouda, Ninette; Priest, Stacey E; Rizzuto, Vanessa I; MacDonald, Maureen J

2018-05-04

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases, may influence brachial artery endothelial function. Fifty-three healthy adults (22{plus minus}3 yrs; 20 men, 15 NAT, 18 second, third or fourth generation OCP) underwent assessments of sex hormones and endothelial (flow-mediated dilation test, FMD) and smooth muscle (nitroglycerin test, NTG) function. Men were tested three times at one-week intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, mid-follicular, luteal; OCP: placebo/no pill, 'early' and 'late' active pill). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase (p=0.36) but increased throughout a NAT cycle (p<0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than men (p=0.005), whereas scaled NTG was lower only in NAT women (p=0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD (r2=0.01, p=0.62) or NTG (r2=0.09, p=0.13). Duration of OCP use was negatively associated with the average relative FMD for second generation OCP users only (r=-0.65, p=0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer term use of second generation OCPs.

Rapid, Fully Automated Digital Immunoassay for p24 Protein with the Sensitivity of Nucleic Acid Amplification for Detecting Acute HIV Infection.

PubMed

Cabrera, Carlos; Chang, Lei; Stone, Mars; Busch, Michael; Wilson, David H

2015-11-01

Nucleic acid testing (NAT) has become the standard for high sensitivity in detecting low levels of virus. However, adoption of NAT can be cost prohibitive in low-resource settings where access to extreme sensitivity could be clinically advantageous for early detection of infection. We report development and preliminary validation of a simple, low-cost, fully automated digital p24 antigen immunoassay with the sensitivity of quantitative NAT viral load (NAT-VL) methods for detection of acute HIV infection. We developed an investigational 69-min immunoassay for p24 capsid protein for use on a novel digital analyzer on the basis of single-molecule-array technology. We evaluated the assay for sensitivity by dilution of standardized preparations of p24, cultured HIV, and preseroconversion samples. We characterized analytical performance and concordance with 2 NAT-VL methods and 2 contemporary p24 Ag/Ab combination immunoassays with dilutions of viral isolates and samples from the earliest stages of HIV infection. Analytical sensitivity was 0.0025 ng/L p24, equivalent to 60 HIV RNA copies/mL. The limit of quantification was 0.0076 ng/L, and imprecision across 10 runs was <10% for samples as low as 0.09 ng/L. Clinical specificity was 95.1%. Sensitivity concordance vs NAT-VL on dilutions of preseroconversion samples and Group M viral isolates was 100%. The digital immunoassay exhibited >4000-fold greater sensitivity than contemporary immunoassays for p24 and sensitivity equivalent to that of NAT methods for early detection of HIV. The data indicate that NAT-level sensitivity for acute HIV infection is possible with a simple, low-cost digital immunoassay. © 2015 American Association for Clinical Chemistry.

Infectivity of HBV DNA positive donations identified in look-back studies in Hyogo-Prefecture, Japan.

PubMed

Bouike, Y; Imoto, S; Mabuchi, O; Kokubunji, A; Kai, S; Okada, M; Taniguchi, R; Momose, S; Uchida, S; Nishio, H

2011-04-01

To clarify transfusion incidence of hepatitis B virus (HBV) infected blood negative for mini pool-nucleic acid amplification testing (MP-NAT). Japanese Red Cross (JRC) blood centres screen donated blood to avoid contamination with HBV. However, a low copy number of HBV may be overlooked. In Hyogo-Prefecture, JRC blood centres screened 787 695 donations for HBV from April 2005 to March 2009. Of these, 685 844 were donations from the repeat donors. To detect the donors with HBV, serological tests, MP-NAT and/or individual donation (ID)-NAT were performed. To detect the recipients with transfusion-transmitted HBV infection (TTHBI), serological analysis and/or ID-NAT were performed. In this study, 265 of the 685 844 repeat donations were serologically and/or MP-NAT positive for HBV. Their repository samples from the previous donation were examined in a look-back study; 13 of the 265 repository samples proved ID-NAT positive. Twelve recipients were transfused with HBV-infected blood components derived from 10 of the 13 HBV-infected donors. Only 1 of the 12 recipients was identified as TTHBI case. Seven of the 12 recipients escaped from our follow-up study and 4 recipients were negative for HBV during the observation period. On the basis of the look-back study among the repeat donors in Hyogo-Prefecture, Japan, donations with HBV-infected blood negative for MP-NAT occurred with a frequency of 13 in 685 844 donations (∼1/53 000 donations). However, more than half of the recipients transfused with HBV-infected blood negative for MP-NAT could not be followed up. It is necessary to establish a more cautious follow-up system. © 2010 The Authors. Transfusion Medicine © 2010 British Blood Transfusion Society.

N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study

PubMed Central

Adole, Prashant S.; Kharbanda, Parampreet S.; Sharma, Sadhna

2016-01-01

Background & objectives: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Methods: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. Results: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Interpretation & conclusions: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures. PMID:27488001

Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80.

PubMed

Goris, Marianne; Magin, Robert S; Foyn, Håvard; Myklebust, Line M; Varland, Sylvia; Ree, Rasmus; Drazic, Adrian; Bhambra, Parminder; Støve, Svein I; Baumann, Markus; Haug, Bengt Erik; Marmorstein, Ronen; Arnesen, Thomas

2018-04-24

N-terminal (Nt) acetylation is a major protein modification catalyzed by N-terminal acetyltransferases (NATs). Methionine acidic N termini, including actin, are cotranslationally Nt acetylated by NatB in all eukaryotes, but animal actins containing acidic N termini, are additionally posttranslationally Nt acetylated by NAA80. Actin Nt acetylation was found to regulate cytoskeletal dynamics and motility, thus making NAA80 a potential target for cell migration regulation. In this work, we developed potent and selective bisubstrate inhibitors for NAA80 and determined the crystal structure of NAA80 in complex with such an inhibitor, revealing that NAA80 adopts a fold similar to other NAT enzymes but with a more open substrate binding region. Furthermore, in contrast to most other NATs, the substrate specificity of NAA80 is mainly derived through interactions between the enzyme and the acidic amino acids at positions 2 and 3 of the actin substrate and not residues 1 and 2. A yeast model revealed that ectopic expression of NAA80 in a strain lacking NatB activity partially restored Nt acetylation of NatB substrates, including yeast actin. Thus, NAA80 holds intrinsic capacity to posttranslationally Nt acetylate NatB-type substrates in vivo. In sum, the presence of a dominant cotranslational NatB in all eukaryotes, the specific posttranslational actin methionine removal in animals, and finally, the unique structural features of NAA80 leave only the processed actins as in vivo substrates of NAA80. Together, this study reveals the molecular and cellular basis of NAA80 Nt acetylation and provides a scaffold for development of inhibitors for the regulation of cytoskeletal properties. Copyright © 2018 the Author(s). Published by PNAS.

NAT2, meat consumption and colorectal cancer incidence: an ecological study among 27 countries.

PubMed

Ognjanovic, Simona; Yamamoto, Jennifer; Maskarinec, Gertraud; Le Marchand, Loïc

2006-11-01

The polymorphic gene NAT2 is a major determinant of N-acetyltransferase activity and, thus, may be responsible for differences in one's ability to bioactivate heterocyclic amines, a class of procarcinogens in cooked meat. An unusually marked geographic variation in enzyme activity has been described for NAT2. The present study re-examines the international direct correlation reported for meat intake and colorectal cancer (CRC) incidence, and evaluates the potential modifying effects of NAT2 phenotype and other lifestyle factors on this correlation. Country-specific CRC incidence data, per capita consumption data for meat and other dietary factors, prevalence of the rapid/intermediate NAT2 phenotype, and prevalence of smoking for 27 countries were used. Multiple linear regression models were fit and partial correlation coefficients (PCCs) were computed for men and women separately. Inclusion of the rapid/intermediate NAT2 phenotype with meat consumption improved the fit of the regression model for CRC incidence in both sexes (males-R (2) = 0.78, compared to 0.70 for meat alone; p for difference in model fit-0.009; females-R (2) = 0.76 compared to 0.69 for meat alone; p = 0.02). Vegetable consumption (inversely and in both sexes) and fish consumption (directly and in men only) were also weakly correlated with CRC, whereas smoking prevalence and alcohol consumption had no effects on the models. The PCC between NAT2 and CRC incidence was 0.46 in males and 0.48 in females when meat consumption was included in the model, compared to 0.14 and 0.15, respectively, when it was not. These data suggest that, in combination with meat intake, some proportion of the international variability in CRC incidence may be attributable to genetic susceptibility to heterocyclic amines, as determined by NAT2 genotype.

Cosmology with negative absolute temperatures

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

Vieira, J.P.P.; Byrnes, Christian T.; Lewis, Antony, E-mail: J.Pinto-Vieira@sussex.ac.uk, E-mail: ctb22@sussex.ac.uk, E-mail: antony@cosmologist.info

Negative absolute temperatures (NAT) are an exotic thermodynamical consequence of quantum physics which has been known since the 1950's (having been achieved in the lab on a number of occasions). Recently, the work of Braun et al. [1] has rekindled interest in negative temperatures and hinted at a possibility of using NAT systems in the lab as dark energy analogues. This paper goes one step further, looking into the cosmological consequences of the existence of a NAT component in the Universe. NAT-dominated expanding Universes experience a borderline phantom expansion ( w < -1) with no Big Rip, and their contractingmore » counterparts are forced to bounce after the energy density becomes sufficiently large. Both scenarios might be used to solve horizon and flatness problems analogously to standard inflation and bouncing cosmologies. We discuss the difficulties in obtaining and ending a NAT-dominated epoch, and possible ways of obtaining density perturbations with an acceptable spectrum.« less

Arylamine N-acetyltransferase 2 genotype-dependent N-acetylation of isoniazid in cryopreserved human hepatocytes.

PubMed

Doll, Mark A; Salazar-González, Raúl A; Bodduluri, Srineil; Hein, David W

2017-07-01

Cryopreserved human hepatocytes were used to investigate the role of arylamine N -acetyltransferase 2 (NAT2; EC 2.3.1.5) polymorphism on the N -acetylation of isoniazid (INH). NAT2 genotype was determined by Taqman allelic discrimination assay and INH N -acetylation was measured by high performance liquid chromatography. INH N -acetylation rates in vitro exhibited a robust and highly significant ( P <0.005) NAT2 phenotype-dependent metabolism. N -acetylation rates in situ were INH concentration- and time-dependent. Following incubation for 24 h with 12.5 or 100 µmol/L INH, acetyl-INH concentrations varied significantly ( P = 0.0023 and P = 0.0002) across cryopreserved human hepatocytes samples from rapid, intermediate, and slow acetylators, respectively. The clear association between NAT2 genotype and phenotype supports use of NAT2 genotype to guide INH dosing strategies in the treatment and prevention of tuberculosis.

Excitation functions of nuclear reactions induced by alpha particles up to 42 MeV on natTi for monitoring purposes and TLA

NASA Astrophysics Data System (ADS)

Hermanne, A.; Sonck, M.; Takács, S.; Szelecsényi, F.; Tárkányi, F.

1999-05-01

Excitation functions for the reactions induced by alpha particles on natTi foils and leading to the formation of 44m,44g,46,47,48Sc; 48,51Cr and 48V were determined using the stacked foil technique for energies from the respective reaction thresholds up to 42 MeV. The new experimental values are compared to earlier literature values and generally good accordance is found. It appears that the natTi(α,x) 51Cr reaction is particularly useful for monitoring α-beams in the 10-20 MeV region while for energies above 20 MeV the natTi(α,x) 47Sc reaction or the natTi(α,x) 48V reaction are more suited. The excitation functions established can be used to determine calibration curves for thin layer activation (TLA) as well.

Excitation functions of the natCr(p,x)44Ti, 56Fe(p,x)44Ti, natNi(p,x)44Ti and 93Nb(p,x)44Ti reactions at energies up to 2.6 GeV

NASA Astrophysics Data System (ADS)

Titarenko, Yu. E.; Batyaev, V. F.; Pavlov, K. V.; Titarenko, A. Yu.; Zhivun, V. M.; Chauzova, M. V.; Balyuk, S. A.; Bebenin, P. V.; Ignatyuk, A. V.; Mashnik, S. G.; Leray, S.; Boudard, A.; David, J. C.; Mancusi, D.; Cugnon, J.; Yariv, Y.; Nishihara, K.; Matsuda, N.; Kumawat, H.; Stankovskiy, A. Yu.

2016-06-01

The paper presents the measured cumulative yields of 44Ti for natCr, 56Fe, natNi and 93Nb samples irradiated by protons at the energy range 0.04-2.6 GeV. The obtained excitation functions are compared with calculations of the well-known codes: ISABEL, Bertini, INCL4.2+ABLA, INCL4.5+ABLA07, PHITS, CASCADE07 and CEM03.02. The predictive power of these codes regarding the studied nuclides is analyzed.

The expression of xenobiotic-metabolizing enzymes in human prostate and in prostate epithelial cells (PECs) derived from primary cultures.

PubMed

Al-Buheissi, S Z; Cole, K J; Hewer, A; Kumar, V; Bryan, R L; Hudson, D L; Patel, H R; Nathan, S; Miller, R A; Phillips, D H

2006-06-01

Dietary heterocyclic amines (HCAs) are carcinogenic in rodent prostate requiring activation by enzymes such as cytochrome P450 (CYP) and N-acetyltransferase (NAT). We investigated by Western blotting and immunohistochemistry the expression of CYP1A1, CYP1A2, and NAT1 in human prostate and in prostate epithelial cells (PECs) derived from primary cultures and tested their ability to activate the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and its N-hydroxy metabolite (N-OH-IQ) to DNA-damaging moieties. Western blotting identified CYP1A1, CYP1A2, and NAT1. Immunohistochemistry localized NAT1 to the cytoplasm of PECs. Inter-individual variation was observed in the expression levels of CYP1A1, 1A2, and NAT1 (11, 75, and 35-fold, respectively). PECs expressed CYP1A1 and NAT1 but not CYP1A2. When incubated with IQ or N-OH-IQ, PECs formed DNA adducts indicating their ability to metabolically activate these compounds. Prostate cells possess the capacity to activate dietary carcinogens. PECs may provide a useful model system to study their role in prostate carcinogenesis.

The Neighborhood Auditing Tool: a hybrid interface for auditing the UMLS.

PubMed

Morrey, C Paul; Geller, James; Halper, Michael; Perl, Yehoshua

2009-06-01

The UMLS's integration of more than 100 source vocabularies, not necessarily consistent with one another, causes some inconsistencies. The purpose of auditing the UMLS is to detect such inconsistencies and to suggest how to resolve them while observing the requirement of fully representing the content of each source in the UMLS. A software tool, called the Neighborhood Auditing Tool (NAT), that facilitates UMLS auditing is presented. The NAT supports "neighborhood-based" auditing, where, at any given time, an auditor concentrates on a single-focus concept and one of a variety of neighborhoods of its closely related concepts. Typical diagrammatic displays of concept networks have a number of shortcomings, so the NAT utilizes a hybrid diagram/text interface that features stylized neighborhood views which retain some of the best features of both the diagrammatic layouts and text windows while avoiding the shortcomings. The NAT allows an auditor to display knowledge from both the Metathesaurus (concept) level and the Semantic Network (semantic type) level. Various additional features of the NAT that support the auditing process are described. The usefulness of the NAT is demonstrated through a group of case studies. Its impact is tested with a study involving a select group of auditors.

Ion Implantation in Polymers.

DTIC Science & Technology

1983-08-01

cases, the crystalline regions are often lamellar in struct- rg and the lamellae fre- quently occur in some form of spherulitic morphology. Since, in a...12181 Dr. D. H. Whitmore Department of Materials Science Dr. A. P. B. Lever Northwestern University Chemistry Department Evanston, Illinois 60201 1 York

Assessing diversity and phytoremediation potential of seagrass in tropical region

USDA-ARS?s Scientific Manuscript database

Seagrass ecosystem is one of the most important resources in the coastal areas. Seagrasses support and provide habitats for many coastal organisms in tropical region. Seagrasses are specialized marine flowering plants that have adapted to the nearshore environment with heterogeneous landscape struct...

Evaluation of the Procleix Ultrio Elite Assay and the Panther-System for Individual NAT Screening of Blood, Hematopoietic Stem Cell, Tissue and Organ Donors

PubMed Central

Heim, Albert

2016-01-01

Summary Background The performance of the multiplex Procleix Ultrio Elite assay as individual donor nucleic acid test (ID-NAT) for the detection of HIV-1, HIV-2, HCV, and HBV was evaluated in a retrospective, single center study. Methods ID-NAT results of 21,181 blood donors, 984 tissue donors, 293 hematopoietic stem cell donors and 4 organ donors were reviewed in synopsis with results of serological screening and additional discriminatory and repetitive NAT in case of positive donors. Results Specificity of the initial Procleix Ultrio Elite assay was 99.98% and after discriminatory testing 100.00%. Initially invalid results were observed in 75 of 21,181 blood donors (0.35%) but 16 of 984 tissue donors (1.62%, p < 0.001) which included non-heart-beating (‘cadaveric’) donors. All these had valid negative ID-NAT results after repeated testing or testing of 1:5 diluted specimens in case of tissue donors. Occult hepatitis B (defined here as HBV DNAemia without HBsAg detection) was demonstrated by ID-NAT in two anti-HBc-positive tissue donors and suspected in two other tissue donors, where a definite diagnosis was not achieved due to the insufficient sample volumes available. Conclusion The Procleix Ultrio Elite assay proved to be specific, robust and rapid. Therefore, routine ID-NAT may also be feasible for organ and granulocyte donors. PMID:27403089

Role for human arylamine N-acetyltransferase 1 in the methionine salvage pathway.

PubMed

Witham, Katey L; Minchin, Rodney F; Butcher, Neville J

2017-02-01

The Phase II drug metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) has been implicated in the growth and survival of cancer cells, although the mechanisms that underlies these effects are unknown. Here, a focused metabolomics approach was used to identify changes in folate catabolism as well as the S-adenosylmethionine (SAM) cycle following NAT1 knockdown with shRNA. Although acetylation of the folate catabolite p-aminobenzoylglutamate (pABG) was significantly decreased, there were no changes in intracellular pABG or the various components of the SAM cycle. By contrast, the flux of homocysteine in the medium was different following NAT1 knockdown after the methionine content was exhausted suggesting a need for this metabolite in methionine synthesis. Analysis of the growth of various cancer cells in methylthioadenosine-supplemented medium showed that NAT1 knockdown inhibited the methionine salvage pathway in HT-29 cells but not in HeLa or MDA-MB-436 cells. The cause of this was a low level of expression of the isomerase MRI-1 in the HT-29 cells. Knocking down both NAT1 and MRI-1 in HeLa cells with siRNA further demonstrated a redundancy between these 2 enzymes, although direct isomerase activity by NAT1 could not be demonstrated. The present study has identified a novel endogenous role for human NAT1 that might explain some of its effects in cancer cell growth and survival. Copyright © 2016 Elsevier Inc. All rights reserved.

Solid-state NMR study of various mono- and divalent cation forms of the natural zeolite natrolite.

PubMed

Park, Min Bum; Vicente, Aurélie; Fernandez, Christian; Hong, Suk Bong

2013-05-28

Here we present the one-dimensional (29)Si and (27)Al MAS NMR and two-dimensional (27)Al MQMAS and DQF-STMAS NMR spectra of the monovalent (Na(+), K(+), Rb(+), Cs(+) and NH4(+)) and divalent (Ca(2+), Sr(2+) and Ba(2+)) cation forms of the natural zeolite natrolite (framework type NAT) with complete Si-Al ordering over the crystallographically distinct tetrahedral sites and with the same hydration state (hydrated, partially dehydrated or fully dehydrated). In the case of monovalent cation-exchanged natrolites, the differences in their crystal symmetry evidenced by (29)Si MAS NMR were found to be in good agreement with those determined by crystallographic analyses. However, (27)Al DQF-STMAS NMR spectroscopy shows the presence of two distinct Al sites in dehydrated K-NAT, Rb-NAT and NH4-NAT, suggesting that their actual crystal symmetry is lower than the reported one (i.e., orthorhombic Fdd2). The MAS NMR results also show that the space group of hydrated Ca-NAT is lower than that (monoclinic F1d1) of hydrated scolecite, the natural calcium counterpart of natrolite, which is also the case with hydrated Sr-NAT and Ba-NAT. We believe that the unexpected diversity in the crystal symmetry of natrolite caused by exchange of various mono- and divalent ions, as well as by dehydration, may be inherently due to the high framework flexibility of this natural zeolite.

SP-100 GES/NAT radiation shielding systems design and development testing

NASA Astrophysics Data System (ADS)

Disney, Richard K.; Kulikowski, Henry D.; McGinnis, Cynthia A.; Reese, James C.; Thomas, Kevin; Wiltshire, Frank

1991-01-01

Advanced Energy Systems (AES) of Westinghouse Electric Corporation is under subcontract to the General Electric Company to supply nuclear radiation shielding components for the SP-100 Ground Engineering System (GES) Nuclear Assembly Test to be conducted at Westinghouse Hanford Company at Richland, Washington. The radiation shielding components are integral to the Nuclear Assembly Test (NAT) assembly and include prototypic and non-prototypic radiation shielding components which provide prototypic test conditions for the SP-100 reactor subsystem and reactor control subsystem components during the GES/NAT operations. W-AES is designing three radiation shield components for the NAT assembly; a prototypic Generic Flight System (GFS) shield, the Lower Internal Facility Shield (LIFS), and the Upper Internal Facility Shield (UIFS). This paper describes the design approach and development testing to support the design, fabrication, and assembly of these three shield components for use within the vacuum vessel of the GES/NAT. The GES/NAT shields must be designed to operate in a high vacuum which simulates space operations. The GFS shield and LIFS must provide prototypic radiation/thermal environments and mechanical interfaces for reactor system components. The NAT shields, in combination with the test facility shielding, must provide adequate radiation attenuation for overall test operations. Special design considerations account for the ground test facility effects on the prototypic GFS shield. Validation of the GFS shield design and performance will be based on detailed Monte Carlo analyses and developmental testing of design features. Full scale prototype testing of the shield subsystems is not planned.

West Nile virus blood transfusion-related infection despite nucleic acid testing.

PubMed

Macedo de Oliveira, Alexandre; Beecham, Brady D; Montgomery, Susan P; Lanciotti, Robert S; Linnen, Jeffrey M; Giachetti, Cristina; Pietrelli, Larry A; Stramer, Susan L; Safranek, Thomas J

2004-12-01

A case of West Nile virus (WNV) encephalitis associated with transfusion of blood that did not react when tested for WNV by minipool (MP) nucleic acid testing (NAT) is described. A Nebraska man developed clinical encephalitis 13 days after surgery and transfusion of 26 blood components. Antibody testing confirmed WNV infection. An investigation was initiated to determine the source of this infection. The patient's family members were interviewed to identify risk factors for WNV infection. Residual samples were retested for WNV RNA using transcription-mediated amplification (TMA) assay and two polymerase chain reaction (PCR) assays. Blood donors' follow-up serum samples were collected. All samples were tested for WNV-specific immunoglobulin M antibodies. The patient's family denied recent mosquito exposure. The 20 blood components collected after July 2003 did not react when tested for WNV in a six-member MP-NAT at the time of donation. Retrospective individual testing identified one sample as WNV-reactive by the TMA assay and one of the PCR assays. Seroconversion was demonstrated in the donor associated with this sample. WNV RNA detection by individual donation NAT demonstrates viremic blood escaping MP-NAT and supports transfusion-related WNV transmission. MP-NAT may not detect all WNV-infected blood donors, allowing WNV transmission to continue at low levels. WNV NAT assays might vary in sensitivity and pooling donations could further impact test performance. Understanding MP NAT limitations can improve strategies to maintain safety of the blood supply in the United States.

Reconstructing Plate Motions on Europa with GPlates

NASA Astrophysics Data System (ADS)

Cutler, B. B.; Collins, G. C.; Prockter, L. M.; Patterson, G.; Kattenhorn, S. A.; Rhoden, A.; Cooper, C. M.

2015-12-01

Observations of past plate tectonic - like motions in Europa's icy lithosphere have been reported in previous studies. Quantifying the nature, age, and amount of plate motion is important for geophysical models of Europa's ice shell and for astrobiology, since subsumed pates could drive the flow of nutrients into the subsurface ocean. We have used GPlates software (Williams et al., GSA Today 2012) and a mosaic of regional-resolution Galileo SSI data from orbits E11, E15, E17, and E19 to make interactive reconstructions of both the Northern Falga region (60N, 220W) and the Castalia Macula region (0N, 225W). The advantage of this method is that plate motions are calculated on a sphere, while still maintaining the original Galileo image pieces in their proper geographic locations. Previous work on the Castalia Macula region (Patterson et al. J.Struct.Geol. 2006) and the adjacent Phaidra Linea region (Patterson and Ernst, LPSC 2011) found offsets along spreading boundaries, and then calculated the best fit finite rotations to close those offsets. Though this method is mathematically rigorous and gives a statistical goodness of fit, it is not easy to test multiple hypotheses for candidate piercing points or divisions of candidate plate boundaries. Through the interactive environment, we found that we could better account for observed offsets in this region by breaking it into 32 different plates. Patterson and Ernst broke the Phaidra region into 6 plates which exhibited nonrigid behavior, where our study breaks it into 16 rigid plates. The Northern Falga Regio area is interesting due to the potential for large amounts of subsumption of Europa's icy crust in this location. The previous reconstruction (Kattenhorn and Prockter, Nat.Geosci. 2014) was based on planar geometry, and we have replicated these results using a spherically-based reconstruction. We will present the plate maps and reconstructions for both of these regions, along with the best fit rotation poles.

DEVELOPMENT OF HIGHLY-EFFICIENT AQUAPORIN-BASED WATER TREATMENTMEMBRANES FOR DESALINATION AND CONTAMINANT REMOVAL

EPA Science Inventory

As an outcome of this project data on the applicability of protein polymer membranes for application to water desalination will be obtained. This will provide information on the stability and permeability of these membranes under simulated desalination conditions. The struct...

Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity.

PubMed

Sharma, Surendra K; Jha, Brajesh Kumar; Sharma, Abhishek; Sreenivas, V; Upadhyay, Vishwanath; Jaisinghani, Chandrita; Singla, Rohit; Mishra, Hemant Kumar; Soneja, Manish

2016-12-01

The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH). In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8%) and non-DIH (77.2%) patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56%) group as compared to non-DIH (39%) group (odds ratio 2.02; P=0.006). The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

The Hamburg Selection Procedure for Dental Students – Introduction of the HAM-Nat as subject-specific test for study aptitude

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2013-01-01

Introduction: The present study examines the question whether the selection of dental students should be based solely on average school-leaving grades (GPA) or whether it could be improved by using a subject-specific aptitude test. Methods: The HAM-Nat Natural Sciences Test was piloted with freshmen during their first study week in 2006 and 2007. In 2009 and 2010 it was used in the dental student selection process. The sample size in the regression models varies between 32 and 55 students. Results: Used as a supplement to the German GPA, the HAM-Nat test explained up to 12% of the variance in preclinical examination performance. We confirmed the prognostic validity of GPA reported in earlier studies in some, but not all of the individual preclinical examination results. Conclusion: The HAM-Nat test is a reliable selection tool for dental students. Use of the HAM-Nat yielded a significant improvement in prediction of preclinical academic success in dentistry. PMID:24282449

Measurement of the natHf(d,x)177Ta cross section and impact of erroneous gamma-ray intensities

NASA Astrophysics Data System (ADS)

Simonelli, F.; Abbas, K.; Bulgheroni, A.; Pommé, S.; Altzitzoglou, T.; Suliman, G.

2012-08-01

In this work, excitation functions for deuteron-induced reactions on natural hafnium have been measured in the energy range 7-17 MeV, using the stacked-foil technique. Particular attention has been paid to the reaction natHf(d,x)177Ta, because reported γ-ray intensities have been found to be in disagreement with previously published data. This discrepancy is due to an error in the 2003 ENSDF absolute γ-ray intensities of 177Hf following the decay of 177Ta, which are about a factor of three higher compared to other available data. As a consquence, some peer reviewed papers reporting on natHf(d,x)177Ta, and also on natHf(p,x) 177Ta and natW(p,x) 177Ta, need to be reviewed. An upcoming re-evaluation of the 177Ta decay data shows new significant changes in the absolute γ-ray intensities, which in turn will affect again the 177Ta producing cross sections.

The BiolAD-DB system : an informatics system for clinical and genetic data.

PubMed

Nielsen, David A; Leidner, Marty; Haynes, Chad; Krauthammer, Michael; Kreek, Mary Jeanne

2007-01-01

The Biology of Addictive Diseases-Database (BiolAD-DB) system is a research bioinformatics system for archiving, analyzing, and processing of complex clinical and genetic data. The database schema employs design principles for handling complex clinical information, such as response items in genetic questionnaires. Data access and validation is provided by the BiolAD-DB client application, which features a data validation engine tightly coupled to a graphical user interface. Data integrity is provided by the password-protected BiolAD-DB SQL compliant server and database. BiolAD-DB tools further provide functionalities for generating customized reports and views. The BiolAD-DB system schema, client, and installation instructions are freely available at http://www.rockefeller.edu/biolad-db/.

Toxicokinetics of novel psychoactive substances: characterization of N-acetyltransferase (NAT) isoenzymes involved in the phase II metabolism of 2C designer drugs.

PubMed

Meyer, Markus R; Robert, Anja; Maurer, Hans H

2014-06-05

The 2,5-dimethoxyphenethylamine-derived designer drugs (so-called "2Cs") recently became of great importance on the illicit drug market as stimulating hallucinogens. They are distributed and consumed as "novel psychoactive substances" (NPS) without any safety testing at the forefront. As previous studies have shown, the 2Cs are mainly metabolized by O-demethylation, N-acetylation, or deamination. Therefore, the aim of this study was to elucidate the role of the recombinant human N-acetyltransferase (NAT) isoforms 1 and 2 in the phase II metabolism of 2Cs. For these studies, cDNA-expressed recombinant human NATs were used and formation of metabolites after incubation was measured using GC-MS. NAT2 could be shown to be the only isoform catalyzing the reaction in vitro, hence it should be the only relevant enzyme for in vivo acetylation. In general, all metabolite formation reactions followed classic Michaelis-Menten kinetics and the affinity to human NAT2 was increasing with the volume of the 4-substituent. In consequence, a slow acetylator phenotype or inhibition of NAT2 could lead to decreased N-acetylation and might lead to an increased risk of side effects caused by these novel psychoactive substances. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Crystal structure of bacillus subtilis YdaF protein : a putative ribosomal N-acetyltransferase.

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

Brunzelle, J. S.; Wu, R.; Korolev, S. V.

2004-12-01

Comparative sequence analysis suggests that the ydaF gene encodes a protein (YdaF) that functions as an N-acetyltransferase, more specifically, a ribosomal N-acetyltransferase. Sequence analysis using basic local alignment search tool (BLAST) suggests that YdaF belongs to a large family of proteins (199 proteins found in 88 unique species of bacteria, archaea, and eukaryotes). YdaF also belongs to the COG1670, which includes the Escherichia coli RimL protein that is known to acetylate ribosomal protein L12. N-acetylation (NAT) has been found in all kingdoms. NAT enzymes catalyze the transfer of an acetyl group from acetyl-CoA (AcCoA) to a primary amino group. Formore » example, NATs can acetylate the N-terminal {alpha}-amino group, the {epsilon}-amino group of lysine residues, aminoglycoside antibiotics, spermine/speridine, or arylalkylamines such as serotonin. The crystal structure of the alleged ribosomal NAT protein, YdaF, from Bacillus subtilis presented here was determined as a part of the Midwest Center for Structural Genomics. The structure maintains the conserved tertiary structure of other known NATs and a high sequence similarity in the presumed AcCoA binding pocket in spite of a very low overall level of sequence identity to other NATs of known structure.« less

The Neighborhood Auditing Tool: A Hybrid Interface for Auditing the UMLS

PubMed Central

Morrey, C. Paul; Geller, James; Halper, Michael; Perl, Yehoshua

2009-01-01

The UMLS’s integration of more than 100 source vocabularies, not necessarily consistent with one another, causes some inconsistencies. The purpose of auditing the UMLS is to detect such inconsistencies and to suggest how to resolve them while observing the requirement of fully representing the content of each source in the UMLS. A software tool, called the Neighborhood Auditing Tool (NAT), that facilitates UMLS auditing is presented. The NAT supports “neighborhood-based” auditing, where, at any given time, an auditor concentrates on a single focus concept and one of a variety of neighborhoods of its closely related concepts. Typical diagrammatic displays of concept networks have a number of shortcomings, so the NAT utilizes a hybrid diagram/text interface that features stylized neighborhood views which retain some of the best features of both the diagrammatic layouts and text windows while avoiding the shortcomings. The NAT allows an auditor to display knowledge from both the Metathesaurus (concept) level and the Semantic Network (semantic type) level. Various additional features of the NAT that support the auditing process are described. The usefulness of the NAT is demonstrated through a group of case studies. Its impact is tested with a study involving a select group of auditors. PMID:19475725

A new approach to the characterization of subtle errors in everyday action: implications for mild cognitive impairment.

PubMed

Seligman, Sarah C; Giovannetti, Tania; Sestito, John; Libon, David J

2014-01-01

Mild functional difficulties have been associated with early cognitive decline in older adults and increased risk for conversion to dementia in mild cognitive impairment, but our understanding of this decline has been limited by a dearth of objective methods. This study evaluated the reliability and validity of a new system to code subtle errors on an established performance-based measure of everyday action and described preliminary findings within the context of a theoretical model of action disruption. Here 45 older adults completed the Naturalistic Action Test (NAT) and neuropsychological measures. NAT performance was coded for overt errors, and subtle action difficulties were scored using a novel coding system. An inter-rater reliability coefficient was calculated. Validity of the coding system was assessed using a repeated-measures ANOVA with NAT task (simple versus complex) and error type (overt versus subtle) as within-group factors. Correlation/regression analyses were conducted among overt NAT errors, subtle NAT errors, and neuropsychological variables. The coding of subtle action errors was reliable and valid, and episodic memory breakdown predicted subtle action disruption. Results suggest that the NAT can be useful in objectively assessing subtle functional decline. Treatments targeting episodic memory may be most effective in addressing early functional impairment in older age.

The importance of surgeon involvement in the evaluation of non-accidental trauma patients.

PubMed

Larimer, Emily L; Fallon, Sara C; Westfall, Jaimee; Frost, Mary; Wesson, David E; Naik-Mathuria, Bindi J

2013-06-01

Non-Accidental Trauma (NAT) is a significant cause of childhood morbidity and mortality, causing 50% of trauma-related deaths at our institution. Our purpose was to evaluate the necessity of primary surgical evaluation and admission to the trauma service for children presenting with NAT. We reviewed all NAT patients from 2007-2011. Injury types, demographic data, and hospitalization information were collected. Comparisons to accidental trauma (AT) patients were made using Wilcoxon rank sum and Student's t tests. We identified 267 NAT patients presenting with 473 acute injuries. Injuries in NAT patients were more severe than in AT patients, and Injury Severity Scores, ICU admission rates, and mortality were all significantly (p<0.001) higher. The majority suffered from polytrauma. Multiple areas of injury were seen in patients with closed head injuries (72%), extremity fractures (51%), rib fractures (82%), and abdominal/thoracic trauma (80%). Despite these complex injury patterns, only 56% received surgical consults, resulting in potential delays in diagnosis, as 24% of abdominal CT scans were obtained >12 hours after hospitalization. Given the high incidence of polytrauma in NAT patients, prompt surgical evaluation is necessary to determine the scope of injury. Admission to the trauma service and a thorough tertiary survey should be considered for all patients. Copyright © 2013 Elsevier Inc. All rights reserved.

Non-accidental Trauma Injury Patterns and Outcomes: A Single Institutional Experience.

PubMed

Ward, Austin; Iocono, Joseph A; Brown, Samuel; Ashley, Phillip; Draus, John M

2015-09-01

Non-accidental trauma (NAT) victims account for a significant percentage of our pediatric trauma population. We sought to better understand the injury patterns and outcomes of NAT victims who were treated at our level I pediatric trauma center. Trauma registry data were used to identify NAT victims between January 2008 and December 2012. Demographic data, injury severity, hospital course, and outcomes were evaluated. One hundred and eighty-eight cases of suspected NAT were identified. Children were mostly male and white. The median age was 1.1 years; the median Injury Severity Score was 9. Traumatic brain injuries, lower extremity fractures, and skull fractures were the most common injuries. Twenty-seven per cent required medical procedures; most were performed by orthopedic surgery. Twenty-four per cent required admission to the pediatric intensive care unit. The median length of stay was two days. The mortality rate was 9.6 per cent. We generated a hot spot map of our catchment area and identified areas of our state where NAT occurs at increased rates. NAT victims sustain significant morbidity and mortality. Due to the severity of injuries, pediatric trauma surgeons should be involved in the evaluation and management of these children. Much work is needed to prevent the death and disability incurred by victims of child abuse.

An Acetyltransferase Conferring Tolerance to Toxic Aromatic Amine Chemicals

PubMed Central

Martins, Marta; Rodrigues-Lima, Fernando; Dairou, Julien; Lamouri, Aazdine; Malagnac, Fabienne; Silar, Philippe; Dupret, Jean-Marie

2009-01-01

Aromatic amines (AA) are a major class of environmental pollutants that have been shown to have genotoxic and cytotoxic potentials toward most living organisms. Fungi are able to tolerate a diverse range of chemical compounds including certain AA and have long been used as models to understand general biological processes. Deciphering the mechanisms underlying this tolerance may improve our understanding of the adaptation of organisms to stressful environments and pave the way for novel pharmaceutical and/or biotechnological applications. We have identified and characterized two arylamine N-acetyltransferase (NAT) enzymes (PaNAT1 and PaNAT2) from the model fungus Podospora anserina that acetylate a wide range of AA. Targeted gene disruption experiments revealed that PaNAT2 was required for the growth and survival of the fungus in the presence of toxic AA. Functional studies using the knock-out strains and chemically acetylated AA indicated that tolerance of P. anserina to toxic AA was due to the N-acetylation of these chemicals by PaNAT2. Moreover, we provide proof-of-concept remediation experiments where P. anserina, through its PaNAT2 enzyme, is able to detoxify the highly toxic pesticide residue 3,4-dichloroaniline in experimentally contaminated soil samples. Overall, our data show that a single xenobiotic-metabolizing enzyme can mediate tolerance to a major class of pollutants in a eukaryotic species. These findings expand the understanding of the role of xenobiotic-metabolizing enzyme and in particular of NATs in the adaptation of organisms to their chemical environment and provide a basis for new systems for the bioremediation of contaminated soils. PMID:19416981

Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

PubMed Central

Ramírez-Alcántara, Verónica

2014-01-01

Pharmacotherapy based on 5-aminosalicylic acid (5-ASA) is a preferred treatment for ulcerative colitis, but variable patient response to this therapy is observed. Inflammation can affect therapeutic outcomes by regulating the expression and activity of drug-metabolizing enzymes; its effect on 5-ASA metabolism by the colonic arylamine N-acetyltransferase (NAT) enzyme isoforms is not firmly established. We examined if inflammation affects the capacity for colonic 5-ASA metabolism and NAT enzyme expression. 5-ASA metabolism by colonic mucosal homogenates was directly measured with a novel fluorimetric rate assay. 5-ASA metabolism reported by the assay was dependent on Ac-CoA, inhibited by alternative NAT substrates (isoniazid, p-aminobenzoylglutamate), and saturable with Km (5-ASA) = 5.8 μM. A mouse model of acute dextran sulfate sodium (DSS) colitis caused pronounced inflammation in central and distal colon, and modest inflammation of proximal colon, defined by myeloperoxidase activity and histology. DSS colitis reduced capacity for 5-ASA metabolism in central and distal colon segments by 52 and 51%, respectively. Use of selective substrates of NAT isoforms to inhibit 5-ASA metabolism suggested that mNAT2 mediated 5-ASA metabolism in normal and colitis conditions. Western blot and real-time RT-PCR identified that proximal and distal mucosa had a decreased mNAT2 protein-to-mRNA ratio after DSS. In conclusion, an acute colonic inflammation impairs the expression and function of mNAT2 enzyme, thereby diminishing the capacity for 5-ASA metabolism by colonic mucosa. PMID:24742986

SP-100 GES/NAT radiation shielding systems design and development testing

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

Disney, R.K.; Kulikowski, H.D.; McGinnis, C.A.

1991-01-10

Advanced Energy Systems (AES) of Westinghouse Electric Corporation is under subcontract to the General Electric Company to supply nuclear radiation shielding components for the SP-100 Ground Engineering System (GES) Nuclear Assembly Test to be conducted at Westinghouse Hanford Company at Richland, Washington. The radiation shielding components are integral to the Nuclear Assembly Test (NAT) assembly and include prototypic and non-prototypic radiation shielding components which provide prototypic test conditions for the SP-100 reactor subsystem and reactor control subsystem components during the GES/NAT operations. W-AES is designing three radiation shield components for the NAT assembly; a prototypic Generic Flight System (GFS) shield,more » the Lower Internal Facility Shield (LIFS), and the Upper Internal Facility Shield (UIFS). This paper describes the design approach and development testing to support the design, fabrication, and assembly of these three shield components for use within the vacuum vessel of the GES/NAT. The GES/NAT shields must be designed to operate in a high vacuum which simulates space operations. The GFS shield and LIFS must provide prototypic radiation/thermal environments and mechanical interfaces for reactor system components. The NAT shields, in combination with the test facility shielding, must provide adequate radiation attenuation for overall test operations. Special design considerations account for the ground test facility effects on the prototypic GFS shield. Validation of the GFS shield design and performance will be based on detailed Monte Carlo analyses and developmental testing of design features. Full scale prototype testing of the shield subsystems is not planned.« less

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy.

PubMed

Azuma, Junichi; Ohno, Masako; Kubota, Ryuji; Yokota, Soichiro; Nagai, Takayuki; Tsuyuguchi, Kazunari; Okuda, Yasuhisa; Takashima, Tetsuya; Kamimura, Sayaka; Fujio, Yasushi; Kawase, Ichiro

2013-05-01

This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2 4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2 4: intermediate acetylators; 2.5 mg/kg, patients without NAT2 4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the 8th week. One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

N-acetyltransferase (nat) Is a Critical Conjunct of Photoperiodism between the Circadian System and Endocrine Axis in Antheraea pernyi

PubMed Central

Bembenek, Jadwiga; Hiragaki, Susumu; Suzuki, Takeshi; Takeda, Makio

2014-01-01

Since its discovery in 1923, the biology of photoperiodism remains a mystery in many ways. We sought the link connecting the circadian system to an endocrine switch, using Antheraea pernyi. PER-, CLK- and CYC-ir were co-expressed in two pairs of dorsolateral neurons of the protocerebrum, suggesting that these are the circadian neurons that also express melatonin-, NAT- and HIOMT-ir. The results suggest that a melatonin pathway is present in the circadian neurons. Melatonin receptor (MT2 or MEL-1B-R)-ir in PTTH-ir neurons juxtaposing clock neurons suggests that melatonin gates PTTH release. RIA showed a melatonin rhythm with a peak four hours after lights off in adult brain both under LD16∶8 (LD) and LD12∶12 (SD), and both the peak and the baseline levels were higher under LD than SD, suggesting a photoperiodic influence. When pupae in diapause were exposed to 10 cycles of LD, or stored at 4°C for 4 months under constant darkness, an increase of NAT activity was observed when PTTH released ecdysone. DNA sequence upstream of nat contained E-boxes to which CYC/CLK could bind, and nat transcription was turned off by clk or cyc dsRNA. dsRNANAT caused dysfunction of photoperiodism. dsRNAPER upregulated nat transcription as anticipated, based on findings in the Drosophila melanogaster circadian system. Transcription of nat, cyc and clk peaked at ZT12. RIA showed that dsRNANAT decreased melatonin while dsRNAPER increased melatonin. Thus nat, a clock controlled gene, is the critical link between the circadian clock and endocrine switch. MT-binding may release PTTH, resulting in termination of diapause. This study thus examined all of the basic functional units from the clock: a photoperiodic counter as an accumulator of mRNANAT, to endocrine switch for photoperiodism in A. pernyi showing this system is self-complete without additional device especially for photoperiodism. PMID:24667367

Arylamine N-Acetyltransferase 2 (NAT2) Genetic Diversity and Traditional Subsistence: A Worldwide Population Survey

PubMed Central

Sabbagh, Audrey; Darlu, Pierre; Crouau-Roy, Brigitte; Poloni, Estella S.

2011-01-01

Arylamine N-acetyltransferase 2 (NAT2) is involved in human physiological responses to a variety of xenobiotic compounds, including common therapeutic drugs and exogenous chemicals present in the diet and the environment. Many questions remain about the evolutionary mechanisms that have led to the high prevalence of slow acetylators in the human species. Evidence from recent surveys of NAT2 gene variation suggests that NAT2 slow-causing variants might have become targets of positive selection as a consequence of the shift in modes of subsistence and lifestyle in human populations in the last 10,000 years. We aimed to test more extensively the hypothesis that slow acetylation prevalence in humans is related to the subsistence strategy adopted by the past populations. To this end, published frequency data on the most relevant genetic variants of NAT2 were collected from 128 population samples (14,679 individuals) representing different subsistence modes and dietary habits, allowing a thorough analysis at both a worldwide and continent scale. A significantly higher prevalence of the slow acetylation phenotype was observed in populations practicing farming (45.4%) and herding (48.2%) as compared to populations mostly relying on hunting and gathering (22.4%) (P = 0.0007). This was closely mirrored by the frequency of the slow 590A variant that was found to occur at a three-fold higher frequency in food producers (25%) as compared to hunter-gatherers (8%). These findings are consistent with the hypothesis that the Neolithic transition to subsistence economies based on agricultural and pastoral resources modified the selective regime affecting the NAT2 acetylation pathway. Furthermore, the vast amount of data collected enabled us to provide a comprehensive and up-to-date description of NAT2 worldwide genetic diversity, thus building up a useful resource of frequency data for further studies interested in epidemiological or anthropological research questions involving NAT2. PMID:21494681

Fundamental Studies on Crashworthiness Design with Uncertainties in the System

DTIC Science & Technology

2005-01-01

studied; examples include using the Response Surface Methods (RSM) and Design of Experiment (DOE) [2-4]. Space Mapping (SM) is another practical...Exposed to Impact Load Using a Space Mapping Technique,” Struct. Multidisc. Optim., Vol. 27, pp. 411-420 (2004). 6. Mayer, R. R., Kikuchi, N. and Scott

Fundamental Studies on Crashworthiness Design with Uncertainties in the System

DTIC Science & Technology

2005-01-01

studied; examples include using the Response Surface Methods (RSM) and Design of Experiment (DOE) [2-4]. Space Mapping (SM) is another practical...to Impact Load Using a Space Mapping Technique," Struct. Multidisc. Optim., Vol. 27, pp. 411-420 (2004). 6. Mayer, R. R., Kikuchi, N. and Scott, R

Scaling Concolic Execution of Binary Programs for Security Applications

DTIC Science & Technology

2013-08-01

Byte Array “<><><>” “<>” (89 times) 4/5 672 1 Sendmail 2 struct passwd (Linux) (“”,“root”,0,0,“root”,“”,“”) (“”,“root”,0,0,“rootroo”,“”,“”) 1/1 526

PKSOI Bulletin. Volume 2, Issue 4, July 2010

DTIC Science & Technology

2010-07-01

are a “ blogger ” and would like to check out our blogs related to Peace and Stability Operations please visit our website and make comments. You may...leaders and officials. In several instances, the USG had con- structed beautiful facilities-a school and a clinic-without engaging sufficiently with

Listeria monocytogenes DNA glycosylase AdiP affects flagellar motility, biofilm formation, virulence, and stress responses

USDA-ARS?s Scientific Manuscript database

The temperature-dependent alteration of flagellar motility gene expression is critical for the foodborne pathogen Listeria monocytogenes to respond to a changing environment. In this study, a genetic determinant, L. monocytogenes f2365_0220 (lmof2365_0220), encoding a putative protein that is struct...

Corrigendum to ;Monoalkylated barbiturate derivatives: X-ray crystal structure, theoretical studies, and biological activities; [J. Mol. Struct. 1141 (2017) 624-633

NASA Astrophysics Data System (ADS)

Barakat, Assem; Al-Majid, Abdullah Mohammed; Soliman, Saied M.; Islam, Mohammad Shahidul; Ghawas, Hussain Mansur; Yousuf, Sammer; Choudhary, M. Iqbal; Wadood, Abdul

2017-09-01

;The correct CCDC reference for the compound 3k is 1546475 instead of 1024287 as mentioned in the text on page 625. The authors regret this error and would like to apologize for any inconvenience caused to anyone.;

Measurement of activation cross-section of long-lived products in deuteron induced nuclear reactions on palladium in the 30-50MeV energy range.

PubMed

Ditrói, F; Tárkányi, F; Takács, S; Hermanne, A; Ignatyuk, A V

2017-10-01

Excitation functions were measured in the 31-49.2MeV energy range for the nat Pd(d,xn) 111,110m,106m,105,104g,103 Ag, nat Pd(d,x) 111m,109,101,100 Pd, nat Pd(d,x), 105,102m,102g,101m,101g,100,99m,99g Rh and nat Pd(d,x) 103,97 Ru nuclear reactions by using the stacked foil irradiation technique. The experimental results are compared with our previous results and with the theoretical predictions calculated with the ALICE-D, EMPIRE-D and TALYS (TENDL libraries) codes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Computational systems chemical biology.

PubMed

Oprea, Tudor I; May, Elebeoba E; Leitão, Andrei; Tropsha, Alexander

2011-01-01

There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology (SCB) (Nat Chem Biol 3: 447-450, 2007).The overarching goal of computational SCB is to develop tools for integrated chemical-biological data acquisition, filtering and processing, by taking into account relevant information related to interactions between proteins and small molecules, possible metabolic transformations of small molecules, as well as associated information related to genes, networks, small molecules, and, where applicable, mutants and variants of those proteins. There is yet an unmet need to develop an integrated in silico pharmacology/systems biology continuum that embeds drug-target-clinical outcome (DTCO) triplets, a capability that is vital to the future of chemical biology, pharmacology, and systems biology. Through the development of the SCB approach, scientists will be able to start addressing, in an integrated simulation environment, questions that make the best use of our ever-growing chemical and biological data repositories at the system-wide level. This chapter reviews some of the major research concepts and describes key components that constitute the emerging area of computational systems chemical biology.

Detection of occult hepatitis B and window period infection among blood donors by individual donation nucleic acid testing in a tertiary care center in South India.

PubMed

Keechilot, Cinzia S; Shenoy, Veena; Kumar, Anil; Biswas, Lalitha; Vijayrajratnam, Sukhithasri; Dinesh, Kavitha; Nair, Prem

With the introduction of highly sensitive hepatitis B surface antigen immunoassay, transfusion associated HBV infection have reduced drastically but they still tend to occur due to blood donors with occult hepatitis B infection (OBI) and window period (WP) infection. Sera from, 24338 healthy voluntary blood donors were screened for HBsAg, HIV and HCV antibody using Vitros Enhanced Chemiluminescent Immunoassay. The median age of the donor population was 30 (range 18-54) with male preponderance (98%). All serologically negative samples were screened by nucleic acid testing (NAT) for viral DNA and RNA. NAT-positive samples were subjected to discriminatory NAT for HBV, HCV, and HIV and all samples positive for HBV DNA were tested for anti-HBc, anti-HBs, HBeAg. Viral load was determined using artus HBV RG PCR Kit. Of the 24,338 donors screened, 99.81% (24292/24338) were HBsAg negative of which NAT was positive for HBV DNA in 0.0205% (5/24292) donors. Four NAT positive donors had viral load of <200 IU/ml making them true cases of OBI. One NAT positive donor was negative for all antibodies making it a case of WP infection. Among OBI donors, 75% (3/4) were immune and all were negative for HBeAg. Precise HBV viral load could not be determined in all (5/5) NAT positive donors due to viral loads below the detection limit of the artus HBV RG PCR Kit. The overall incidence of OBI and WP infections was found to be low at 1 in 6503 and 1 in 24214 donations, respectively. More studies are needed to determine the actual burden of WP infections in Indian blood donors.

Association Between N-acetyltransferase 2 Polymorphism and Bladder Cancer Risk: Results From Studies of the Past Decade and a Meta-Analysis.

PubMed

Wu, Haoran; Wang, Xugang; Zhang, Liang; Mo, Naixin; Lv, Zhong

2016-04-01

Numerous studies have identified that the slow acetylation status of N-acetyltransferase 2 (NAT2) is associated with an elevated bladder cancer risk. However, the results remain inconclusive. The aim of our study was to evaluate the effect of NAT2 acetylation status in patients with bladder cancer. Electronic databases were searched to retrieve related studies published in the past decade. The pooled odds ratio (OR) with its 95% confidence interval (CI) was used to calculate the strength of this relationship. Overall, a total of 18 studies were selected for the analysis, which included 4473 bladder cancer cases and 7204 matched controls. Our result showed that the NAT2 slow acetylation phenotypes were significantly associated with an increased risk of bladder cancer compared with the rapid phenotypes (OR, 1.56; 95% CI, 1.33-1.82; P < .00001) in a random-effect model. This significant association was also found in a subgroup analysis of ethnicity (P < .05). Furthermore, the NAT2 slow phenotypes also significantly increased the risk of bladder cancer in smokers (OR, 0.75; 95% CI, 0.62-0.90; P = .002). However, no correlation was found between the combined effect of NAT2 slow phenotypes and gender with bladder cancer risk (OR, 0.89; 95% CI, 0.28-2.78; P = .84). In conclusion, our results suggest that the NAT2 slow acetylator, in particular, the NAT2 slow acetylator combined with smoking, are associated with an increased bladder cancer risk. Future well-designed studies with large populations and more ethnicities are needed to clarify this association further. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular Characterization of a Novel N-Acetyltransferase from Chryseobacterium sp.

PubMed Central

Yoshida, Kenji; Tanaka, Kosei; Yoshida, Ken-ichi

2014-01-01

N-Acetyltransferase from Chryseobacterium sp. strain 5-3B is an acetyl coenzyme A (acetyl-CoA)-dependent enzyme that catalyzes the enantioselective transfer of an acetyl group from acetyl-CoA to the amino group of l-2-phenylglycine to produce (2S)-2-acetylamino-2-phenylacetic acid. We purified the enzyme from strain 5-3B and deduced the N-terminal amino acid sequence. The gene, designated natA, was cloned with two other hypothetical protein genes; the three genes probably form a 2.5-kb operon. The deduced amino acid sequence of NatA showed high levels of identity to sequences of putative N-acetyltransferases of Chryseobacterium spp. but not to other known arylamine and arylalkylamine N-acetyltransferases. Phylogenetic analysis indicated that NatA forms a distinct lineage from known N-acetyltransferases. We heterologously expressed recombinant NatA (rNatA) in Escherichia coli and purified it. rNatA showed high activity for l-2-phenylglycine and its chloro- and hydroxyl-derivatives. The Km and Vmax values for l-2-phenylglycine were 0.145 ± 0.026 mM and 43.6 ± 2.39 μmol · min−1 · mg protein−1, respectively. The enzyme showed low activity for 5-aminosalicylic acid and 5-hydroxytryptamine, which are reported as good substrates of a known arylamine N-acetyltransferase and an arylalkylamine N-acetyltransferase. rNatA had a comparatively broad acyl donor specificity, transferring acyl groups to l-2-phenylglycine and producing the corresponding 2-acetylamino-2-phenylacetic acids (relative activity with acetyl donors acetyl-CoA, propanoyl-CoA, butanoyl-CoA, pentanoyl-CoA, and hexanoyl-CoA, 100:108:122:10:<1). PMID:24375143

Risks on N-acetyltransferase 2 and bladder cancer: a meta-analysis.

PubMed

Zhu, Zongheng; Zhang, Jinshan; Jiang, Wei; Zhang, Xianjue; Li, Youkong; Xu, Xiaoming

2015-01-01

It is known that bladder cancer disease is closely related to aromatic amine compounds, which could cause cancer by regulating of N-acetylation and N-acetyltransferase 1 and 2 (NAT1 and NAT2). The NAT2 slowed acetylation and would increase the risk of bladder cancer, with tobacco smoke being regarded as a risk factor for this increased risk. However, the relationship between NAT2 slow acetylation and bladder cancer is still debatable at present. This study aims to explore preliminarily correlation of NAT2 slow acetylation and the risk of bladder cancer. The articles were searched from PubMed, Cochran, McGrane English databases, CBM, CNKI, and other databases. The extraction of bladder cancer patients and a control group related with the NAT2 gene were detected by the state, and the referenced articles and publications were also used for data retrieval. Using a random effects model, the model assumes that the studies included in the analysis cases belong to the overall population in the study of random sampling, and considering the variables within and between studies. Data were analyzed using STATA Version 6.0 software, using the META module. According to the inclusion and exclusion criteria of the literature study, 20 independent studies are included in this meta-analysis. The results showed that the individual differences of bladder cancer susceptibility might be part of the metabolism of carcinogens. Slow acetylation status of bladder cancer associated with the pooled odds ratio was 1.31 (95% confidence interval: 1.11-1.55). The status of NAT2 slow N-acetylation is associated with bladder cancer risks, and may increase the risk of bladder cancer.

An assessment of differences in costs and health benefits of serology and NAT screening of donations for blood transfusion in different Western countries.

PubMed

Janssen, M P; van Hulst, M; Custer, B

2017-08-01

The cost-utility of safety interventions is becoming increasingly important as a driver of implementation decisions. The aim of this study was to compare the cost-utility of different blood screening strategies in various settings, and to analyse the extent and cause of differences in health economic results. For eight Western countries (Australia, Canada, Denmark, Finland, France, The Netherlands, UK and the United States of America), data were collected on donor and recipient populations, blood products, screening tests, and on patient treatment practices and costs. An existing ISBT web-tool model was used to assess the cost-utility of various strategies for HIV, HCV and HBV screening. The cost-utility ratio of serology screening for these eight countries ranges between -11 000 and 92 000 US$ per QALY, and for NAT between -12 000 and 113 000 US$ per QALY when compared to no screening. Combined serology and NAT ranges between 600 and 217 000 US$ per QALY. The incremental cost-utility of NAT after implementation of serology screening ranges from 2 231 000 to 15 778 000 US$ per QALY. There are substantial differences in costs per QALY between countries for various HIV, HBV and HCV screening strategies. These differences are primarily caused by costs of screening tests and infection rates in the donor population. Within each country, similar cost per QALY results for serology and NAT compared to no screening, coupled with evidence of limited value of serology and NAT together prompts the need for further discussion on the acceptability of parallel testing by serology and NAT. © 2017 International Society of Blood Transfusion.

Regulation of an antisense RNA with the transition of neonatal to IIb myosin heavy chain during postnatal development and hypothyroidism in rat skeletal muscle

PubMed Central

Jiang, Weihua; Qin, Anqi X.; Bodell, Paul W.; Baldwin, Kenneth M.; Haddad, Fadia

2012-01-01

Postnatal development of fast skeletal muscle is characterized by a transition in expression of myosin heavy chain (MHC) isoforms, from primarily neonatal MHC at birth to primarily IIb MHC in adults, in a tightly coordinated manner. These isoforms are encoded by distinct genes, which are separated by ∼17 kb on rat chromosome 10. The neonatal-to-IIb MHC transition is inhibited by a hypothyroid state. We examined RNA products [mRNA, pre-mRNA, and natural antisense transcript (NAT)] of developmental and adult-expressed MHC genes (embryonic, neonatal, I, IIa, IIx, and IIb) at 2, 10, 20, and 40 days after birth in normal and thyroid-deficient rat neonates treated with propylthiouracil. We found that a long noncoding antisense-oriented RNA transcript, termed bII NAT, is transcribed from a site within the IIb-Neo intergenic region and across most of the IIb MHC gene. NATs have previously been shown to mediate transcriptional repression of sense-oriented counterparts. The bII NAT is transcriptionally regulated during postnatal development and in response to hypothyroidism. Evidence for a regulatory mechanism is suggested by an inverse relationship between IIb MHC and bII NAT in normal and hypothyroid-treated muscle. Neonatal MHC transcription is coordinately expressed with bII NAT. A comparative phylogenetic analysis also suggests that bII NAT-mediated regulation has been a conserved trait of placental mammals for most of the eutherian evolutionary history. The evidence in support of the regulatory model implicates long noncoding antisense RNA as a mechanism to coordinate the transition between neonatal and IIb MHC during postnatal development. PMID:22262309

Regulation of an antisense RNA with the transition of neonatal to IIb myosin heavy chain during postnatal development and hypothyroidism in rat skeletal muscle.

PubMed

Pandorf, Clay E; Jiang, Weihua; Qin, Anqi X; Bodell, Paul W; Baldwin, Kenneth M; Haddad, Fadia

2012-04-01

Postnatal development of fast skeletal muscle is characterized by a transition in expression of myosin heavy chain (MHC) isoforms, from primarily neonatal MHC at birth to primarily IIb MHC in adults, in a tightly coordinated manner. These isoforms are encoded by distinct genes, which are separated by ∼17 kb on rat chromosome 10. The neonatal-to-IIb MHC transition is inhibited by a hypothyroid state. We examined RNA products [mRNA, pre-mRNA, and natural antisense transcript (NAT)] of developmental and adult-expressed MHC genes (embryonic, neonatal, I, IIa, IIx, and IIb) at 2, 10, 20, and 40 days after birth in normal and thyroid-deficient rat neonates treated with propylthiouracil. We found that a long noncoding antisense-oriented RNA transcript, termed bII NAT, is transcribed from a site within the IIb-Neo intergenic region and across most of the IIb MHC gene. NATs have previously been shown to mediate transcriptional repression of sense-oriented counterparts. The bII NAT is transcriptionally regulated during postnatal development and in response to hypothyroidism. Evidence for a regulatory mechanism is suggested by an inverse relationship between IIb MHC and bII NAT in normal and hypothyroid-treated muscle. Neonatal MHC transcription is coordinately expressed with bII NAT. A comparative phylogenetic analysis also suggests that bII NAT-mediated regulation has been a conserved trait of placental mammals for most of the eutherian evolutionary history. The evidence in support of the regulatory model implicates long noncoding antisense RNA as a mechanism to coordinate the transition between neonatal and IIb MHC during postnatal development.

Identification of N-Acetyltaurine as a Novel Metabolite of Ethanol through Metabolomics-guided Biochemical Analysis*

PubMed Central

Shi, Xiaolei; Yao, Dan; Chen, Chi

2012-01-01

The influence of ethanol on the small molecule metabolome and the role of CYP2E1 in ethanol-induced hepatotoxicity were investigated using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics platform and Cyp2e1-null mouse model. Histological and biochemical examinations of ethanol-exposed mice indicated that the Cyp2e1-null mice were more resistant to ethanol-induced hepatic steatosis and transaminase leakage than the wild-type mice, suggesting CYP2E1 contributes to ethanol-induced toxicity. Metabolomic analysis of urinary metabolites revealed time- and dose-dependent changes in the chemical composition of urine. Along with ethyl glucuronide and ethyl sulfate, N-acetyltaurine (NAT) was identified as a urinary metabolite that is highly responsive to ethanol exposure and is correlated with the presence of CYP2E1. Subsequent stable isotope labeling analysis using deuterated ethanol determined that NAT is a novel metabolite of ethanol. Among three possible substrates of NAT biosynthesis (taurine, acetyl-CoA, and acetate), the level of taurine was significantly reduced, whereas the levels of acetyl-CoA and acetate were dramatically increased after ethanol exposure. In vitro incubation assays suggested that acetate is the main precursor of NAT, which was further confirmed by the stable isotope labeling analysis using deuterated acetate. The incubations of tissues and cellular fractions with taurine and acetate indicated that the kidney has the highest NAT synthase activity among the tested organs, whereas the cytosol is the main site of NAT biosynthesis inside the cell. Overall, the combination of biochemical and metabolomic analysis revealed NAT is a novel metabolite of ethanol and a potential biomarker of hyperacetatemia. PMID:22228769

Red meat intake, NAT2, and risk of colorectal cancer: A pooled analysis of 11 studies

PubMed Central

Ananthakrishnan, Ashwin N.; Du, Mengmeng; Berndt, Sonja I.; Brenner, Hermann; Caan, Bette J.; Casey, Graham; Chang-Claude, Jenny; Duggan, David; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hou, Lifang; Hsu, Li; Jenkins, Mark A.; Kraft, Peter; Ma, Jing; Nan, Hongmei; Newcomb, Polly A.; Ogino, Shuji; Potter, John D.; Seminara, Daniela; Slattery, Martha L.; Thornquist, Mark; White, Emily; Wu, Kana; Peters, Ulrike; Chan, Andrew T.

2014-01-01

Background Red meat intake has been associated with risk of colorectal cancer (CRC), potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and CRC has been inconsistently reported. Methods We used pooled individual-level data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. Results From 11 studies, 8,290 CRC cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of CRC compared to the lowest quartile (OR 1.41, 95%CI 1.29 – 1.55). However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with CRC in those with a rapid/intermediate NAT2 genotype (OR 1.38, 95%CI 1.20 – 1.59) as with a slow genotype (OR 1.43, 95%CI 1.28 – 1.61) (p- interaction=0.9). Conclusion We found that high red meat intake was associated with increased risk of CRC only from retrospective case-control studies and not modified by NAT2 enzyme activity. Impact Our results suggest no interaction between NAT2 genotype and red-meat intake in mediating risk of CRC. PMID:25342387

Reduced 4-Aminobiphenyl-Induced Liver Tumorigenicity but not DNA Damage in Arylamine N-Acetyltransferase Null Mice

PubMed Central

Sugamori, Kim S.; Brenneman, Debbie; Sanchez, Otto; Doll, Mark A.; Hein, David W.; Pierce, William M.; Grant, Denis M.

2012-01-01

The aromatic amine 4-aminobiphenyl (ABP) is a liver procarcinogen in mice, requiring enzymatic bioactivation to exert its tumorigenic effect. To assess the role of arylamine N-acetyltransferase (NAT)-dependent acetylation capacity in the risk for ABP-induced liver tumors, we compared 1-year liver tumor incidence following the postnatal exposure of wild-type and NAT-deficient Nat1/2(−/−) mice to ABP. At an ABP exposure of 1200 nmoles, male Nat1/2(−/−) mice had a liver tumor incidence of 36% compared to 69% in wild-type males, and at 600 nmoles there was a complete absence of tumors compared to 60% in wild-type mice. Only one female wild-type mouse had a tumor using this exposure protocol. However, levels of N-deoxyguanosin-8-yl-ABP-DNA adducts did not correlate with either the strain or sex differences in tumor incidence. These results suggest that female sex and NAT deficiency reduce risk for ABP-induced liver tumors, but by mechanisms unrelated to differences in DNA-damaging events. PMID:22193722

Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug-induced liver injury: a meta-analysis.

PubMed

Shi, Jing; Xie, Min; Wang, Jianmiao; Xu, Yongjian; Liu, Xiansheng

2015-12-01

This study aimed to evaluate the association between N-acetyltransferase 2 (NAT2) gene polymorphisms and the risk of antituberculosis drug-induced liver injury (ATLI). A meta-analysis was performed including 27 studies with 1289 cases and 5462 controls. Odds ratio with 95% CI was used to evaluate the strength of association. Our meta-analysis found that NAT2 slow acetylators were associated with increased risk of ATLI compared with fast and intermediate acetylators when standard dose of isoniazid was administrated (odds ratio: 3.08; 95% CI: 2.29-4.15). Individuals with NAT2 slow acetylators may have increased risk of ATLI when standard dose of isoniazid was used. Detection of NAT2 genotype may benefit to the prevention of ATLI.

A national look at carbon capture and storage-National carbon sequestration database and geographical information system (NatCarb)

USGS Publications Warehouse

Carr, T.R.; Iqbal, A.; Callaghan, N.; ,; Look, K.; Saving, S.; Nelson, K.

2009-01-01

The US Department of Energy's Regional Carbon Sequestration Partnerships (RCSPs) are responsible for generating geospatial data for the maps displayed in the Carbon Sequestration Atlas of the United States and Canada. Key geospatial data (carbon sources, potential storage sites, transportation, land use, etc.) are required for the Atlas, and for efficient implementation of carbon sequestration on a national and regional scale. The National Carbon Sequestration Database and Geographical Information System (NatCarb) is a relational database and geographic information system (GIS) that integrates carbon storage data generated and maintained by the RCSPs and various other sources. The purpose of NatCarb is to provide a national view of the carbon capture and storage potential in the U.S. and Canada. The digital spatial database allows users to estimate the amount of CO2 emitted by sources (such as power plants, refineries and other fossil-fuel-consuming industries) in relation to geologic formations that can provide safe, secure storage sites over long periods of time. The NatCarb project is working to provide all stakeholders with improved online tools for the display and analysis of CO2 carbon capture and storage data. NatCarb is organizing and enhancing the critical information about CO2 sources and developing the technology needed to access, query, model, analyze, display, and distribute natural resource data related to carbon management. Data are generated, maintained and enhanced locally at the RCSP level, or at specialized data warehouses, and assembled, accessed, and analyzed in real-time through a single geoportal. NatCarb is a functional demonstration of distributed data-management systems that cross the boundaries between institutions and geographic areas. It forms the first step toward a functioning National Carbon Cyberinfrastructure (NCCI). NatCarb provides access to first-order information to evaluate the costs, economic potential and societal issues of CO2 capture and storage, including public perception and regulatory aspects. NatCarb online access has been modified to address the broad needs of a spectrum of users. NatCarb includes not only GIS and database query tools for high-end user, but simplified display for the general public using readily available web tools such as Google Earth???and Google Maps???. Not only is NatCarb connected to all the RCSPs, but data are also pulled from public servers including the U.S. Geological Survey-EROS Data Center and from the Geography Network. Data for major CO2 sources have been obtained from U.S. Environmental Protection Agency (EPA) databases, and data on major coal basins and coalbed methane wells were obtained from the Energy Information Administration (EIA). ?? 2009 Elsevier Ltd. All rights reserved.

Electromagnetic Scattering from Two Dielectric Spheres: Comparison between Theory and Experiment,

DTIC Science & Technology

1982-08-30

struct, a very complex computer program to perform the calculations. It should be noted that several errors (probably typographical) were disco - vered in...their equations and virtually all of them had to be rederived. In a future publication we will present a corrected set of equations along with several

Development of laboratory testing facility for evaluation of base-soil behavior under repeated loading : phase 1 : feasibility study.

DOT National Transportation Integrated Search

2005-02-01

Accelerated load testing of paved and unpaved roads is the application of a large number of load repetitions in a short period of time. This type of testing is an economic way to determine the behavior of roads and compare different materials, struct...

Synthesis and Characterization of Selected 4,4'-Diaminoalkoxyazobenzenes

EPA Science Inventory

The role of the -N(CH2CH20H)2 group in producing a mutagenic response from 4-«3-(2h) Uroxyethoxy)4-amino)phenylazo)-N,N-bis(2-hydroxyethyl)-aniline has been investigated. To accomplish this goal, a group ofsubstituted 4,4'-diaminoazobenzene dyes was synthesized, and their struct...

Soyasaponin Bh, a Triterpene Saponin Containing a Unique Hemiacetal-Functional Five-Membered Ring from Glycine max (Soybeans)

USDA-ARS?s Scientific Manuscript database

Soybeans (Glycine max L. Merill) and soy-based food products are major dietary sources of saponins. An oleanane triterpenoid saponin, soyasaponin Bh (1) containing a unique five-membered ring with a hemiacetal functionality together with seven known saponins were isolated from soybeans. Their struct...

Corrigendum to "Electronic structure and photoelectron spectra of nickel (II) acetylacetonate and its thio- and amino-substituted analogues" [J. Mol. Struct. 1099 (2015) 579-587

NASA Astrophysics Data System (ADS)

Vovna, Vitaliy I.; Korochentsev, Vladimir V.; Komissarov, Alexander A.; L'vov, Igor B.; Myshakina, Nataliya S.

2016-01-01

The authors regret to inform that it was given erroneous spelling of Vitaliy I. Vovna author name in the published version of the article. It was written "Vitaliy V. Vovna" instead of "Vitaliy I. Vovna".

HIV Testing

MedlinePlus

... NAT means. Taking pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) may also reduce the accuracy of NAT if you have HIV. An antigen/antibody test looks for both HIV antibodies and antigens. Antibodies ...

A mathematical approach to estimate the efficacy of individual-donation and minipool nucleic acid amplification test options in preventing transmission risk by window period and occult hepatitis B virus infections

PubMed Central

Vermeulen, Marion; van Drimmelen, Harry; Coleman, Charl; Mitchel, Josephine; Reddy, Ravi; Lelie, Nico

2016-01-01

BACKGROUND Sensitivity data from a head-to-head comparison study in South Africa were used to compare the efficacy of the Ultrio Plus assay in individual-donation (ID) and minipool (MP)4 and MP8 formats with that of TaqScreen MP6 in preventing hepatitis B virus (HBV) transmission risk. STUDY DESIGN AND METHODS The replicate nucleic acid test (NAT) results on 106 HBV NAT (Ultrio)-yield samples and 29 HBV DNA (Ultrio)-negative, hepatitis B surface antigen (HBsAg)-positive samples were used to determine the viral load in copies/mL against the Eurohep HBV standard by probit analysis. Random viral load distributions were established in 32 pre-HBsAg window period (WP), 15 post-HBsAg WP, and 56 occult HBV infection (OBI) donations. Regression analysis of log viral load and Poisson distribution statistics of infectious HBV particles in blood components was used to predict infectivity and efficacy of NAT options in removing HBV transmission risk. RESULTS For red blood cell transfusions (20 mL of plasma), the modeling predicted an Ultrio Plus ID-NAT efficacy of 68 and 83% in removing WP and (antibody to hepatitis B surface antigen–negative) OBI transmission risk, respectively, compared to 52 and 49% by TaqScreen MP6. For 200 mL of fresh-frozen plasma the estimated efficacy levels by these ID- and MP6-NAT options reduced to 57 and 44% for WP and to 67 and 34% for OBI donations, respectively. CONCLUSION The efficacy of the currently available commercial NAT systems in reducing HBV transmission risk is mainly driven by the pool size and the transfusion plasma volume. The modeled OBI transmission risk and NAT efficacy levels were in line with those recently reported in three lookback studies and give more insight in the incremental safety provided by HBsAg and antibody to hepatitis B core antigen testing of ID-NAT screened blood. PMID:24749834

Adjuvant Brachytherapy Removes Survival Disadvantage of Local Disease Extension in Stage IIIC Endometrial Cancer: A SEER Registry Analysis

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

Rossi, Peter J.; Jani, Ashesh B.; Horowitz, Ira R.

2008-01-01

Purpose: To assess the role of radiotherapy (RT) in women with Stage IIIC endometrial cancer. Methods and Materials: The 17-registry Survival, Epidemiology, and End Results (SEER) database was searched for patients with lymph node-positive non-Stage IV epithelial endometrial cancer diagnosed and treated between 1988 and 1998. Two subgroups were identified: those with organ-confined Stage IIIC endometrial cancer and those with Stage IIIC endometrial cancer with direct extension of the primary tumor. RT was coded as external beam RT (EBRT) or brachytherapy (BT). Observed survival (OS) was reported with a minimum of 5 years of follow-up; the survival curves were comparedmore » using the log-rank test. Results: The therapy data revealed 611 women with Stage IIIC endometrial cancer during this period. Of these women, 51% were treated with adjuvant EBRT, 21% with EBRT and BT, and 28% with no additional RT (NAT). Of the 611 patients, 293 had organ-confined Stage IIIC endometrial cancer and 318 patients had Stage IIIC endometrial cancer with direct extension of the primary tumor. The 5-year OS rate for all patients was 40% with NAT, 56% after EBRT, and 64% after EBRT/BT. Adjuvant RT improved survival compared with NAT (p <0.001). In patients with organ-confined Stage IIIC endometrial cancer, the 5-year OS rate was 50% for NAT, 64% for EBRT, and 67% for EBRT/BT. Again, adjuvant RT contributed to improved survival compared with NAT (p = 0.02). In patients with Stage IIIC endometrial cancer and direct tumor extension, the 5-year OS rate was 34% for NAT, 47% for EBRT, and 63% for EBRT/BT. RT improved OS compared with NAT (p <0.001). Also, in this high-risk subgroup, adding BT to EBRT was superior to EBRT alone (p = 0.002). Conclusion: Women with Stage IIIC endometrial cancer receiving adjuvant EBRT and EBRT/BT had improved OS compared with patients receiving NAT. When direct extension of the primary tumor was present, the addition of BT to EBRT was even more beneficial.« less

Adjuvant brachytherapy removes survival disadvantage of local disease extension in stage IIIC endometrial cancer: a SEER registry analysis.

PubMed

Rossi, Peter J; Jani, Ashesh B; Horowitz, Ira R; Johnstone, Peter A S

2008-01-01

To assess the role of radiotherapy (RT) in women with Stage IIIC endometrial cancer. The 17-registry Survival, Epidemiology, and End Results (SEER) database was searched for patients with lymph node-positive non-Stage IV epithelial endometrial cancer diagnosed and treated between 1988 and 1998. Two subgroups were identified: those with organ-confined Stage IIIC endometrial cancer and those with Stage IIIC endometrial cancer with direct extension of the primary tumor. RT was coded as external beam RT (EBRT) or brachytherapy (BT). Observed survival (OS) was reported with a minimum of 5 years of follow-up; the survival curves were compared using the log-rank test. The therapy data revealed 611 women with Stage IIIC endometrial cancer during this period. Of these women, 51% were treated with adjuvant EBRT, 21% with EBRT and BT, and 28% with no additional RT (NAT). Of the 611 patients, 293 had organ-confined Stage IIIC endometrial cancer and 318 patients had Stage IIIC endometrial cancer with direct extension of the primary tumor. The 5-year OS rate for all patients was 40% with NAT, 56% after EBRT, and 64% after EBRT/BT. Adjuvant RT improved survival compared with NAT (p <0.001). In patients with organ-confined Stage IIIC endometrial cancer, the 5-year OS rate was 50% for NAT, 64% for EBRT, and 67% for EBRT/BT. Again, adjuvant RT contributed to improved survival compared with NAT (p = 0.02). In patients with Stage IIIC endometrial cancer and direct tumor extension, the 5-year OS rate was 34% for NAT, 47% for EBRT, and 63% for EBRT/BT. RT improved OS compared with NAT (p <0.001). Also, in this high-risk subgroup, adding BT to EBRT was superior to EBRT alone (p = 0.002). Women with Stage IIIC endometrial cancer receiving adjuvant EBRT and EBRT/BT had improved OS compared with patients receiving NAT. When direct extension of the primary tumor was present, the addition of BT to EBRT was even more beneficial.

Genetics Home Reference: Williams syndrome

MedlinePlus

... Berman KF. Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci. 2005 Aug;8( ... syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci. 2006 May;7( ...

An Integrated Procedure for the Structural Design of a Composite Rotor-Hydrofoil of a Water Current Turbine (WCT)

NASA Astrophysics Data System (ADS)

Oller Aramayo, S. A.; Nallim, L. G.; Oller, S.

2013-12-01

This paper shows an integrated structural design optimization of a composite rotor-hydrofoil of a water current turbine by means the finite elements method (FEM), using a Serial/Parallel mixing theory (Rastellini et al. Comput. Struct. 86:879-896, 2008, Martinez et al., 2007, Martinez and Oller Arch. Comput. Methods. 16(4):357-397, 2009, Martinez et al. Compos. Part B Eng. 42(2011):134-144, 2010) coupled with a fluid-dynamic formulation and multi-objective optimization algorithm (Gen and Cheng 1997, Lee et al. Compos. Struct. 99:181-192, 2013, Lee et al. Compos. Struct. 94(3):1087-1096, 2012). The composite hydrofoil of the turbine rotor has been design using a reinforced laminate composites, taking into account the optimization of the carbon fiber orientation to obtain the maximum strength and lower rotational-inertia. Also, these results have been compared with a steel hydrofoil remarking the different performance on both structures. The mechanical and geometrical parameters involved in the design of this fiber-reinforced composite material are the fiber orientation, number of layers, stacking sequence and laminate thickness. Water pressure in the rotor of the turbine is obtained from a coupled fluid-dynamic simulation (CFD), whose detail can be found in the reference Oller et al. (2012). The main purpose of this paper is to achieve a very low inertia rotor minimizing the start-stop effect, because it is applied in axial water flow turbine currently in design by the authors, in which is important to take the maximum advantage of the kinetic energy. The FEM simulation codes are engineered by CIMNE (International Center for Numerical Method in Engineering, Barcelona, Spain), COMPack for the solids problem application, KRATOS for fluid dynamic application and RMOP for the structural optimization. To validate the procedure here presented, many turbine rotors made of composite materials are analyzed and three of them are compared with the steel one.

The implementation of nucleic acid amplification technology testing for living tissue donors.

PubMed

Westby, J; Lomas, R J; Kearney, J N

2010-05-01

There is a significant requirement within the United Kingdom for tissue grafts from living donors. To ensure safety, blood samples from these donors are tested for pathogens at donation, and at 180 days post donation. Nucleic acid amplification technology (NAT) permits more sensitive detection of pathogens in blood samples than serum antigen testing. NAT testing can be applied to samples from living tissue donors to eliminate the need to re-test these donors 180 days post-donation before grafts can be implanted. This has major financial and operational advantages for a tissue bank, and this manuscript describes how NAT testing was assessed and implemented by NHSBT Tissue Services. When compared to traditional serum antigen testing, NAT testing was more cost effective, more convenient for donors and resulted in a greater proportion of donated grafts being made available for transplant.

Cost effectiveness of adding nucleic acid testing to hepatitis B, hepatitis C, and human immunodeficiency virus screening of blood donations in Zimbabwe.

PubMed

Mafirakureva, Nyashadzaishe; Mapako, Tonderai; Khoza, Star; Emmanuel, Jean C; Marowa, Lucy; Mvere, David; Postma, Maarten J; van Hulst, Marinus

2016-12-01

The aim of this study was to assess the cost effectiveness of introducing individual-donation nucleic acid testing (ID-NAT), in addition to serologic tests, compared with the exclusive use of serologic tests for the identification of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) I and II among blood donors in Zimbabwe. The costs, health consequences, and cost effectiveness of adding ID-NAT to serologic tests, compared with serologic testing alone, were estimated from a health care perspective using a decision-analytic model. The introduction of ID-NAT in addition to serologic tests would lower the risk of HBV, HCV, and HIV transmission to 46.9, 0.3, and 2.7 per 100,000 donations, respectively. ID-NAT would prevent an estimated 25, 6, and 9 HBV, HCV, and HIV transfusion-transmitted infections per 100,000 donations, respectively. The introduction of this intervention would result in an estimated 212 quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio is estimated at US$17,774/QALY, a value far more than three times the gross national income per capita for Zimbabwe. Although the introduction of NAT could further improve the safety of the blood supply, current evidence suggests that it cannot be considered cost effective. Reducing the test costs for NAT through efficient donor recruitment, negotiating the price of reagents, and the efficient use of technology will improve cost effectiveness. © 2016 AABB.

Injury patterns of child abuse: Experience of two Level 1 pediatric trauma centers.

PubMed

Yu, Yangyang R; DeMello, Annalyn S; Greeley, Christopher S; Cox, Charles S; Naik-Mathuria, Bindi J; Wesson, David E

2018-05-01

This study examines non-accidental trauma (NAT) fatalities as a percentage of all injury fatalities and identifies injury patterns in NAT admissions to two level 1 pediatric trauma centers. We reviewed all children (<5years old) treated for NAT from 2011 to 2015. Patient demographics, injury sites, and survival were obtained from both institutional trauma registries. Of 4623 trauma admissions, 557 (12%) were due to NAT. However, 43 (46%) of 93 overall trauma fatalities were due to NAT. Head injuries were the most common injuries sustained (60%) and led to the greatest increased risk of death (RR 5.1, 95% CI 2.0-12.7). Less common injuries that increased the risk of death were facial injuries (14%, RR 2.9, 95% CI 1.6-5.3), abdominal injuries (8%, RR 2.8, 95% CI 1.4-5.6), and spinal injuries (3%, RR 3.9, 95% CI 1.8-8.8). Although 76% of head injuries occurred in infants <1year, children ages 1-4years old with head injuries had a significantly higher case fatality rate (27% vs. 6%, p<0.001). Child abuse accounts for a large proportion of trauma fatalities in children under 5years of age. Intracranial injuries are common in child abuse and increase the risk of death substantially. Preventing NAT in infants and young children should be a public health priority. Retrospective Review. II. Copyright © 2018. Published by Elsevier Inc.

Structure of the beta 2 homodimer of bacterial luciferase from Vibrio harveyi: X-ray analysis of a kinetic protein folding trap.

PubMed Central

Thoden, J. B.; Holden, H. M.; Fisher, A. J.; Sinclair, J. F.; Wesenberg, G.; Baldwin, T. O.; Rayment, I.

1997-01-01

Luciferase, as isolated from Vibrio harveyi, is an alpha beta heterodimer. When allowed to fold in the absence of the alpha subunit, either in vitro or in vivo, the beta subunit of enzyme will form a kinetically stable homodimer that does not unfold even after prolonged incubation in 5 M urea at pH 7.0 and 18 degrees C. This form of the beta subunit, arising via kinetic partitioning on the folding pathway, appears to constitute a kinetically trapped alternative to the heterodimeric enzyme (Sinclair JF, Ziegler MM, Baldwin TO. 1994. Kinetic partitioning during protein folding yields multiple native states. Nature Struct Biol 1: 320-326). Here we describe the X-ray crystal structure of the beta 2 homodimer of luciferase from V. harveyi determined and refined at 1.95 A resolution. Crystals employed in the investigational belonged to the orthorhombic space group P2(1)2(1)2(1) with unit cell dimensions of a = 58.8 A, b = 62.0 A, and c = 218.2 A and contained one dimer per asymmetric unit. Like that observed in the functional luciferase alpha beta heterodimer, the major tertiary structural motif of each beta subunit consists of an (alpha/beta)8 barrel (Fisher AJ, Raushel FM, Baldwin TO, Rayment I. 1995. Three-dimensional structure of bacterial luciferase from Vibrio harveyi at 2.4 A resolution. Biochemistry 34: 6581-6586). The root-mean-square deviation of the alpha-carbon coordinates between the beta subunits of the hetero- and homodimers is 0.7 A. This high resolution X-ray analysis demonstrated that "domain" or "loop" swapping has not occurred upon formation of the beta 2 homodimer and thus the stability of the beta 2 species to denaturation cannot be explained in such simple terms. In fact, the subunit:subunit interfaces observed in both the beta 2 homodimer and alpha beta heterodimer are remarkably similar in hydrogen-bonding patterns and buried surface areas. PMID:9007973

Validation of the use of exogenous gonadotropins (PG600) to increase the efficiency of gilt development programs without affecting lifetime productivity in the breeding herd.

PubMed

Patterson, J; Triemert, E; Gustafson, B; Werner, T; Holden, N; Pinilla, J C; Foxcroft, G

2016-02-01

The objective of this study was to validate the use of exogenous gonadotropin (PG600) treatment for stimulating estrus in noncyclic gilts and to compare lifetime productivity of gilts recorded as having natural (NAT) versus PG600-induced (PG600) first estrus in a commercial setting. Prepubertal Camborough gilts ( = 4,489) were delivered to a gilt development unit (GDU) with the goal of delivering known cyclic breeding-eligible females to the sow farm (SF). A boar exposure area (BEAR) was designed to facilitate stimulation and detection of puberty by providing fence line and direct contact (15 min daily) with mature boars over an intensive 28-d period, starting at approximately d 160 (d 0). At d 14, nonpubertal gilts were mixed in new pen groups. At d 23, noncyclic "opportunity" gilts with no record of vulval development and required to meet breeding targets, were eligible for treatment with PG600 to induce puberty. Overall, 77.6% ( = 3,475) of gilts exhibited standing estrus (NAT = 2,654; PG600 = 821) and were eligible for shipping to the SF at approximately 35 d, and 76.6% of gilts that were administered PG600 exhibited the standing reflex within 13 d of treatment. Ultimately, 72.0% of gilts entering the GDU were delivered to the SF as breeding-eligible females. Considering the gilts delivered, a greater proportion of NAT than PG600 gilts were successfully bred ( < 0.001) and had better farrowing rates to first service, and overall farrowing rates (including gilts that returned to estrus and were rebred) were greater for NAT compared to PG600 gilts ( < 0.001) . Farrowing rates at second and third parity were similar between NAT and PG600 gilts; however, at fourth parity, a greater proportion of NAT gilts farrowed. In comparison, considering only gilts served, there was no difference ( > 0.05) in the proportion of NAT and PG600 gilts farrowing a third litter, but a greater proportion of NAT than PG600 gilts farrowed their fourth litter ( < 0.001). There was no difference between NAT and PG600 gilts for litter size at parity 1 through 4 or total pigs born over 4 parities ( > 0.05). A negative correlation ( < 0.0001) was detected between age at puberty and lifetime growth rate at puberty, and growth rate classification affected age and weight at puberty. However, retention rates and total sow productivity to parity 4 were not affected by growth rate classification at puberty.

Efficient Planning of Wind-Optimal Routes in North Atlantic Oceanic Airspace

NASA Technical Reports Server (NTRS)

Rodionova, Olga; Sridhar, Banavar

2017-01-01

The North Atlantic oceanic airspace (NAT) is crossed daily by more than a thousand flights, which are greatly affected by strong jet stream air currents. Several studies devoted to generating wind-optimal (WO) aircraft trajectories in the NAT demonstrated great efficiency of such an approach for individual flights. However, because of the large separation norms imposed in the NAT, previously proposed WO trajectories induce a large number of potential conflicts. Much work has been done on strategic conflict detection and resolution (CDR) in the NAT. The work presented here extends previous methods and attempts to take advantage of the NAT traffic structure to simplify the problem and improve the results of CDR. Four approaches are studied in this work: 1) subdividing the existing CDR problem into sub-problems of smaller sizes, which are easier to handle; 2) more efficient data reorganization within the considered time period; 3) problem localization, i.e. concentrating the resolution effort in the most conflicted regions; 4) applying CDR to the pre-tactical decision horizon (a couple of hours in advance). Obtained results show that these methods efficiently resolve potential conflicts at the strategic and pre-tactical levels by keeping the resulting trajectories close to the initial WO ones.

N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis.

PubMed

Hemanth Kumar, A K; Ramesh, K; Kannan, T; Sudha, V; Haribabu, Hemalatha; Lavanya, J; Swaminathan, Soumya; Ramachandran, Geetha

2017-01-01

Variations in the N-acetyltransferase (NAT2) gene among different populations could affect the metabolism and disposition of isoniazid (INH). This study was performed to genotype NAT2 gene polymorphisms in tuberculosis (TB) patients from Chennai, India, and compare plasma INH concentrations among the different genotypes. Adult patients with TB treated in the Revised National TB Control Programme (RNTCP) in Chennai, Tamil Nadu, were genotyped for NAT2 gene polymorphism, and two-hour post-dosing INH concentrations were compared between the different genotypes. Plasma INH was determined by high-performance liquid chromatography. Genotyping of the NAT2 gene polymorphism was performed by real-time polymerase chain reaction method. Among the 326 patients genotyped, there were 189 (58%), 114 (35%) and 23 (7%) slow, intermediate and fast acetylators, respectively. The median two-hour INH concentrations in slow, intermediate and fast acetylators were 10.2, 8.1 and 4.1 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.001). Genotyping of TB patients from south India for NAT2 gene polymorphism revealed that 58 per cent of the study population comprised slow acetylators. Two-hour INH concentrations differed significantly among the three genotypes.

Locomotor Stability in a Model Swimmer: Coupling Fluid Dynamics, Neurophysiology and Muscle Mechanics

DTIC Science & Technology

2017-07-05

springs which resist deformation. (C) Inset that shows the position of the muscle segments. Cohen, Holmes, Rand, J. Math Biol. 1982 A representative...numbers are the segment number, labeled from head to tail. Cohen, Holmes, Rand, J. Math Biol. 1982 The signals are periodic. Cohen, Holmes, Rand, J... Math Biol. 1982 From head to tail there is a phase lag on each side. Cohen, Holmes, Rand, J. Math Biol. 1982 On a given segment, the signals are in

Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk

PubMed Central

Eichholzer, Monika; Rohrmann, Sabine; Barbir, Aline; Hermann, Silke; Teucher, Birgit; Kaaks, Rudolf; Linseisen, Jakob

2012-01-01

Colorectal adenoma (CRA) and colorectal cancer (CRC) risks have been linked to the intake of red and processed meat. Heterocyclic aromatic amines (HCA) formed herein during high temperature cooking, are metabolized by a variety of enzymes, and allelic variation in the coding genes could influence individual CRA risk. Associations of polymorphisms in NAT1, NAT2, GSTA1, SULT1A1, CYP1A2, UGT1A7, UGT1A9, GSTP1 genes with colorectal adenoma risk were investigated in a nested case-control study of the EPIC-Heidelberg cohort including 428 cases matched by age, sex and year of recruitment with one or two controls (n=828) with negative colonoscopy per case. Genoyping was preformed with the Sequenom MassArray system and the LightCycler 480. Conditional logistic regression was used to compute odds ratios (OR) and corresponding 95% confidence intervals (CI). For rs15561 (NAT1) and rs1057126 (NAT1), the rarer allel was significantly inversely associated with adenoma risk OR=0.80 (95% CI 0.65-0.97) and (OR=0.81 (95% CI 0.65-0.99) and, respectively). For the combined NAT2 alleles encoding for enzymes with medium (versus slow) activity we also observed a significantly inverse association with adenoma risk (OR=0.75; 95% CI 0.85-0.97). In addition, homozygous carriers of the A allele of rs3957357 (GSTA1), i.e., those with a decreased enzyme activity, had a decreased risk of colorectal adenoma with an OR of 0.68 (95% CI 0.50-0.92; AA versus GG/GA). Polymorphisms in the other tested genes did not modify the risk of colorectal adenomas. In conclusion, polymorphisms in NAT1, NAT2, and GSTA1 are related to colorectal adenoma risk in this German cohort. PMID:22724046

Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk.

PubMed

Eichholzer, Monika; Rohrmann, Sabine; Barbir, Aline; Hermann, Silke; Teucher, Birgit; Kaaks, Rudolf; Linseisen, Jakob

2012-01-01

Colorectal adenoma (CRA) and colorectal cancer (CRC) risks have been linked to the intake of red and processed meat. Heterocyclic aromatic amines (HCA) formed herein during high temperature cooking, are metabolized by a variety of enzymes, and allelic variation in the coding genes could influence individual CRA risk. Associations of polymorphisms in NAT1, NAT2, GSTA1, SULT1A1, CYP1A2, UGT1A7, UGT1A9, GSTP1 genes with colorectal adenoma risk were investigated in a nested case-control study of the EPIC-Heidelberg cohort including 428 cases matched by age, sex and year of recruitment with one or two controls (n=828) with negative colonoscopy per case. Genoyping was preformed with the Sequenom MassArray system and the LightCycler 480. Conditional logistic regression was used to compute odds ratios (OR) and corresponding 95% confidence intervals (CI). For rs15561 (NAT1) and rs1057126 (NAT1), the rarer allel was significantly inversely associated with adenoma risk OR=0.80 (95% CI 0.65-0.97) and (OR=0.81 (95% CI 0.65-0.99) and, respectively). For the combined NAT2 alleles encoding for enzymes with medium (versus slow) activity we also observed a significantly inverse association with adenoma risk (OR=0.75; 95% CI 0.85-0.97). In addition, homozygous carriers of the A allele of rs3957357 (GSTA1), i.e., those with a decreased enzyme activity, had a decreased risk of colorectal adenoma with an OR of 0.68 (95% CI 0.50-0.92; AA versus GG/GA). Polymorphisms in the other tested genes did not modify the risk of colorectal adenomas. In conclusion, polymorphisms in NAT1, NAT2, and GSTA1 are related to colorectal adenoma risk in this German cohort.

Molecular basis of essential amino acid transport from studies of insect nutrient amino acid transporters of the SLC6 family (NAT-SLC6)

PubMed Central

Boudko, Dmitri Y.

2012-01-01

Two protein families that represent major components of essential amino acid transport in insects have been identified. They are annotated as the SLC6 and SLC7 families of transporters according to phylogenetic proximity to characterized amino acid transporters (HUGO nomenclature). Members of these families have been identified as important apical and basolateral parts of transepithelial essential amino acid absorption in the metazoan alimentary canal. Synergistically, they play critical physiological roles as essential substrate providers to diverse metabolic processes, including generic protein synthesis. This review briefly clarifies the requirements for amino acid transport and a variety of amino acid transport mechanisms, including the aforementioned families. Further it focuses on the large group of Nutrient Amino acid Transporters (NATs), which comprise a recently identified subfamily of the Neurotransmitter Sodium Symporter family (NSS or SLC6). The first insect NAT, cloned from the caterpillar gut, has a broad substrate spectrum similar to mammalian B0 transporters. Several new NAT-SLC6 members have been characterized in an effort to explore mechanisms for the essential amino acid absorption in model dipteran insects. The identification and functional characterization of new B0-like and narrow specificity transporters of essential amino acids in fruit fly and mosquitoes leads to a fundamentally important insight: that NATs evolved and act together as the integrated active core of a transport network that mediates active alimentary absorption and systemic distribution of essential amino acids. This role of NATs is projected from the most primitive prokaryotes to the most complex metazoan organisms, and represents an interesting platform for unraveling the molecular evolution of amino acid transport and modeling amino acid transport disorders. The comparative study of NATs elucidates important adaptive differences between essential amino acid transportomes of invertebrate and vertebrate organisms, outlining a new possibility for selective targeting of essential amino acid absorption mechanisms to control medically and economically important arthropods and other invertebrate organisms. PMID:22230793

Dose-related antihyperglycemic and hypolipidemic effects of two novel thiazolidin-4-ones in a rodent model of metabolic syndrome.

PubMed

Karot, Sarine Sebastian; Surenahalli, Vasantharaju Gowdra; Kishore, Anoop; Mudgal, Jayesh; Nandakumar, Krishnadas; Chirayil, Magith Thambi; Mathew, Geetha; Nampurath, Gopalan Kutty

2016-09-01

The replacement of the thiazolidinedione moiety with a thiazolidinone may yield antidiabetic compounds with similar pleiotropic effects. Hence, the aim of the present study was to explore the dose-related antihyperglycemic and hypolipidemic effects of two synthesized novel thiazolidin-4-one derivatives, one with a nicotinamide and the other with a p-chlorophenoxyacetamide substitution at the N3 position of the thiazolidinone ring (NAT1 and PAT1, respectively), in a rodent model of metabolic syndrome (MetS). Metabolic syndrome was induced in Wistar rats by neonatal administration of monosodium glutamate (i.p.) on 4 consecutive days followed by high-sucrose diet feeding for 6 months. The effects of NAT1 (33 and 66 mg/kg) and molar equivalent doses of PAT1 (40 and 80 mg/kg) on relevant biochemical parameters were evaluated. Because MetS is a state of chronic low-grade inflammation, we also evaluated the effects of these compounds on proinflammatory markers, namely interleukin (IL)-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), and nitric oxide (NO). Both NAT1 and PAT1 attenuated hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, and glucose intolerance. PAT1 exhibited superior antihyperglycemic and antihypoalphalipoproteinemic effects than NAT1. However, NAT1 had a better triglyceride-lowering effect. At the lower dose tested, both compounds significantly reduced elevated malondialdehyde levels. In addition, PAT1 (80 mg/kg) restored hepatic superoxide dismutase enzyme levels. There was a tendency for NAT1 and PAT1 to inhibit elevated hepatic IL-6 and TNF-α levels, but the differences did not reach statistical significance. In addition, PAT1 exhibited in vitro anti-inflammatory activity by reducing proinflammatory ROS and NO levels in RAW264.7 macrophages. The novel thiazolidin-4-ones NAT1 and PAT1 could be potential pleiotropic drug candidates targeting MetS. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Clean Energy for the Commonwealth Powered by UMass

DTIC Science & Technology

2009-04-15

Nanomagnetics Zeolite membranes Polymer-inorganic nanocomposites MEMS Nanostructured catalysts Plant Biotechnology Biochem., Cell wall struct., Agronomy Crambe...power management Low-power device networks Energy scavenging Flame Modeling Combustion chemistry Molecular-beam mass spectrometry Building Design...Thayumanavan, PhD. UMass Amherst Professor of Chemistry and Director, Fueling the Future Center for Chemical Innovation – Paul Osenar, PhD. Chief

A Circuit Extraction System and Graphical Display for VLSI (Very Large Scale Integrated) Design.

DTIC Science & Technology

1989-12-01

understandable as a net-list. The file contains information on the different physical layers of a polysilicon chip, not how these layers combine to form...yperc; struct vwsurf vsurf =DEFAULT_VWSURF(pixwt-ndd); stt-uct vwsurf vsurf2 DEFAULT-VWSURF(pixwfLndd); ma in) another[ Ol =IV while (anothler[0O = ’y

Development of a non invasion real-time PCR assay for the quantitation of chicken parvovirus in fecal swabs

USDA-ARS?s Scientific Manuscript database

The present study describes the development of a real time Taqman polymerase chain reaction (PCR) assay using a fluorescent labeled probe for the detection and quantitation of chicken parvovirus (ChPV) in feces. The primers and probes were designed based on the nucleotide sequence of the non struct...

Polymorphisms in NAT2 (N-acetyltransferase 2) gene in patients with systemic lupus erythematosus.

PubMed

Santos, Elaine Cristina Lima Dos; Pinto, Amanda Chaves; Klumb, Evandro Mendes; Macedo, Jacyara Maria Brito

To investigate potential associations of four substitutions in NAT2 gene and of acetylator phenotype of NAT2 with systemic lupus erythematosus (SLE) and clinical phenotypes. Molecular analysis of 481C>T, 590G>A, 857G>A, and 191G>A substitutions in the NAT2 gene was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, from DNA extracted from peripheral blood samples obtained from patients with SLE (n=91) and controls (n=97). The 857GA genotype was more prevalent among nonwhite SLE patients (OR=4.01, 95% CI=1.18-13.59). The 481T allele showed a positive association with hematological disorders that involve autoimmune mechanisms, specifically autoimmune hemolytic anemia or autoimmune thrombocytopenia (OR=1.97; 95% CI=1.01-3.81). Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

The neutron transmission of natFe, 197Au and natW

NASA Astrophysics Data System (ADS)

Beyer, Roland; Junghans, Arnd R.; Schillebeeckx, Peter; Sirakov, Ivan; Song, Tae-Yung; Bemmerer, Daniel; Capote, Roberto; Ferrari, Anna; Hartmann, Andreas; Hannaske, Ronald; Heyse, Jan; Il Kim, Hyeon; Woon Kim, Jong; Kögler, Toni; Woo Lee, Cheol; Lee, Young-Ouk; Massarczyk, Ralph; Müller, Stefan E.; Reinhardt, Tobias P.; Röder, Marko; Schmidt, Konrad; Schwengner, Ronald; Szücs, Tamás; Takács, Marcell P.; Wagner, Andreas; Wagner, Louis; Yang, Sung-Chul

2018-05-01

Neutron total cross sections of natFe, 197Au and natW have been measured at the n ELBE neutron time-of-flight facility in the energy range 0.15-8MeV with an uncertainty due to counting statistics of up to 2% and a total uncertainty due to systematic effects of 1%. The neutrons are produced with the superconducting electron accelerator ELBE using a liquid lead circuit as photo-neutron target. By periodical sample-in-sample-out measurements the transmission of the sample materials has been determined using a low-threshold plastic scintillation detector. The resulting effective total cross sections show good agreement with previously measured data that cover only part of the energy range available at n ELBE. The results have also been compared to evaluated library files and recent calculations based on a dispersive coupled channel optical model potential.

Disease activity return after natalizumab cessation in multiple sclerosis.

PubMed

Rasenack, Maria; Derfuss, Tobias

2016-05-01

Natalizumab (NAT) was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis. Its considerable and sustained efficacy has been demonstrated in two phase III studies. However, there are several reasons why its use is limited in clinical practice. The main argument for stopping use of the drug is the risk of the rare but serious progressive multifocal leukencephalopathy. Other reasons are neutralizing antibodies and pregnancy. There is compelling evidence from some clinical trials and many case series that disease activity returns upon suspension or cessation of NAT. Several therapeutic strategies that have been tested to prevent or reduce the recurrence of disease activity will be reviewed in this article. Considering these data, it is evident that the decision to stop NAT treatment has different implications and consequences. A subsequent therapy after cessation of NAT is needed to reduce the risk of disease recurrence.

Modifying effect of N-acetyltransferase 2 genotype on the association between systemic lupus erythematosus and consumption of alcohol and caffeine-rich beverages.

PubMed

Kiyohara, Chikako; Washio, Masakazu; Horiuchi, Takahiko; Asami, Toyoko; Ide, Saburo; Atsumi, Tatsuya; Kobashi, Gen; Takahashi, Hiroki; Tada, Yoshifumi

2014-07-01

N-acetyltransferase 2 (NAT2) is involved in the metabolism of various environmental substances, both with and without carcinogenic potential. Alcoholic and nonalcoholic caffeine-rich beverages may be associated with markers of inflammation. Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease. We investigated the effects of alcoholic and nonalcoholic caffeine-rich beverages on risk of SLE and determined whether the effects were modified by NAT2 status. The NAT2 polymorphism was genotyped in 152 SLE cases and 427 healthy controls, all women and Japanese. We assessed effect modification by testing an interaction term for the NAT2 polymorphism and consumption of beverages. Consumption of black tea (odds ratio [OR] 1.88, 95% confidence interval [95% CI] 1.03-3.41) and coffee (OR 1.57, 95% CI 0.95-2.61), but not green tea, was associated with an increased risk of SLE, while alcohol use (OR 0.33, 95% CI 0.20-0.55) was associated with a decreased risk of SLE. There were significant interactions between the NAT2 polymorphism and either alcohol use (Pinteraction = 0.026) or consumption of black tea (Pinteraction = 0.048). The NAT2 polymorphism significantly modified the effects of alcohol use and black tea consumption on SLE, emphasizing the importance of incorporating genetic and metabolic information in studies on management of SLE. Additional studies are warranted to confirm the findings suggested in this study. Copyright © 2014 by the American College of Rheumatology.

Strategy for selecting nanotechnology carriers to overcome immunological and hematological toxicities challenging clinical translation of nucleic acid-based therapeutics.

PubMed

Dobrovolskaia, Marina A; McNeil, Scott E

2015-07-01

Clinical translation of nucleic acid-based therapeutics (NATs) is hampered by assorted challenges in immunotoxicity, hematotoxicity, pharmacokinetics, toxicology and formulation. Nanotechnology-based platforms are being considered to help address some of these challenges due to the nanoparticles' ability to change drug biodistribution, stability, circulation half-life, route of administration and dosage. Addressing toxicology and pharmacology concerns by various means including NATs reformulation using nanotechnology-based carriers has been reviewed before. However, little attention was given to the immunological and hematological issues associated with nanotechnology reformulation. This review focuses on application of nanotechnology carriers for delivery of various types of NATs, and how reformulation using nanoparticles affects immunological and hematological toxicities of this promising class of therapeutic agents. NATs share several immunological and hematological toxicities with common nanotechnology carriers. In order to avoid synergy or exaggeration of undesirable immunological and hematological effects of NATs by a nanocarrier, it is critical to consider the immunological compatibility of the nanotechnology platform and its components. Since receptors sensing nucleic acids are located essentially in all cellular compartments, a strategy for developing a nanoformulation with reduced immunotoxicity should first focus on precise delivery to the target site/cells and then on optimizing intracellular distribution.

N-acetyltransferase gene polymorphisms & plasma isoniazid concentrations in patients with tuberculosis

PubMed Central

Hemanth Kumar, A. K.; Ramesh, K.; Kannan, T.; Sudha, V.; Haribabu, Hemalatha; Lavanya, J.; Swaminathan, Soumya; Ramachandran, Geetha

2017-01-01

Background & objectives: Variations in the N-acetyltransferase (NAT2) gene among different populations could affect the metabolism and disposition of isoniazid (INH). This study was performed to genotype NAT2 gene polymorphisms in tuberculosis (TB) patients from Chennai, India, and compare plasma INH concentrations among the different genotypes. Methods: Adult patients with TB treated in the Revised National TB Control Programme (RNTCP) in Chennai, Tamil Nadu, were genotyped for NAT2 gene polymorphism, and two-hour post-dosing INH concentrations were compared between the different genotypes. Plasma INH was determined by high-performance liquid chromatography. Genotyping of the NAT2 gene polymorphism was performed by real-time polymerase chain reaction method. Results: Among the 326 patients genotyped, there were 189 (58%), 114 (35%) and 23 (7%) slow, intermediate and fast acetylators, respectively. The median two-hour INH concentrations in slow, intermediate and fast acetylators were 10.2, 8.1 and 4.1 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.001). Interpretation & conclusions: Genotyping of TB patients from south India for NAT2 gene polymorphism revealed that 58 per cent of the study population comprised slow acetylators. Two-hour INH concentrations differed significantly among the three genotypes. PMID:28574024

Diagnostic laparoscopy should be performed before definitive resection for pancreatic cancer: a financial argument.

PubMed

Jayakrishnan, Thejus T; Nadeem, Hasan; Groeschl, Ryan T; George, Ben; Thomas, James P; Ritch, Paul S; Christians, Kathleen K; Tsai, Susan; Evans, Douglas B; Pappas, Sam G; Gamblin, T Clark; Turaga, Kiran K

2015-02-01

Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50,000/quality-adjusted life year). Base case costs were US$34,921 for ExLap and US$33,442 for DL in SF patients, and US$39,633 for ExLap and US$39,713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10,695/QALM in SF and US$4158/QALM in NAT patients. The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT. © 2014 International Hepato-Pancreato-Biliary Association.

Contribution of different PSC types to Arctic ozone depletion caused by chlorine activation and denitrification

NASA Astrophysics Data System (ADS)

Kirner, Oliver; Khosrawi, Farah; Müller, Rolf; Weimer, Michael; Ruhnke, Roland

2017-04-01

Heterogeneous reactions on the surfaces of PSC particles and denitrification of the stratosphere are the cause for polar ozone depletion in spring. In a former study we investigated the impact of different types of PSCs on Antarctic ozone depletion with the help of the chemistry-climate model ECHAM5/MESSy Atmospheric chemistry (EMAC). In this study, we investigate the impact of PSCs on Arctic ozone loss. One standard and four sensitivity EMAC simulations (nudged with ERA-Interim) have been performed to evaluate the contribution of liquid, NAT and ice particles to ozone depletion in the Arctic winters 2010/2011 and 2015/2016 due to chlorine activation by heterogeneous chemistry on their surfaces and due to denitrification of the stratosphere. In the first three sensitivity simulations, we changed the heterogeneous chemistry on PSC particles by switching on and off the chemistry on liquid, NAT and ice particles. One further sensitivity simulation without NAT formation (only liquid and ice particles) was performed to evaluate the contribution of NAT to Arctic ozone depletion due to denitrification of the stratosphere. With the help of these different EMAC simulations, we will show the significance of liquid, NAT and ice particles to Arctic ozone depletion caused by chlorine activation and denitrification.

N-terminal acetylation -an Essential Protein Modification Emerges as an Important Regulator of Stress Responses.

PubMed

Linster, Eric; Wirtz, Markus

2018-06-26

N-terminal acetylation (NTA) is a prevalent protein modification in eukaryotes. The majority of proteins is acetylated at their N-terminus in a co-translational manner by ribosome-associated N-terminal acetyltransferases (NAT). However, the recent discovery of Golgi-membrane localized NATs in metazoan, and plastid-localized NATs in plants challenged the dogma of static, co-translational imprinting of the proteome by NTA. Indeed, NTA by the cytosolic NatA is highly dynamic and under hormonal control in plants. Such active control has not been evidenced yet in other eukaryotes and might be an adaptation to the sessile lifestyle of plants forcing them to cope with diverse environmental challenges. The function of NTA for individual proteins is distinct and yet unpredictable. In yeast and humans, NTA has been shown to affect protein-protein interactions, subcellular localization, folding, aggregation, or degradation of a handful of proteins. In particular, the impact of NTA on the protein-turnover is documented by diverse examples in yeast. Consequently, NTA has recently dicovered to be a degradation signal in a distinct branch of the N-end rule pathway ubiquitin-mediated proteolysis. In this review, we summarize the current knowledge on the NAT machinery in higher plants and discuss the potential function of NTA during biotic and abiotic stresses.

Bystander protein protects potential vaccine-targeting ligands against intestinal proteolysis.

PubMed

Reuter, Fabian; Bade, Steffen; Hirst, Timothy R; Frey, Andreas

2009-07-20

Endowing mucosal vaccines with ligands that target antigen to mucosal lymphoid tissues may improve immunization efficacy provided that the ligands withstand the proteolytic environment of the gastro-intestinal tract until they reach their destination. Our aim was to investigate whether and how three renowned ligands - Ulex europaeus agglutinin I and the B subunits of cholera toxin and E. coli heat-labile enterotoxin - master this challenge. We assessed the digestive power of natural murine intestinal fluid (natIF) using assays for trypsin, chymotrypsin and pancreatic elastase along with a test for nonspecific proteolysis. The natIF was compared with simulated murine intestinal fluid (simIF) that resembled the trypsin, chymotrypsin and elastase activities of its natural counterpart but lacked or contained albumins as additional protease substrates. The ligands were exposed to the digestive fluids and degradation was determined. The studies revealed that (i) the three pancreatic endoproteases constitute only one third of the total protease activity of natIF and (ii) the ligands resist proteolysis in natIF and protein-enriched simIF over 3 h but (iii) are partially destroyed in simIF that lacks additional protease substrate. We assume that the proteins of natIF are preferred substrates for the intestinal proteases and thus can protect vaccine-targeting ligands from destruction.

Nitroxidative chemistry interferes with fluorescent probe chemistry: implications for nitric oxide detection using 2,3-diaminonaphthalene.

PubMed

Hu, Teh-Min; Chiu, Shih-Jiuan; Hsu, Yu-Ming

2014-08-22

Simultaneous production of nitric oxide (NO) and superoxide generates peroxynitrite and causes nitroxidative stress. The fluorometric method for NO detection is based on the formation of a fluorescent product from the reaction of a nonfluorescent probe molecule with NO-derived nitrosating species. Here, we present an example of how nitroxidative chemistry could interact with fluorescent probe chemistry. 2,3-Naphthotriazole (NAT) is the NO-derived fluorescent product of 2,3-diaminonaphthalene (DAN), a commonly used NO-detecting molecule. We show that NO/superoxide cogeneration, and particularly peroxynitrite, mediates the chemical decomposition of NAT. Moreover, the extent of NAT decomposition depends on the relative fluxes of NO and superoxide; the maximum effect being reached at almost equivalent generation rates for both radicals. The rate constant for the reaction of NAT with peroxynitrite was determined to be 2.2×10(3)M(-1)s(-1). Further, various peroxynitrite scavengers were shown to effectively inhibit NO/superoxide- and peroxynitrite-mediated decomposition of NAT. Taken together, the present study suggests that the interference of a fluorometric NO assay can be originated from the interaction between the final fluorescent product and the formed reactive nitrogen and oxygen species. Copyright © 2014 Elsevier Inc. All rights reserved.

Heterogeneous nucleation of nitric acid trihydrate on clay minerals: relevance to type ia polar stratospheric clouds.

PubMed

Hatch, Courtney D; Gough, Raina V; Toon, Owen B; Tolbert, Margaret A

2008-01-17

Although critical to atmospheric modeling of stratospheric ozone depletion, selective heterogeneous nuclei that promote the formation of Type Ia polar stratospheric clouds (PSCs) are largely unknown. While mineral particles are known to be good ice nuclei, it is currently not clear whether they are also good nuclei for PSCs. In the present study, a high-vacuum chamber equipped with transmission Fourier transform infrared spectroscopy and a quadrupole mass spectrometer was used to study heterogeneous nucleation of nitric acid trihydrate (NAT) on two clay minerals-Na-montmorillonite and kaolinite-as analogs of atmospheric terrestrial and extraterrestrial minerals. The minerals are first coated with a 3:1 supercooled H2O/HNO3 solution prior to the observed nucleation of crystalline NAT. At 220 K, NAT formation was observed at low SNAT values of 12 and 7 on kaolinite and montmorillonite clays, respectively. These are the lowest SNAT values reported in the literature on any substrate. However, NAT nucleation exhibited significant temperature dependence. At lower temperatures, representative of typical polar stratospheric conditions, much higher supersaturations were required before nucleation was observed. Our results suggest that NAT nucleation on mineral particles, not previously treated with sulfuric acid, may not be an important nucleation platform for Type Ia PSCs under normal polar stratospheric conditions.

Cocaine alters Homer1 natural antisense transcript in the nucleus accumbens.

PubMed

Sartor, Gregory C; Powell, Samuel K; Velmeshev, Dmitry; Lin, David Y; Magistri, Marco; Wiedner, Hannah J; Malvezzi, Andrea M; Andrade, Nadja S; Faghihi, Mohammad A; Wahlestedt, Claes

2017-12-01

Natural antisense transcripts (NATs) are an abundant class of long noncoding RNAs that have recently been shown to be key regulators of chromatin dynamics and gene expression in nervous system development and neurological disorders. However, it is currently unclear if NAT-based mechanisms also play a role in drug-induced neuroadaptations. Aberrant regulation of gene expression is one critical factor underlying the long-lasting behavioral abnormalities that characterize substance use disorder, and it is possible that some drug-induced transcriptional responses are mediated, in part, by perturbations in NAT activity. To test this hypothesis, we used an automated algorithm that mines the NCBI AceView transcriptomics database to identify NAT overlapping genes linked to addiction. We found that 22% of the genes examined contain NATs and that expression of Homer1 natural antisense transcript (Homer1-AS) was altered in the nucleus accumbens (NAc) of mice 2h and 10days following repeated cocaine administration. In in vitro studies, depletion of Homer1-AS lead to an increase in the corresponding sense gene expression, indicating a potential regulatory mechanisms of Homer1 expression by its corresponding antisense transcript. Future in vivo studies are needed to definitely determine a role for Homer1-AS in cocaine-induced behavioral and molecular adaptations. Copyright © 2017 Elsevier Inc. All rights reserved.

EDITORIAL: Annual prizes for best papers

NASA Astrophysics Data System (ADS)

2006-09-01

2005 Roberts Prize The publishers of Physics in Medicine and Biology (PMB) in association with the Institute of Physics and Engineering in Medicine (IPEM) jointly award an annual prize for an article published in PMB during the previous year. The following 14 articles, listed below in chronological order, were rated the best of 2005 based on the (two or three) referees' assessments: P Kundrát et al 2005 Probabilistic two-stage model of cell inactivation by ionizing particles Phys. Med. Biol. 50 1433-47 D Arora et al 2005 Direct thermal dose control of constrained focused ultrasound treatments: phantom and in vivo evaluation Phys. Med. Biol. 50 1919-35 J S Dysart et al 2005 Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro Phys. Med. Biol. 50 2597-616 M Defrise et al 2005 Fourier rebinning of time-of-flight PET data Phys. Med. Biol. 50 2749-63 Z Su et al 2005 Systematic investigation of the signal properties of polycrystalline HgI2 detectors under mammographic, radiographic, fluoroscopic and radiotherapy irradiation conditions Phys. Med. Biol. 50 2907-28 E Bräuer-Krisch et al 2005 New irradiation geometry for microbeam radiation therapy Phys. Med. Biol. 50 3103-11 H C Pyo et al 2005 Identification of current density distribution in electrically conducting subject with anisotropic conductivity distribution Phys. Med. Biol. 50 3183-96 R P Findlay et al 2005 Effects of posture on FDTD calculations of specific absorption rate in a voxel model of the human body Phys. Med. Biol. 50 3825-35 G Alexandrakis et al 2005 Tomographic bioluminescence imaging by use of a combined optical-PET (OPET) system: a computer simulation feasibility study Phys. Med. Biol. 50 4225-41 J Keshvari et al 2005 Comparison of radio frequency energy absorption in ear and eye region of children and adults at 900, 1800 and 2450 MHz Phys. Med. Biol. 50 4355-69 J Laufer et al 2005 In vitro measurements of absolute blood oxygen saturation using pulsed near-infrared photoacoustic spectroscopy: accuracy and resolution Phys. Med. Biol. 50 4409-28 Z Cao et al 2005 Optimal number of pinholes in multi-pinhole SPECT for mouse brain imaging---a simulation study Phys. Med. Biol. 50 4609-24 R Dharmakumar et al 2005 A novel microbubble construct for intracardiac or intravascular MR manometry: a theoretical study Phys. Med. Biol. 50 4745-62 R Chopra et al 2005 Method for MRI-guided conformal thermal therapy of prostate with planar transurethral ultrasound heating applicators Phys. Med. Biol. 50 4957-75 The IPEM Publications Committee then assessed and rated these papers in order to choose a winner. We have much pleasure in advising readers that the 2005 Roberts Prize is awarded to: J S Dysart and M S Patterson 2005 Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro Phys. Med. Biol. 50 2597-616 2006 Prize for the Highest Cited Paper The annual prize for the most highly cited paper is awarded by the journal publishers to the article published in PMB that has received the most citations1 in the previous 5 years (in this case for the period 2001 to 2005 inclusive). We have much pleasure in advising readers that the 2006 prize is awarded to: P J Keall, V R Kini, S S Vedam and R Mohan 2001 Motion adaptive x-ray therapy: a feasibility study Phys. Med. Biol. 46 1-10 Simon Harris, Publisher Steve Webb, Editor-in-Chief 1 Figures taken from Thomson/ISI

Comparative genomic and phylogenetic investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes characterized in several bacteria and eukaryotic organisms. We report a comprehensive phylogenetic analysis employing an exhaustive dataset of NAT-homologous sequences recovered through inspection of 2445 genomes. We describe ...

Poetic Praxis: Engaging Body, Mind, and Soul in the Social Foundations Classroom

ERIC Educational Resources Information Center

MacKenzie, Sarah K.,

2013-01-01

Across the space of this paper I seek to share a particular attempt to holistically engage students enrolled in a Social Foundations of Education course, in the process of de(con)structing knowledge, through the work of collectively creating found poetry. I do not seek to show right pedagogical practice; rather, it is my hope that this paper may…

Dollar Summary of Federal Supply Classification and Service Category by Company, FY83, Part 6 (W061-Z299).

DTIC Science & Technology

1983-01-01

RENT OF FAC /FUEL SUPPLY 29 X299 AUTO TECHNIQUE BELGIQUE S A BELGIUM ARMY LEASE-RENT OF FAC /OTHER NON-BLDG STRUCT 31 HOFFMAN CO VIRGINIA ARMY LEASE...HARRISON & PALMI RIDGE ELECTRICAL E INC MISSOURI ARMY CONSTR: CONSTRUCTION/PARFING FACILITIES $ 123 SUSSEX ELECTRICO C MARYLAND ARMY CONSTR: CONSTRUCTION

FoxP2 is significantly associated with schizophrenia and major depression in the Chinese Han population.

PubMed

Li, Tao; Zeng, Zhen; Zhao, Qian; Wang, Ti; Huang, Ke; Li, Junyan; Li, You; Liu, Jie; Wei, Zhiyun; Wang, Yang; Feng, Guoyin; He, Lin; Shi, Yongyong

2013-03-01

The FoxP2 gene, located on 7q31, encodes a transcription factor. It was first discovered through investigations of a large multigenerational family (the KE family) with a rare severe speech and language disorder (Fisher et al., Nat. Genet. 1998;18:168; Lai et al., Nature 2001;413:519). Subsequent studies gave powerful and convincing functional evidence to the connection between FoxP2 and language disorder ( Vernes et al. 2006 ; Groszer et al., Curr Biol 2008;18:354; Vernes et al., New Engl J Med 359(22):2337). Language disorder is commonly considered as a core symptom of schizophrenia and some other mental diseases; thus, we decided to investigate whether the FoxP2 gene played a significant role in schizophrenia, major depression or bipolar disorder in a sample set recruited from the Chinese Han population. In this study, we focused on 12 SNPs in the FoxP2 gene and carried out case-control studies in 1135 schizophrenia patients, 1135 unrelated major depression patients, 1135 unrelated bipolar disorder patients and 1135 unrelated normal controls recruited from the Chinese Han population. We found rs10447760 was significantly associated with schizophrenia (allelic P = 0.00069) and major depression (allelic P = 0.0011). Our study indicated that the rare variant rs10447760 in FoxP2 may play an important role in schizophrenia and major depression in the Chinese Han population.

Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort

PubMed Central

Gonzalez, Antonio; Hyde, Embriette; Sangwan, Naseer; Gilbert, Jack A.; Viirre, Erik

2016-01-01

ABSTRACT Nitrates, such as cardiac therapeutics and food additives, are common headache triggers, with nitric oxide playing an important role. Facultative anaerobic bacteria in the oral cavity may contribute migraine-triggering levels of nitric oxide through the salivary nitrate-nitrite-nitric oxide pathway. Using high-throughput sequencing technologies, we detected observable and significantly higher abundances of nitrate, nitrite, and nitric oxide reductase genes in migraineurs versus nonmigraineurs in samples collected from the oral cavity and a slight but significant difference in fecal samples. IMPORTANCE Recent work has demonstrated a potentially symbiotic relationship between oral commensal bacteria and humans through the salivary nitrate-nitrite-nitric oxide pathway (C. Duncan et al., Nat Med 1:546–551, 1995, http://dx.doi.org/10.1038/nm0695-546). Oral nitrate-reducing bacteria contribute physiologically relevant levels of nitrite and nitric oxide to the human host that may have positive downstream effects on cardiovascular health (V. Kapil et al., Free Radic Biol Med 55:93–100, 2013, http://dx.doi.org/10.1016/j.freeradbiomed.2012.11.013). In the work presented here, we used 16S rRNA Illumina sequencing to determine whether a connection exists between oral nitrate-reducing bacteria, nitrates for cardiovascular disease, and migraines, which are a common side effect of nitrate medications (U. Thadani and T. Rodgers, Expert Opin Drug Saf 5:667–674, 2006, http://dx.doi.org/10.1517/14740338.5.5.667). PMID:27822557

Focal Contacts as Mechanosensors

PubMed Central

Riveline, Daniel; Zamir, Eli; Balaban, Nathalie Q.; Schwarz, Ulrich S.; Ishizaki, Toshimasa; Narumiya, Shuh; Kam, Zvi; Geiger, Benjamin; Bershadsky, Alexander D.

2001-01-01

The transition of cell–matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II–driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein–tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136–143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force. PMID:11402062

Single nucleotide polymorphism coverage and inference of N-acetyltransferase-2 acetylator phenotypes in wordwide population groups.

PubMed

Suarez-Kurtz, Guilherme; Fuchshuber-Moraes, Mateus; Struchiner, Claudio J; Parra, Esteban J

2016-08-01

Several algorithms have been proposed to reduce the genotyping effort and cost, while retaining the accuracy of N-acetyltransferase-2 (NAT2) phenotype prediction. Data from the 1000 Genomes (1KG) project and an admixed cohort of Black Brazilians were used to assess the accuracy of NAT2 phenotype prediction using algorithms based on paired single nucleotide polymorphisms (SNPs) (rs1041983 and rs1801280) or a tag SNP (rs1495741). NAT2 haplotypes comprising SNPs rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208 and rs1799931 were assigned according to the arylamine N-acetyltransferases database. Contingency tables were used to visualize the agreement between the NAT2 acetylator phenotypes on the basis of these haplotypes versus phenotypes inferred by the prediction algorithms. The paired and tag SNP algorithms provided more than 96% agreement with the 7-SNP derived phenotypes in Europeans, East Asians, South Asians and Admixed Americans, but discordance of phenotype prediction occurred in 30.2 and 24.8% 1KG Africans and in 14.4 and 18.6% Black Brazilians, respectively. Paired SNP panel misclassification occurs in carriers of NATs haplotypes *13A (282T alone), *12B (282T and 803G), *6B (590A alone) and *14A (191A alone), whereas haplotype *14, defined by the 191A allele, is the major culprit of misclassification by the tag allele. Both the paired SNP and the tag SNP algorithms may be used, with economy of scale, to infer NAT2 acetylator phenotypes, including the ultra-slow phenotype, in European, East Asian, South Asian and American populations represented in the 1KG cohort. Both algorithms, however, perform poorly in populations of predominant African descent, including admixed African-Americans, African Caribbeans and Black Brazilians.

Interactions of Cigarette Smoking with NAT2 Polymorphisms Impact Rheumatoid Arthritis Risk in African Americans

PubMed Central

Mikuls, Ted R.; LeVan, Tricia; Gould, Karen A.; Yu, Fang; Thiele, Geoffrey M.; Bynote, Kimberly K.; Conn, Doyt; Jonas, Beth L.; Callahan, Leigh F.; Smith, Edwin; Brasington, Richard; Moreland, Larry W.; Reynolds, Richard; Gaffo, Angelo; Bridges, S. Louis

2011-01-01

Objective To examine whether polymorphisms in genes coding for drug metabolizing enzymes (DMEs) impact rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans. Methods Smoking status was evaluated in African American RA cases and non-RA controls categorized as heavy (≥ 10 pack-years) vs. other. Individuals were genotyped for a homozygous deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) in addition to tagging single nucleotide polymorphisms (SNPs) in N-acetyltransferase (NAT)1, NAT2, and epoxide hydrolase (EPXH1). Associations of genotypes with RA were examined using logistic regression and gene-smoking interactions were assessed. Results There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and NAT2 SNPs rs9987109 (Padd = 0.000003) and rs1208 (Padd = 0.00001); attributable proportions (APs) due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant after adjustment for multiple testing in overall disease risk. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to anti-citrullinated protein antibody (ACPA) positive individuals. Conclusion Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA with relative risks that are at least two-fold higher compared to non-smokers lacking these risk alleles. PMID:21989592

Lack of association between NAT2 polymorphism and prostate cancer risk: a meta-analysis and trial sequential analysis

PubMed Central

Tang, Jingyuan; Xu, Lingyan; Xu, Haoxiang; Li, Ran; Han, Peng; Yang, Haiwei

2017-01-01

Previous studies have investigated the association between NAT2 polymorphism and the risk of prostate cancer (PCa). However, the findings from these studies remained inconsistent. Hence, we performed a meta-analysis to provide a more reliable conclusion about such associations. In the present meta-analysis, 13 independent case-control studies were included with a total of 14,469 PCa patients and 10,689 controls. All relevant studies published were searched in the databates PubMed, EMBASE, and Web of Science, till March 1st, 2017. We used the pooled odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association between NAT2*4 allele and susceptibility to PCa. Subgroup analysis was carried out by ethnicity, source of controls and genotyping method. What's more, we also performed trial sequential analysis (TSA) to reduce the risk of type I error and evaluate whether the evidence of the results was firm. Firstly, our results indicated that NAT2*4 allele was not associated with PCa susceptibility (OR = 1.00, 95% CI= 0.95–1.05; P = 0.100). However, after excluding two studies for its heterogeneity and publication bias, no significant relationship was also detected between NAT2*4 allele and the increased risk of PCa, in fixed-effect model (OR = 0.99, 95% CI= 0.94–1.04; P = 0.451). Meanwhile, no significant increased risk of PCa was found in the subgroup analyses by ethnicity, source of controls and genotyping method. Moreover, TSA demonstrated that such association was confirmed in the present study. Therefore, this meta-analysis suggested that no significant association between NAT2 polymorphism and the risk of PCa was found. PMID:28915684

Cancer-specific production of N-acetylaspartate via NAT8L overexpression in non-small cell lung cancer and its potential as a circulating biomarker

PubMed Central

Lou, Tzu-Fang; Sethuraman, Deepa; Dospoy, Patrick; Srivastva, Pallevi; Kim, Hyun Seok; Kim, Joongsoo; Ma, Xiaotu; Chen, Pei-Hsuan; Huffman, Kenneth E.; Frink, Robin E.; Larsen, Jill E.; Lewis, Cheryl; Um, Sang-Won; Kim, Duk-Hwan; Ahn, Jung-Mo; DeBerardinis, Ralph J.; White, Michael A.; Minna, John D.; Yoo, Hyuntae

2015-01-01

In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA) in cancer cells — undetectable in normal lung epithelium. NAA’s cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA’s cancer-specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N=577), with minimal expression in all non-malignant lung tissues (N=74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA’s clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N=13) in comparison with age-matched healthy controls (N=21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression and its extracellular secretion can be detected in blood. PMID:26511490

Impact of nucleic acid testing relative to antigen/antibody combination immunoassay on the detection of acute HIV infection.

PubMed

De Souza, Mark S; Phanuphak, Nittaya; Pinyakorn, Suteeraporn; Trichavaroj, Rapee; Pattanachaiwit, Supanit; Chomchey, Nitiya; Fletcher, James L; Kroon, Eugene D; Michael, Nelson L; Phanuphak, Praphan; Kim, Jerome H; Ananworanich, Jintanat

2015-04-24

To assess the addition of HIV nucleic acid testing (NAT) to fourth-generation (4thG) HIV antigen/antibody combination immunoassay in improving detection of acute HIV infection (AHI). Participants attending a major voluntary counseling and testing site in Thailand were screened for AHI using 4thG HIV antigen/antibody immunoassay and sequential less sensitive HIV antibody immunoassay. Samples nonreactive by 4thG antigen/antibody immunoassay were further screened using pooled NAT to identify additional AHI. HIV infection status was verified following enrollment into an AHI study with follow-up visits and additional diagnostic tests. Among 74 334 clients screened for HIV infection, HIV prevalence was 10.9% and the overall incidence of AHI (N = 112) was 2.2 per 100 person-years. The inclusion of pooled NAT in the testing algorithm increased the number of acutely infected patients detected, from 81 to 112 (38%), relative to 4thG HIV antigen/antibody immunoassay. Follow-up testing within 5 days of screening marginally improved the 4thG immunoassay detection rate (26%). The median CD4 T-cell count at the enrollment visit was 353 cells/μl and HIV plasma viral load was 598 289 copies/ml. The incorporation of pooled NAT into the HIV testing algorithm in high-risk populations may be beneficial in the long term. The addition of pooled NAT testing resulted in an increase in screening costs of 22% to identify AHI: from $8.33 per screened patient to $10.16. Risk factors of the testing population should be considered prior to NAT implementation given the additional testing complexity and costs.

Conflict Resolution for Wind-Optimal Aircraft Trajectories in North Atlantic Oceanic Airspace with Wind Uncertainties

NASA Technical Reports Server (NTRS)

Rodionova, Olga; Sridhar, Banavar; Ng, Hok K.

2016-01-01

Air traffic in the North Atlantic oceanic airspace (NAT) experiences very strong winds caused by jet streams. Flying wind-optimal trajectories increases individual flight efficiency, which is advantageous when operating in the NAT. However, as the NAT is highly congested during peak hours, a large number of potential conflicts between flights are detected for the sets of wind-optimal trajectories. Conflict resolution performed at the strategic level of flight planning can significantly reduce the airspace congestion. However, being completed far in advance, strategic planning can only use predicted environmental conditions that may significantly differ from the real conditions experienced further by aircraft. The forecast uncertainties result in uncertainties in conflict prediction, and thus, conflict resolution becomes less efficient. This work considers wind uncertainties in order to improve the robustness of conflict resolution in the NAT. First, the influence of wind uncertainties on conflict prediction is investigated. Then, conflict resolution methods accounting for wind uncertainties are proposed.

Activation cross-sections of proton induced reactions on natHf in the 38-65 MeV energy range: Production of 172Lu and of 169Yb

NASA Astrophysics Data System (ADS)

Tárkányi, F.; Hermanne, A.; Ditrói, F.; Takács, S.; Ignatyuk, A. V.

2018-07-01

In the frame of a systematical study of light ion induced nuclear reactions on hafnium, activation cross sections for proton induced reactions were investigated. Excitation functions were measured in the 38-65 MeV energy range for the natHf(p,xn)180g,177,176,175,173Ta, natHf(p,x)180m,179m,175,173,172,171Hf, 177g,173,172,171,170,169Lu and natHf(p,x)169Yb reactions by using the activation method, combining stacked foil irradiation and off line gamma ray spectroscopy. The experimental results are compared with earlier results in the overlapping energy range, and with the theoretical predictions of the ALICE IPPE and EMPIRE theoretical codes and of the TALYS code reported in the TENDL-2015 and TENDL-2017 libraries. The production routes of 172Lu (and its parent 172Hf) and of 169Yb are reviewed.

77 FR 26300 - National Institute of Environmental Health Sciences; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-03

... Structural Biology. Place: Nat. Inst. of Environmental Health Sciences, Building 101, Rodbell Auditorium, 111... Environmental Health Sciences, Building 101, Rodbell Auditorium, 111 T. W. Alexander Drive, Research Triangle... Sessions. Place: Nat. Inst. of Environmental Health Sciences, Building 101, Rodbell Auditorium, 111 T. W...

AmeriFlux US-SP1 Slashpine-Austin Cary- 65yrs nat regen

DOE Data Explorer

Martin, Tim [University of Florida

2016-01-01

This is the AmeriFlux version of the carbon flux data for the site US-SP1 Slashpine-Austin Cary- 65yrs nat regen. Site Description - The ACMF site is a 67 hectare naturally regenerated Pinus palustris and Pinus elliottii mixed stand.

Rabbit N-acetyltransferase 2 genotyping method to investigate role of acetylation polymorphism on N- and O-acetylation of aromatic and heterocyclic amine carcinogens.

PubMed

Hein, David W; Doll, Mark A

2017-09-01

The rabbit was the initial animal model to investigate the acetylation polymorphism expressed in humans. Use of the rabbit model is compromised by lack of a rapid non-invasive method for determining acetylator phenotype. Slow acetylator phenotype in the rabbit results from deletion of the N-acetyltransferase 2 (NAT2) gene. A relatively quick and non-invasive method for identifying the gene deletion was developed and acetylator phenotypes confirmed by measurement of N- and O-acetyltransferase activities in hepatic cytosols. Rabbit liver cytosols catalyzed the N-acetylation of sulfamethazine (p = 0.0014), benzidine (p = 0.0257), 4-aminobiphenyl (p = 0.0012), and the O-acetylation of N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP; p = 0.002) at rates significantly higher in rabbits possessing NAT2 gene than rabbits with NAT2 gene deleted. In contrast, hepatic cytosols catalyzed the N-acetylation of p-aminobenzoic acid (an N-acetyltransferase 1 selective substrate) at rates that did not differ significantly (p > 0.05) between rabbits positive and negative for NAT2. The new NAT2 genotyping method facilitates use of the rabbit model to investigate the role of acetylator polymorphism in the metabolism of aromatic and heterocyclic amine drugs and carcinogens.

Evaluation of COBAS AmpliPrep/COBAS TaqMan CMV Test for use in hematopoietic stem cell transplant recipients.

PubMed

Ramanan, Poornima; Razonable, Raymund R

2017-07-01

Cytomegalovirus (CMV) is a common opportunistic infection that contributes to poor outcomes in hematopoietic stem cell transplant (HSCT) recipients. Prevention of CMV end-organ disease in allogeneic HSCT recipients is commonly achieved by preemptive antiviral therapy of asymptomatic CMV reactivation that is detected by serial nucleic acid testing (NAT). However, there was no standardized CMV NAT until the development of the World Health Organization (WHO) International Standard. Areas covered: This article provides a comprehensive review on COBAS AmpliPrep/TaqMan (CAP/CTM) CMV assay (Roche) and emphasizes the limitations in the clinical use of CMV NAT in HSCT recipients. Expert commentary: The CAP/CTM CMV Test is the first US FDA approved commercial quantitative NAT for CMV viral load monitoring of plasma samples in solid organ transplant and HSCT recipients. The CAP/CTM assay has wide linear range of DNA quantification and demonstrates colinearity to the WHO International Standard. Studies of CAP/CTM CMV assay in HSCT recipients are still limited, but are now being reported to define viral thresholds for diagnosis, surveillance and monitoring. Results from these early studies in HSCT recipients suggest that, while the WHO IS has improved the inter-laboratory result variances, there are still important factors that continue to contribute to assay variability. This lack of harmony among NAT highlights the need for further standardization.

Diagnostic laparoscopy should be performed before definitive resection for pancreatic cancer: a financial argument

PubMed Central

Jayakrishnan, Thejus T; Nadeem, Hasan; Groeschl, Ryan T; George, Ben; Thomas, James P; Ritch, Paul S; Christians, Kathleen K; Tsai, Susan; Evans, Douglas B; Pappas, Sam G; Gamblin, T Clark; Turaga, Kiran K

2015-01-01

Objectives Laparoscopy is recommended to detect radiographically occult metastases in patients with pancreatic cancer before curative resection. This study was conducted to test the hypothesis that diagnostic laparoscopy (DL) is cost-effective in patients undergoing curative resection with or without neoadjuvant therapy (NAT). Methods Decision tree modelling compared routine DL with exploratory laparotomy (ExLap) at the time of curative resection in resectable cancer treated with surgery first, (SF) and borderline resectable cancer treated with NAT. Costs (US$) from the payer's perspective, quality-adjusted life months (QALMs) and incremental cost-effectiveness ratios (ICERs) were calculated. Base case estimates and multi-way sensitivity analyses were performed. Willingness to pay (WtP) was US$4166/QALM (or US$50 000/quality-adjusted life year). Results Base case costs were US$34 921 for ExLap and US$33 442 for DL in SF patients, and US$39 633 for ExLap and US$39 713 for DL in NAT patients. Routine DL is the dominant (preferred) strategy in both treatment types: it allows for cost reductions of US$10 695/QALM in SF and US$4158/QALM in NAT patients. Conclusions The present analysis supports the cost-effectiveness of routine DL before curative resection in pancreatic cancer patients treated with either SF or NAT. PMID:25123702

Tuning growth cycles of Brassica crops via natural antisense transcripts of BrFLC.

PubMed

Li, Xiaorong; Zhang, Shaofeng; Bai, Jinjuan; He, Yuke

2016-03-01

Several oilseed and vegetable crops of Brassica are biennials that require a prolonged winter cold for flowering, a process called vernalization. FLOWERING LOCUS C (FLC) is a central repressor of flowering. Here, we report that the overexpression of natural antisense transcripts (NATs) of Brassica rapa FLC (BrFLC) greatly shortens plant growth cycles. In rapid-, medium- and slow-cycling crop types, there are four copies of the BrFLC genes, which show extensive variation in sequences and expression levels. In Bre, a biennial crop type that requires vernalization, five NATs derived from the BrFLC2 locus are rapidly induced under cold conditions, while all four BrFLC genes are gradually down-regulated. The transgenic Bre lines overexpressing a long NAT of BrFLC2 do not require vernalization, resulting in a gradient of shortened growth cycles. Among them, a subset of lines both flower and set seeds as early as Yellow sarson, an annual crop type in which all four BrFLC genes have non-sense mutations and are nonfunctional in flowering repression. Our results demonstrate that the growth cycles of biennial crops of Brassica can be altered by changing the expression levels of BrFLC2 NATs. Thus, BrFLC2 NATs and their transgenic lines are useful for the genetic manipulation of crop growth cycles. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Benefit-risk perception of natalizumab therapy in neurologists and a large cohort of multiple sclerosis patients.

PubMed

Heesen, Christoph; Kleiter, Ingo; Meuth, Sven G; Krämer, Julia; Kasper, Jürgen; Köpke, Sascha; Gaissmaier, Wolfgang

2017-05-15

Natalizumab (NAT) is associated with the risk of progressive multifocal leukoencephalopathy (PML). Risk stratification algorithms have been developed, however, without detectable reduction of PML incidence. To evaluate to which extent patients and physicians understand and accept risks associated with NAT treatment. Prospective observational cohort study in German MS centers (n=73) among NAT-treated MS patients (n=801) and their neurologists (n=99). Patients included in this study had mean disease duration of 10.2years and a mean NAT treatment duration of 24months. More than 90% of patients and physicians voted for shared decision making or an informed choice decision making approach. Patients and physicians perceived a similar threat from MS as serious disease and both overestimated treatment benefits from NAT based on trial data. Men perceived MS more severe than women and perception of seriousness increased with age in both groups and in patients as well with increasing disability. Although patients evaluated their PML risk higher, their risk acceptance was significantly higher than of their neurologists. Risk stratification knowledge was good among neurologists and significantly lower among patients. While patients and physicians seem to have realistic risk perception of PML and knowledge of risk stratification concepts, the threat of MS and the perception of treatment benefits may explain the ongoing high acceptance of PML risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Dose Calculations for [131I] Meta-Iodobenzylguanidine-Induced Bystander Effects

PubMed Central

Gow, M. D.; Seymour, C. B.; Boyd, M.; Mairs, R. J.; Prestiwch, W. V.; Mothersill, C. E.

2014-01-01

Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier – Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 – 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 – 0.75 Gy/h for UVW/NAT and 0.07 – 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 – 0.23 Gy for UVW and 0.03 – 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander dose-response profile similar to that generated by external beam gamma irradiation but with significantly greater cell death. PMID:24659931

Detection and identification of occult HBV in blood donors in Taiwan using a commercial, multiplex, multi-dye nucleic acid amplification technology screening test.

PubMed

Lin, K T; Chang, C L; Tsai, M H; Lin, K S; Saldanha, J; Hung, C M

2014-02-01

The ability of a new generation commercial, multiplex, multi-dye test from Roche, the cobas TaqScreen MPX test, version 2.0, to detect and identify occult HBV infections was evaluated using routine donor samples from Kaohsiung Blood Bank, Taiwan. A total of 5973 samples were tested by nucleic acid amplification technology (NAT); 5898 in pools of six, 66 in pools of less than six and nine samples individually. NAT-reactive samples were retested with alternative NAT tests, and follow-up samples from the donors were tested individually by NAT and for all the HBV serological markers. Eight NAT-only-reactive donors were identified, and follow-up samples were obtained from six of the donors. The results indicated that all eight donors had an occult HBV infection with viral loads <12 IU/ml. The cobas(®) TaqScreen MPX test, version 2.0, has an advantage over the current Roche blood screening test, the cobas TaqScreen MPX test, for screening donations in countries with a high prevalence of occult HBV infections since the uncertainty associated with identifying samples with very low viremia is removed by the ability of the test to identify the viral target in samples that are reactive with the cobas TaqScreen MPX test, version 2.0. © 2013 International Society of Blood Transfusion.

Network Traffic Generator for Low-rate Small Network Equipment Software

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

Lanzisera, Steven

2013-05-28

Application that uses the Python low-level socket interface to pass network traffic between devices on the local side of a NAT router and the WAN side of the NAT router. This application is designed to generate traffic that complies with the Energy Star Small Network Equipment Test Method.

78 FR 61366 - Agency Information Collection Activities: Submission to OMB for Review and Approval; Public...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-03

... Collection Request Title: Nurse Anesthetist Traineeship (NAT) Program Application OMB No. 0915-xxxx--NEW... training grants to educational institutions to increase the numbers of Nurse Anesthetists through the NAT... from which enrollees/trainees are graduating, and the distribution of Nurse Anesthetists to practice in...

77 FR 9673 - National Institute of Environmental Health Sciences; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-17

... Neurobiology. Place: Nat. Inst. of Environmental Health Sciences, Building 101, Rodbell Auditorium, 111 T. W... Sciences, Building 101, Rodbell Auditorium, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709...: Nat. Inst. of Environmental Health Sciences, Building 101, Rodbell Auditorium, 111 T. W. Alexander...

Subsurface Assessment at McMurdo Station, Antarctica

DTIC Science & Technology

2017-02-01

collected at the T-site for design and construction of a foundation for a wind turbine (after Oswell et al. 2010...foundation for a wind turbine (after Oswell et al. 2010). 5.3 Surface snowmelt and frost susceptibility The gravelly sand with silts found in this...maximum unfrozen density with low moisture content. Compaction of fill materials for con- structing wind turbine foundations at the T-site commenced

Visual Motion Perception

DTIC Science & Technology

1991-08-15

Conversely, displays Atr con- past experience to the experimental stimuli. structed %xith normal density- controlled KDE cues but %ith 5. Excluding...frame. This 3Ndisplays, gray background is displayed’ on ail introduces 50% -scintillation (density control lion even frames (labelled 1:0). Other non ...video tapes were prepared, each of whsich contained all the experimental ASL signs but distributed 1 2 3 4 into dliffereint. filter groups . Eight

Rhipicephalus (Boophilus) microplus strain Deutsch, 5 BAC clone sequencing, including two encoding Cytochrome P450s and one encoding CzEst9 carboxylesterase

USDA-ARS?s Scientific Manuscript database

The cattle tick, Rhipicephalus (Boophilus) microplus, has a genome over 2.4 times the size of the human genome, and with over 70% of repetitive DNA, this genome would prove very costly to sequence at today's prices and difficult to assemble and analyze. BAC clones give insight into the genome struct...

Corrigendum to "Stereochemical analysis of menthol and menthylamine isomers using calculated and experimental optical rotation data" [J. Mol. Struct. 1103 (2016) 166-176

NASA Astrophysics Data System (ADS)

Reinscheid, F.; Reinscheid, U. M.

2016-04-01

The authors regret to inform that a typographical error occurred in the published version of the article. In the last sentence of the abstract and of the conclusion the correct expression with the specific optical rotation should read "-10 < [α] < +10". We would like to apologize for the inconvenience caused.

EDITORIAL Complexity of advanced radiation therapy necessitates multidisciplinary inquiry into dose reconstruction and risk assessment Complexity of advanced radiation therapy necessitates multidisciplinary inquiry into dose reconstruction and risk assessment

NASA Astrophysics Data System (ADS)

Newhauser, Wayne

2010-07-01

The availability of low-cost, high-performance computing is rapidly transforming the landscape of cancer research. Computational techniques are playing an increasingly important role and have become the third major method of scientific inquiry, supplementing traditional methods of observation and theory. This evolution began in the 1940s when high-performance computing techniques were developed for military applications, including radiation transport calculations. These same basic methods are still widely utilized in a broad spectrum of computational problems in medicine, including radiation cancer therapy (Rogers 2006, Spezi 2010) and radiologic diagnostic imaging (Doi 2006, Kalender 2006). Supercomputing is also now being used to study the genetics and genomics of cancer (Geurts van Kessel 2010), with application to gene sequencing (Mardis 2008), genome-wide association studies (Pearson and Manolio 2008), biomolecular dynamics (Sanbonmatsu and Tung 2007) and systems biology (Wolkenhauer et al 2010). The extensive and growing body of literature is evidence of a remarkable expansion of activity and enormous boost to cancer research from the application of high-performance computing. Early successes were facilitated by inexpensive computing resources and advances in modeling algorithms. Many contemporary models require extensive approximations and phenomenological approaches. In fact, many critical problems remain computationally intractable; the underlying physical and biological processes are simply too complex to model with contemporary theory and computing capacity. In the future, a vast stream of new insights will flow from studies that use increasingly exact models and first-principles approaches. Hence, in the war on cancer the present status of computational research could be summarized as the beginning of the beginning. For these reasons, there is a vital need for scientists and clinicians to periodically discuss progress and future plans regarding computational cancer research, particularly research involving supercomputing. In April 2010, a symposium entitled '4th Joint Symposium on Computational Medical Physics: The Nexus of Research on Cancer, Radiation, and Supercomputing: Dawn of a Golden Age?' was convened at Rice University in Houston, Texas. One objective of this symposium was to provide researchers and clinicians with an overview of recent progress in advanced radiation therapy. Another was to review basic concepts and methods from a wide variety of disciplines related to cancer radiation therapy, including supercomputing, physics, informatics, imaging, and epidemiology. The symposium featured current issues and controversies and, in particular, a review of recent advances in research on proton and photon therapies. Sessions included Current Issues in Proton Therapy for Pediatric Cancers; Current Issues in Advanced Radiotherapy for Prostate Cancer; Charged Particles in Space and Military Applications; Recent Advances in Radiation Epidemiology; Advanced Computing Techniques: Perspectives from Cancer Researchers and Computer Scientists; Radiobiologic, Dosimetric, and Outcomes Modeling; Imaging and Informatics, and a Young Investigators' Symposium. The complete program is available at www.regonline.com/joint_symposium. The symposium was attended by more than 100 delegates who delivered 47 oral presentations. The delegates included leading scientists and clinicians from the fields of epidemiology, particle physics, medical physics, mathematics, oncology, and cancer prevention. This issue of Physics in Medicine and Biology contains 13 original research articles based on selected presentations from the symposium. Each article underwent the journal's usual rigorous peer review process; we are grateful to the many individuals who contributed to this issue, including the publishing editor, board members, referees, and of course the authors, all of whom generously shared their time and expertise. The majority of articles from the symposium are interrelated and focus on dose and risk assessments related to radiation exposures from advanced radiation therapies. These research topics have become increasingly complex and require the combined expertise of researchers with highly specialized and diverse investigational skills. Innovative multidisciplinary teams will be needed to achieve breakthroughs and, ultimately, to translate the research into clinical practice (Disis and Slattery 2010). The symposium's scientific goals included fostering and promoting such multidisciplinary teams, which will work to solve these complex problems and thereby improve cancer outcomes. To help clarify how the 13 articles each contribute to the goal of improving cancer outcomes, a brief digression is necessary. The proportion of patients surviving their cancers for five years or more is large and increasing (Jemal et al 2009). Unfortunately, in survivors who received radiation therapy, the prevalence of radiogenic late effects is likewise large and increasing (cf Altekruse et al 2010, Meadows et al 2009, Hudson et al 2009, Friedman et al 2010), with the potential to become a public health issue of considerable scale (Travis 2006). A multitude of late effects are associated with radiation exposure, including the development of second cancers, cardiac toxicity, cognitive deficits, and musculoskeletal growth abnormalities in children. In modern radiation therapy, much effort is devoted to developing personalized treatments that control the tumor while minimizing acute toxicities to surrounding healthy tissues; comparatively less attention has been paid to minimizing late effects (Durante and Loeffler 2010). In recent years, however, there has been an encouraging increase in research activities seeking to quantify radiation exposures (Stovall et al 2006) and the associated risks of late effects from modern external-beam therapies (Xu et al 2008). In this issue, Zhang et al (2010) report on Monte Carlo and analytical models to predict the stray radiation exposure in a patient receiving proton radiotherapy. In this study, the authors focused on stray neutron radiation that emanated from the treatment unit. Despite the complexity of high-energy neutron dosimetry, the authors succeeded in developing a relatively simple analytical model to predict these exposures. This finding is important because, with further development, it could provide a method to predict stray radiation exposures as an enhanced form of routine treatment planning. Fontenot et al (2010) report on methods to evaluate uncertainties in comparative risk assessments; knowledge of uncertainties is vital to determine the limits of applicability in these assessments, which may in turn affect clinical and policy decisions. Howell et al (2010a) report on the accuracy of a widely used radiation treatment planning system. In particular, they investigated the system's dosimetric accuracy outside the treatment beam, e.g. due to scatter and leakage radiation from external-beam photon therapy. This study provides important illustrative evidence of the need to carefully validate dose algorithms in out-of-field regions. In a related study, Howell et al (2010b) developed a methodology to estimate doses to partially in-field and out-of-field organs. Scarboro et al (2010) report on the impact of organ size and position on out-of-field dose estimates. Taddei et al (2010a) report on the targeting accuracy of a novel device that can be used to treat age-related macular degeneration, the leading cause of blindness in the developed world. Taddei et al (2010b) report on the risks of radiogenic second cancers following proton and photon radiation therapies for liver cancer. Taddei et al (2010c) also compare the risks of radiogenic second cancers from secondary neutrons for a boy and a girl after receiving craniospinal irradiation with passively scattered proton beams. Scanned-beam proton therapy is presently considered the technologically most complex beam delivery approach and is used in only a few centers worldwide. Coutrakon et al (2010) reported on an investigation of dosimetric errors associated with the delivery of scanned proton beams. Titt et al (2010) report on a novel method to adjust the size of scanned proton beams. This study is important because our inability to produce very small beam spot sizes has been an obstacle to realizing the full clinical potential of this technique. Yepes et al (2010) report on the speedup and accuracy of a fast proton dose algorithm that uses an array of graphics processing units; this technique represents a nascent low-cost alternative to the traditional approach of high-performance computing using central processing units. Radiation exposures from kilovoltage computed tomography (CT) procedures have increased dramatically, with the fraction of collective effective dose from CT exposures rising from 3% in the early 1980s to 49% in 2006 (NCRP 2009). Proton CT is an emerging technology that may enable reductions in both proton range uncertainties and the imaging dose to the patient relative to comparable kilovoltage CT techniques. Erdelyi (2010) reports on uncertainties in electron densities estimated using proton CT. Finally, Cheung et al (2010) report on the suitability of advanced composite fiducial markers for localization of the prostate in proton therapy. Their analysis is particularly important because approximately 60% of the proton treatment capacity in the United States is used for patients with prostate cancer. The symposium was the fourth of a series entitled 'Symposia on Computational Cancer Research'. The symposia have alternately been hosted by The University of Texas M D Anderson Cancer Center, Rice University, and Northern Illinois University. The fifth joint symposium will be held in Houston, on 5-7 April 2011, and will focus on survivorship issues after childhood cancers (www.regonline.com/5thjointsymposium). On behalf of the symposium organizing committee, I hope to see you there. Wayne Newhauser, The University of Texas M D Anderson Cancer Center, USA Chairman of 4th Joint Symposium Organizing Committee and Guest Editor References Altekruse S F et al (ed) SEER Cancer Statistics Review, 1975--2007 (Bethesda, MD: National Cancer Institute) (http://seer.cancer.gov/csr/1975_2007/) based on November 2009 SEER data submission, posted to the SEER website, 2010 Cheung J, Kudchadker R J, Zhu X R, Lee A K and Newhauser W D 2010 Dose perturbations and image artifacts caused by carbon-coated ceramic and stainless steel fiducials used in proton therapy for prostate cancer Phys. Med. Biol. 55 7135-47 Coutrakon G, Wang N, Miller D W and Yang Y 2010 Dose error analysis for a scanned proton beam delivery system Phys. Med. Biol. 55 7081-96 Disis M L and Slattery J T 2010 The road we must take: multidisciplinary team science Sci. Transl. Med. 2 22cm9 Doi K 2006 Diagnostic imaging over the last 50 years: research and development in medical imaging science and technology Phys. Med. Biol. 51 R5-27 Durante M and Loeffler J S 2010 Charged particles in radiation oncology Nat. Rev. Clin. Oncol. 7 37-43 Erdelyi B 2010 Electron density uncertainties in proton computed tomography Phys. Med. Biol. 55 7121-34 Fontenot J D, Bloch C, Followill D, Titt U, Zhang M and Newhauser W D 2010 Estimate of the uncertainties in the relative risk of secondary malignant neoplasms following proton therapy and intensity-modulated photon therapy Phys. Med. Biol. 55 6987-98 Friedman D L, Whitton J, Leisenring W, Mertens A C, Hammond S, Stovall M, Donaldson S S, Meadows A T, Robison L L and Neglia J P 2010 Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study J. Natl Cancer Inst. 102 1083-95 Geurts van Kessel A 2010 The 'omics' of cancer Cancer Genet. Cytogenet. 203 37-42 Howell R M, Scarboro S B, Kry S F and Yaldo D Z 2010a Accuracy of out-of-field dose calculations by a commercial treatment planning system Phys. Med. Biol. 55 6999-7008 Howell R M, Scarboro S B, Taddei P J, Krishnan S, Kry S F and Newhauser W D 2010b Methodology for determining doses to in-field, out-of-field and partially in-field organs for late effects studies in proton radiotherapy Phys. Med. Biol. 55 7009-23 Hudson M M, Mulrooney D A, Bowers D C, Sklar C A, Green D M, Donaldson S S, Oeffinger K C, Neglia J P, Meadows A T and Robison L L 2009 High-risk populations identified in Childhood Cancer Survivor Study investigations: implications for risk-based surveillance J. Clin. Oncol. 27 2405-14 Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun M J 2009 Cancer statistics, 2009 CA Cancer J. Clin. 59 225-49 Kalender W A 2006 X-ray computed tomography Phys. Med. Biol. 51 R29-43 Mardis E R 2008 Next-generation DNA sequencing methods Annu. Rev. Genomics Hum. Genet. 9 387-402 Meadows A T, Friedman D L, Neglia J P, Mertens A C, Donaldson S S, Stovall M, Hammond S, Yasui Y and Inskip P D 2009 Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort J. Clin. Oncol. 27 2356-62 NCRP (National Council on Radiation Protection and Measurements) 2009 Ionizing radiation exposure of the population of the United States {\\it NCRP Report No. 160} (Bethesda, MD: NCRP) Pearson T A and Manolio T A 2008 How to interpret a genome-wide association study JAMA 299 1335-44 Rogers D W 2006 Fifty years of Monte Carlo simulations for medical physics Phys. Med. Biol. 51 R287-301 Sanbonmatsu K Y and Tung C S 2007 High performance computing in biology: multimillion atom simulations of nanoscale systems J. Struct. Biol. 157 470-80 Scarboro S B, Stovall M, White A, Smith S A, Yaldo D, Kry S F and Howell R M 2010 Effect of organ size and position on out-of-field dose distributions during radiation therapy Phys. Med. Biol. 55 7025-36 Spezi E (ed) 2010 Special section: Selected papers from the Second European Workshop on Monte Carlo Treatment Planning (MCTP2009) Phys. Med. Biol. 55 (16) 4431-614 Stovall M, Weathers R, Kasper C, Smith S A, Travis L, Ron E and Kleinerman R 2006 Dose reconstruction for therapeutic and diagnostic radiation exposures: use in epidemiological studies Radiat. Res. 166 141-57 Taddei P J, Chell E, Hansen S, Gertner M and Newhauser W D 2010a Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration Phys. Med. Biol. 55 7037-54 Taddei P J, Howell R M, Krishnan S, Scarboro S B, Mirkovic D and Newhauser W D 2010b Risk of second malignant neoplasm following proton versus intensity-modulated photon radiotherapies for hepatocellular carcinoma Phys. Med. Biol. 55 7055-65 Taddei P J, Mahajan A, Mirkovic D, Zhang R, Giebeler A, Kornguth D, Harvey M, Woo S and Newhauser W D 2010c Predicted risks of second malignant neoplasm incidence and mortality due to secondary neutrons in a girl and boy receiving proton craniospinal irradiation Phys. Med. Biol. 55 7067-80 Titt U, Mirkovic D, Sawakuchi G O, Perles L A, Newhauser W D, Taddei P J and Mohan R 2010 Adjustment of the lateral and longitudinal size of scanned proton beam spots using a pre-absorber to optimize penumbrae and delivery efficiency Phys. Med. Biol. 55 7097-106 Travis L B 2006 The epidemiology of second primary cancers Cancer Epidemiol. Biomarkers Prev. 15 2020-6 Wolkenhauer O et al 2010 Systems biologists seek fuller integration of systems biology approaches in new cancer research programs Cancer Res. 70 12-3 Xu X G, Bednarz B and Paganetti H 2008 A review of dosimetry studies on external-beam radiation treatment with respect to second cancer induction Phys. Med. Biol. 53 R193-241 Yepes P, Mirkovic D and Taddei P J 2010 A GPU implementation of a track-repeating algorithm for proton radiotherapy dose calculations Phys. Med. Biol. 55 7107-20 Zhang R, P\\'{e}rez-And\\'{u}jar A, Fontenot J D, Taddei P J and Newhauser W D 2010 An analytic model of neutron ambient dose equivalent and equivalent dose for proton radiotherapy Phys. Med. Biol. 55 6975-85

Non-accidental trauma in pediatric patients: a review of epidemiology, pathophysiology, diagnosis and treatment

PubMed Central

Adamo, Matthew A.

2014-01-01

Non-accidental trauma (NAT) is a leading cause of childhood traumatic injury and death in the United States. It is estimated that 1,400 children died from maltreatment in the United States in 2002 and abusive head trauma (AHT) accounted for 80% of these deaths. This review examines the epidemiology and risk factors for NAT as well as the general presentation and required medical work up of abused children. In addition, potential algorithms for recognizing cases of abuse are reviewed as well as outcomes in children with NAT and potential neurosurgical interventions which may be required. Finally, the evidence for seizure prophylaxis in this population is addressed. PMID:26835337

Ideal Gas with a Varying (Negative Absolute) Temperature: an Alternative to Dark Energy?

NASA Astrophysics Data System (ADS)

Saha, Subhajit; Mondal, Anindita; Corda, Christian

2018-02-01

The present work is an attempt to investigate whether the evolutionary history of the Universe from the offset of inflation can be described by assuming the cosmic fluid to be an ideal gas with a specific gas constant but a varying negative absolute temperature (NAT). The motivation of this work is to search for an alternative to the "exotic" and "supernatural" dark energy (DE). In fact, the NAT works as an "effective quintessence" and there is need to deal neither with exotic matter like DE nor with modified gravity theories. For the sake of completeness, we release some clarifications on NATs in Section 3 of the paper.

MATERNAL SMOKING DURING PREGNANCY, GENETIC VARIATION OF ACETYL-N-TRANSFERASES NAT1 AND NAT2, AND RISK FOR OROFACIAL CLEFTS. (R828292)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Production of ⁶¹Cu by the natZn(p,α) reaction: Improved separation and specific activity determination by titration with three chelators

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

Asad, Ali H.; Smith, Suzanne V.; Morandeau, Laurence M.

In this study, the cyclotron-based production of position-emitting ⁶¹Cu using the (p,α) reaction at 11.7 MeV was investigated starting from natural-zinc ( natZn) and enriched ⁶⁴Zn-foil targets, as well as its subsequent purification. For natZn, a combination of three resins were assessed to separate ⁶¹Cu from contaminating 66,67,68Ga and natZn. The specific activity of the purified ⁶¹Cu determined using ICP-MS analysis ranged from 143.3±14.3(SD) to 506.2±50.6 MBq/μg while the titration method using p-SCN-Bn-DOTA, p-SCN-Bn-NOTA and diamsar gave variable results (4.7±0.2 to 412.5±15.3 MBq/μg), with diamsar lying closest to the ICP-MS values. Results suggest that the p-SCN-Bn-DOTA and p-SCN-Bn-NOTA titration methodsmore » are significantly affected by the presence of trace-metal contaminants.« less

64Cu, a powerful positron emitter for immunoimaging and theranostic: Production via natZnO and natZnO-NPs.

PubMed

Karimi, Zahra; Sadeghi, Mahdi; Mataji-Kojouri, Naimeddin

2018-07-01

64 Cu is one of the most beneficial radionuclide that can be used as a theranostic agent in Positron Emission Tomography (PET) imaging. In this current work, 64 Cu was produced with zinc oxide nanoparticles ( nat ZnONPs) and zinc oxide powder ( nat ZnO) via the 64 Zn(n,p) 64 Cu reaction in Tehran Research Reactor (TRR) and the activity values were compared with each other. The theoretical activity of 64 Cu also was calculated with MCNPX-2.6 and the cross sections of this reaction were calculated by using TALYS-1.8, EMPIRE-3.2.2 and ALICE/ASH nuclear codes and were compared with experimental values. Transmission Electronic Microscopy (TEM), Scanning Electronic Microscopy (SEM) and X-Ray Diffraction (XRD) analysis were used for samples characterizations. From these results, it's concluded that 64 Cu activity value with nanoscale target was achieved more than the bulk state target and had a good adaptation with the MCNPX result. Copyright © 2018 Elsevier Ltd. All rights reserved.

Production of ⁶¹Cu by the natZn(p,α) reaction: Improved separation and specific activity determination by titration with three chelators

DOE PAGES

Asad, Ali H.; Smith, Suzanne V.; Morandeau, Laurence M.; ...

2015-09-01

In this study, the cyclotron-based production of position-emitting ⁶¹Cu using the (p,α) reaction at 11.7 MeV was investigated starting from natural-zinc ( natZn) and enriched ⁶⁴Zn-foil targets, as well as its subsequent purification. For natZn, a combination of three resins were assessed to separate ⁶¹Cu from contaminating 66,67,68Ga and natZn. The specific activity of the purified ⁶¹Cu determined using ICP-MS analysis ranged from 143.3±14.3(SD) to 506.2±50.6 MBq/μg while the titration method using p-SCN-Bn-DOTA, p-SCN-Bn-NOTA and diamsar gave variable results (4.7±0.2 to 412.5±15.3 MBq/μg), with diamsar lying closest to the ICP-MS values. Results suggest that the p-SCN-Bn-DOTA and p-SCN-Bn-NOTA titration methodsmore » are significantly affected by the presence of trace-metal contaminants.« less

Interaction of HCl with a beta-NAT Surface: Prediction of the IR Spectrum

NASA Astrophysics Data System (ADS)

Martin-Llorente, B.; Escribano, R. M.; Fernandez-Torre, D.; Galvez, O.; Herrero, V. J.; Mate, B.; Moreno, M. A.

2009-04-01

Heterogeneous reactions that take place over the surface of polar stratospheric cloud (PSC) particles are thought to play an important role on stratospheric ozone depletion. Chlorine reservoir species, such as HCl and ClONO2, adsorbed on those particles, can be converted to reactive chlorine compounds, responsible for the destruction of ozone. The high temperature phase of nitric acid trihydrate (β-NAT) is one of the most important constituents of PSC. We present here a theoretical study of the system formed by HCl and β-NAT, by means of DFT calculations[1]. The adsorption of HCl on the most favourable site of the (001) surface of the β-NAT crystal[2] is simulated with a suitable model for the description of the vibrational properties of the system. Other possible adsorption sites will also be revised. An assignment of the different spectroscopic features, such as a small band at 2150 cm-1 attributed to the stretching of the adsorbed HCl molecule, is performed by comparing the predicted absorption spectrum with the experimental results[3] [1] J. M. Soler, E. Artacho, J. D. Gale, A. Garc

External quality assurance of malaria nucleic acid testing for clinical trials and eradication surveillance.

PubMed

Murphy, Sean C; Hermsen, Cornelus C; Douglas, Alexander D; Edwards, Nick J; Petersen, Ines; Fahle, Gary A; Adams, Matthew; Berry, Andrea A; Billman, Zachary P; Gilbert, Sarah C; Laurens, Matthew B; Leroy, Odile; Lyke, Kristen E; Plowe, Christopher V; Seilie, Annette M; Strauss, Kathleen A; Teelen, Karina; Hill, Adrian V S; Sauerwein, Robert W

2014-01-01

Nucleic acid testing (NAT) for malaria parasites is an increasingly recommended diagnostic endpoint in clinical trials of vaccine and drug candidates and is also important in surveillance of malaria control and elimination efforts. A variety of reported NAT assays have been described, yet no formal external quality assurance (EQA) program provides validation for the assays in use. Here, we report results of an EQA exercise for malaria NAT assays. Among five centers conducting controlled human malaria infection trials, all centers achieved 100% specificity and demonstrated limits of detection consistent with each laboratory's pre-stated expectations. Quantitative bias of reported results compared to expected results was generally <0.5 log10 parasites/mL except for one laboratory where the EQA effort identified likely reasons for a general quantitative shift. The within-laboratory variation for all assays was low at <10% coefficient of variation across a range of parasite densities. Based on this study, we propose to create a Molecular Malaria Quality Assessment program that fulfills the need for EQA of malaria NAT assays worldwide.

Association of N-acetyltransferase-2 and glutathione S-transferase polymorphisms with idiopathic male infertility in Vietnam male subjects.

PubMed

Trang, Nguyen Thi; Huyen, Vu Thi; Tuan, Nguyen Thanh; Phan, Tran Duc

2018-04-25

N-acetyltransferase-2 (NAT2) and Glutathione S-transferases (GSTs) are phase-II xenobiotic metabolizing enzymes participating in detoxification of toxic arylamines, aromatic amines, hydrazines and reactive oxygen species (ROS), which are produced under oxidative and electrophile stresses. The purpose of this research was to investigate whether two common single-nucleotide polymorphisms (SNP) of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) associated with susceptibility to idiopathic male infertility. A total 300 DNA samples (150 infertile patients and 150 healthy control) were genotyped for the polymorphisms by ARMS - PCR. We revealed a significant association between the NAT2 variant genotypes (CT + TT (rs1799929), (OR: 3.74; p < 0.001)) and (GA + AA (rs1799930), (OR: 3.75; p < 0.001)) or GSTP1 variant genotypes (GA + AA (rs1695), (OR: 5.11; p < 0,001)) and (CT + TT (rs1138272), (OR: 7.42; p < 0,001) with idiopathic infertility risk. Our findings rate the effect of single-nucleotide polymorphisms of GSTP1 and/or NAT2 in modulation of the risk of male infertility in subjects from Vietnam. This pilot study is the first (as far as we know) to reveal that polymorphisms of NAT2 (rs1799929, rs1799930) and GSTP1 (rs1138272, rs1695) are some novel genetic markers for susceptibility to idiopathic male infertility. Copyright © 2018 Elsevier B.V. All rights reserved.

Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

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

Matthew, E.; Parfitt, A.G.; Sugden, D.

1984-02-01

Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects ofmore » diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.« less

Improving Patient Safety in Hospitals: Contributions of High-Reliability Theory and Normal Accident Theory

PubMed Central

Tamuz, Michal; Harrison, Michael I

2006-01-01

Objective To identify the distinctive contributions of high-reliability theory (HRT) and normal accident theory (NAT) as frameworks for examining five patient safety practices. Data Sources/Study Setting We reviewed and drew examples from studies of organization theory and health services research. Study Design After highlighting key differences between HRT and NAT, we applied the frames to five popular safety practices: double-checking medications, crew resource management (CRM), computerized physician order entry (CPOE), incident reporting, and root cause analysis (RCA). Principal Findings HRT highlights how double checking, which is designed to prevent errors, can undermine mindfulness of risk. NAT emphasizes that social redundancy can diffuse and reduce responsibility for locating mistakes. CRM promotes high reliability organizations by fostering deference to expertise, rather than rank. However, HRT also suggests that effective CRM depends on fundamental changes in organizational culture. NAT directs attention to an underinvestigated feature of CPOE: it tightens the coupling of the medication ordering process, and tight coupling increases the chances of a rapid and hard-to-contain spread of infrequent, but harmful errors. Conclusions Each frame can make a valuable contribution to improving patient safety. By applying the HRT and NAT frames, health care researchers and administrators can identify health care settings in which new and existing patient safety interventions are likely to be effective. Furthermore, they can learn how to improve patient safety, not only from analyzing mishaps, but also by studying the organizational consequences of implementing safety measures. PMID:16898984

Improving outcomes for people with progressive cancer: interrupted time series trial of a needs assessment intervention.

PubMed

Waller, Amy; Girgis, Afaf; Johnson, Claire; Lecathelinais, Christophe; Sibbritt, David; Forstner, Dion; Liauw, Winston; Currow, David C

2012-03-01

Improving the effectiveness of cancer care delivery has become a major focus of research. This study assessed the uptake and impact of the Palliative Care Needs Assessment Guidelines and Needs Assessment Tool: Progressive Disease--Cancer (NAT: PD-C) on the outcomes of people with advanced cancer. Given widely varying survival in people with advanced cancer, an interrupted time series design was used, with data on unmet needs, depression, anxiety, and quality of life collected from 195 patients using telephone interviews every two months, for up to 18 months. Patients completed at least two baseline interviews before health professionals were academically detailed in the use of the Palliative Care Needs Assessment Guidelines and NAT: PD-C. Health professionals completed the NAT: PD-C with patients approximately monthly for the remainder of the study. Changes in patients' outcomes were compared prior to and following the introduction of the NAT: PD-C using general estimating equations. Moderate to high needs across all domains were frequently seen in the preintervention phase. The use of the NAT: PD-C was associated with a significant reduction in health system and information and patient care and support needs. These resources have the potential as an efficient and acceptable strategy for supporting needs-based cancer care. Further work is required to determine their unique contribution to improvements in patient outcomes. Copyright © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Sexual activity and perceived health among Finnish middle-aged women

PubMed Central

Ojanlatva, Ansa; Mäkinen, Juha; Helenius, Hans; Korkeila, Katariina; Sundell, Jari; Rautava, Päivi

2006-01-01

Background An increasing awareness of the need to address sexual and orgasm experiences as part of life quality and an understanding of the great individual differences between women play roles in women's health and medical care across the specialities. Information is lacking as to how negative attitude toward self (NATS) and performance impairment (PI) are associated with sexual activity of middle-aged women. We examined the associations of sexual experience, orgasm experience, and lack of sexual desire with perceived health and potential explanatory variables of NATS and PI. Methods Questionnaire was mailed to 2 population-based random samples of menopausal or soon-to-be menopausal women (n = 5510, 70% response) stratified according to age (42–46 and 52–56 years). In multivariate analyses of the associations with the outcome variables, perceived health, NATS, and PI were used as covariates in 6 models in which exercise, menstrual symptoms, and illness indicators were taken into account as well. Results Sexual activity variables were associated with perceived health. When present, NATS formed associations with sexual and orgasm experiences, whereas strenuous exercise formed associations with orgasm among 42–46-year-old women alone. Strenuous exercise was not associated with orgasm experience among older women. Conclusion NATS and PI are closely tied to orgasm experiences and the meaning of the roles needs to be exposed. Sexual activity deserves to be addressed more actively in patient contact at least with perimenopausal women. PMID:16686959

Standing of nucleic acid testing strategies in veterinary diagnosis laboratories to uncover Mycobacterium tuberculosis complex members

PubMed Central

Costa, Pedro; Botelho, Ana; Couto, Isabel; Viveiros, Miguel; Inácio, João

2014-01-01

Nucleic acid testing (NAT) designate any molecular approach used for the detection, identification, and characterization of pathogenic microorganisms, enabling the rapid, specific, and sensitive diagnostic of infectious diseases, such as tuberculosis. These assays have been widely used since the 90s of the last century in human clinical laboratories and, subsequently, also in veterinary diagnostics. Most NAT strategies are based in the polymerase chain reaction (PCR) and its several enhancements and variations. From the conventional PCR, real-time PCR and its combinations, isothermal DNA amplification, to the nanotechnologies, here we review how the NAT assays have been applied to decipher if and which member of the Mycobacterium tuberculosis complex is present in a clinical sample. Recent advances in DNA sequencing also brought new challenges and have made possible to generate rapidly and at a low cost, large amounts of sequence data. This revolution with the high-throughput sequencing (HTS) technologies makes whole genome sequencing (WGS) and metagenomics the trendiest NAT strategies, today. The ranking of NAT techniques in the field of clinical diagnostics is rising, and we provide a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis with our view of the use of molecular diagnostics for detecting tuberculosis in veterinary laboratories, notwithstanding the gold standard being still the classical culture of the agent. The complementary use of both classical and molecular diagnostics approaches is recommended to speed the diagnostic, enabling a fast decision by competent authorities and rapid tackling of the disease. PMID:25988157

Standing of nucleic acid testing strategies in veterinary diagnosis laboratories to uncover Mycobacterium tuberculosis complex members.

PubMed

Costa, Pedro; Botelho, Ana; Couto, Isabel; Viveiros, Miguel; Inácio, João

2014-01-01

Nucleic acid testing (NAT) designate any molecular approach used for the detection, identification, and characterization of pathogenic microorganisms, enabling the rapid, specific, and sensitive diagnostic of infectious diseases, such as tuberculosis. These assays have been widely used since the 90s of the last century in human clinical laboratories and, subsequently, also in veterinary diagnostics. Most NAT strategies are based in the polymerase chain reaction (PCR) and its several enhancements and variations. From the conventional PCR, real-time PCR and its combinations, isothermal DNA amplification, to the nanotechnologies, here we review how the NAT assays have been applied to decipher if and which member of the Mycobacterium tuberculosis complex is present in a clinical sample. Recent advances in DNA sequencing also brought new challenges and have made possible to generate rapidly and at a low cost, large amounts of sequence data. This revolution with the high-throughput sequencing (HTS) technologies makes whole genome sequencing (WGS) and metagenomics the trendiest NAT strategies, today. The ranking of NAT techniques in the field of clinical diagnostics is rising, and we provide a SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis with our view of the use of molecular diagnostics for detecting tuberculosis in veterinary laboratories, notwithstanding the gold standard being still the classical culture of the agent. The complementary use of both classical and molecular diagnostics approaches is recommended to speed the diagnostic, enabling a fast decision by competent authorities and rapid tackling of the disease.

The expression of Per1 and Aa-nat genes in the pineal gland of postnatal rats.

PubMed

Wongchitrat, Prapimpun; Govitrapong, Piyarat; Phansuwan-Pujito, Pansiri

2012-12-01

The circadian rhythm of melatonin synthesis is controlled by the master clock, suprachiasmatic nucleus (SCN). The level of melatonin changes throughout the aging process. The SCN's rhythm is driven by autoregulatory feedback loop composed of a set of clock genes families and their corresponding proteins. The Period (Per1), one of clock gene develops gradually during postnatal ontogenesis in the rat SCN and is also expressed in the pineal gland. It is of interest to study the relationship between the postnatal development of Per1 and Aa-nat, genes that produce the rate-limiting enzyme in melatonin synthesis, in the pineal. Daily profiles of mRNA expression of Per1 and Aa-nat were analyzed in the pineal gland of pups at postnatal ages 4 (P4), P8, P16 and P32, at puberty age of 6 weeks; and in 8 week-old adult rats by real-time PCR. As early as P4, Per1 and Aa-nat mRNAs were expressed and existed at relatively high levels during the nighttime. They gradually increased until puberty and decreased at 8 weeks of age. Additionally, the nocturnal changes of Per1 and Aa-nat mRNA levels in the rat pineal gland from P4 to adults were strongly correlated at r = 0.97 (p < 0.01). The present data indicate that there is a close relationship between the expression pattern of Per1 and that of melatonin synthesis during the development of postnatal rats.

A Navigation Analysis Tool (NAT) to assess spatial behavior in open-field and structured mazes.

PubMed

Jarlier, Frédéric; Arleo, Angelo; Petit, Géraldine H; Lefort, Julie M; Fouquet, Céline; Burguière, Eric; Rondi-Reig, Laure

2013-05-15

Spatial navigation calls upon mnemonic capabilities (e.g. remembering the location of a rewarding site) as well as adaptive motor control (e.g. fine tuning of the trajectory according to the ongoing sensory context). To study this complex process by means of behavioral measurements it is necessary to quantify a large set of meaningful parameters on multiple time scales (from milliseconds to several minutes), and to compare them across different paradigms. Moreover, the issue of automating the behavioral analysis is critical to cope with the consequent computational load and the sophistication of the measurements. We developed a general purpose Navigation Analysis Tool (NAT) that provides an integrated architecture consisting of a data management system (implemented in MySQL), a core analysis toolbox (in MATLAB), and a graphical user interface (in JAVA). Its extensive characterization of trajectories over time, from exploratory behavior to goal-oriented navigation with decision points using a wide range of parameters, makes NAT a powerful analysis tool. In particular, NAT supplies a new set of specific measurements assessing performances in multiple intersection mazes and allowing navigation strategies to be discriminated (e.g. in the starmaze). Its user interface enables easy use while its modular organization provides many opportunities of extension and customization. Importantly, the portability of NAT to any type of maze and environment extends its exploitation far beyond the field of spatial navigation. Copyright © 2013 Elsevier B.V. All rights reserved.

Establishment of the Ph. Eur. Hepatitis A virus RNA for NAT testing BRP batch 1.

PubMed

Chudy, M; Nübling, C M; Blümel, J; Daas, A; Costanzo, A

2017-01-01

Detection of viral contamination in plasma donations is critical to prevent transmission of infectious diseases. The European Pharmacopoeia (Ph. Eur.) monograph 1646 'Human plasma (pooled and treated for virus inactivation)', requires that plasma pools used for the manufacture of this product be tested, among others, for the presence of hepatitis A virus RNA by nucleic acid testing (NAT) using a positive control containing 100 International Units (IU) of hepatitis A virus (HAV) RNA per mL. To this end, the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) organised an international collaborative study under the aegis of the Biological Standardisation Programme, for the establishment of the 1 st Biological Reference Preparation (BRP) for HAV RNA for NAT testing. A freeze-dried candidate material was thus prepared and calibrated against the WHO 2 nd International Standard for HAV for NAT (00/562) in a study in which thirteen European and North American laboratories including Official Medicines Control Laboratories (OMCLs), manufacturers of plasma-derived products, producers of in vitro diagnostic kits and a blood transfusion centre participated. Based on the outcome of the study, an HAV RNA content of 40 000 IU/vial (corresponding approximately to 4.6 log 10 IU/vial) was assigned to the BRP, which was adopted by the Ph. Eur. Commission in March 2016 as Ph. Eur. hepatitis A virus RNA for NAT testing BRP batch 1.

Implications of non-accidental trauma on resource utilization and outcomes.

PubMed

Litz, Cristen N; Amankwah, Ernest K; Danielson, Paul D; Chandler, Nicole M

2018-06-01

The purpose was to compare the resource utilization and outcomes between patients with suspected (SUSP) and confirmed (CONF) non-accidental trauma (NAT). The institutional trauma registry was reviewed for patients aged 0-18 years presenting from 2007 to 2012 with a diagnosis of suspicion for NAT. Patients with suspected and confirmed NAT were compared. There were 281 patients included. CONF presented with a higher heart rate (142 ± 27 vs 128 ± 23 bpm, p < 0.01), lower systolic blood pressure (100 ± 18 vs 105 ± 16 mm Hg, p = 0.03), and higher Injury Severity Score (15 ± 11 vs 9 ± 5, p < 0.01). SUSP received fewer consultations (1.6 ± 0.7 vs 2.4 ± 1.1, 95% CI - 0.58 to - 0.09, p < 0.01) and had a shorter length of stay (1.6 ± 1.3 vs 7.8 ± 9.8 days, 95% CI - 4.58 to - 0.72, p < 0.01). SUSP were more often discharged home (OR 94.22, 95% CI: 21.26-417.476, p < 0.01). CONF had a higher mortality rate (8.2 vs 0%, p < 0.01). Patients with confirmed NAT present with more severe injuries and require more hospital resources compared to patients in whom NAT is suspected and ruled out.

Significance of the genetic polymorphism of CYP2D6 and NAT2 in patients with inflammatory bowel diseases.

PubMed

Dudarewicz, Michał; Rychlik-Sych, Mariola; Barańska, Małgorzata; Wojtczak, Anna; Trzciński, Radzisław; Dziki, Adam; Skrętkowicz, Jadwiga

2014-08-01

The main types of inflammatory bowel diseases (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). There is evidence that, in addition to immunological and environmental factors, genetic factors also play an important role in the pathogenesis of IBD. Determination of polymorphism of CYP2D6 and NAT2 genes encoding I and II phase enzymes of xenobiotic biotransformation may have clinical value as an indicator of individual predisposition to diseases, and also contribute to effective and safe pharmacotherapy. The aim of this study was to investigate the association between genetic polymorphism of CYP2D6 and NAT2 and the incidence of IBD, including UC and CD, among inhabitants of central Poland. The study was performed in 258 individuals from central Poland (115 patients with IBD, including 65 patients with UC and 50 with CD; and in 143 healthy controls). The CYP2D6 genotypes of oxidation and NAT2 genotypes of acetylation were analyzed using the PCR-RFLP method. There were no statistically significant differences in the frequency of the CYP2D6 genotypes and alleles in patients with IBD, UC and CD in comparison with the control group. The relative risk (OR) of IBD, UC and CD was higher in carriers of the allele NAT2*7 and was OR=3.49 (p=0.0019), OR=3.86 (p=0.0019), and OR=3.02 (p=0.0247), respectively. Polymorphism of the gene encoding CYP2D6 does not affect the incidence of inflammatory bowel diseases. The carriers of the NAT2*7 allele which determines slow acetylation may be more predisposed to inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Routine screening of blood donations at Qingdao central blood bank, China, for hepatitis B virus (HBV) DNA with a real-time, multiplex nucleic acid test for HBV, hepatitis C virus, and human immunodeficiency virus Types 1 and 2.

PubMed

Yang, Zhongsi; Xu, Lei; Liu, Li; Feng, Qiuxia; Zhang, Longmu; Ma, Weijuan; Saldanha, John; Wang, Mingmin; Zhao, Lin

2013-10-01

The Roche cobas TaqScreen MPX test was used to evaluate the rate of hepatitis B surface antigen (HBsAg)-negative donations that were hepatitis B virus (HBV) DNA reactive from June 2010 to January 2011 in Qingdao, China. HBsAg-negative samples from 65,800 voluntary blood donors were tested with the cobas TaqScreen MPX test in pools of 6 on the Roche cobas s 201 blood screening platform. Samples positive for HBV DNA and negative for HBsAg were quantitated with the Roche COBAS AmpliPrep/COBAS TaqMan HBV test. In addition, serologic tests for HBsAg, hepatitis B surface antibody, anti-hepatitis B core antigen (anti-HBc), anti-hepatitis B e antigen (anti-HBe), and hepatitis B e antigen (HBe) were done using the Roche electrochemiluminescence immunoassay. A total of 80 nucleic acid amplification technology (NAT) test-reactive pools were identified and 59 pools (74%) resolved to a reactive sample. All samples were HBV DNA reactive and the viral load in each sample was quantitated. The viral loads of the samples ranged from less than 20 to 34,600 IU/mL; 13 samples (22%) had viral loads of more than 20 IU/mL, 27 samples (45.8%) had viral loads of less than 20 IU/mL, and 19 samples (32.2%) had undetectable viral loads. Of the 59 NAT-reactive samples, 40 (67.8%) were anti-HBc positive. Fifteen of the 59 samples could not be confirmed as NAT reactive either by an alternative NAT test or by serology. The HBV NAT yield in blood donors in Qingdao is 0.06% (38/65,800). This study confirmed the value of NAT for interdicting HBV-positive donations and preventing transfusion-transmitted HBV infections. © 2013 American Association of Blood Banks.

Breast cancer, heterocyclic aromatic amines from meat and N-acetyltransferase 2 genotype.

PubMed

Delfino, R J; Sinha, R; Smith, C; West, J; White, E; Lin, H J; Liao, S Y; Gim, J S; Ma, H L; Butler, J; Anton-Culver, H

2000-04-01

Breast cancer risk has been hypothesized to increase with exposure to heterocyclic aromatic amines (HAAs) formed from cooking meat at high temperature. HAAs require enzymatic activation to bind to DNA and initiate carcinogenesis. N-acetyltransferase 2 (NAT2) enzyme activity may play a role, its rate determined by a polymorphic gene. We examined the effect of NAT2 genetic polymorphisms on breast cancer risk from exposure to meat by cooking method, doneness and estimated HAA [2-amino-1-methyl-6-phenylimidazole[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)] intake. Women were recruited with suspicious breast masses and questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. For 114 cases with breast cancer and 280 controls with benign breast disease, NAT2 genotype was determined using allele-specific PCR amplification to detect slow acetylator mutations. HAAs were estimated from interview data on meat type, cooking method and doneness, combined with a quantitative HAA database. Logistic regression models controlled for known risk factors, first including all controls, then 108 with no or low risk (normal breast or no hyperplasia) and finally 149 with high risk (hyperplasia, atypical hyperplasia, complex fibroadenomas). Meat effects were examined within NAT2 strata to assess interactions. We found no association between NAT2 and breast cancer. These Californian women ate more white than red meat (control median 46 versus 8 g/day). There were no significant associations of breast cancer with red meat for any doneness. White meat was significantly protective (>67 versus <26 g/day, OR 0.46, 95% CI 0.23-0.94, P for trend = 0.02), as was chicken, including well done, pan fried and barbecued chicken. MeIQx and DiMeIQx were not associated with breast cancer. A protective effect of PhIP was confounded after controlling for well done chicken. Results were unchanged using low or high risk controls or dropping 30 in situ cases. There was no interaction between NAT2 and HAAs. These findings do not support a role for HAAs from meat or NAT2 in the etiology of breast cancer. Further research is needed to explain the white meat association.

Vibrio Phage KVP40 Encodes a Functional NAD+ Salvage Pathway.

PubMed

Lee, Jae Yun; Li, Zhiqun; Miller, Eric S

2017-05-01

The genome of T4-type Vibrio bacteriophage KVP40 has five genes predicted to encode proteins of pyridine nucleotide metabolism, of which two, nadV and natV , would suffice for an NAD + salvage pathway. NadV is an apparent nicotinamide phosphoribosyltransferase (NAmPRTase), and NatV is an apparent bifunctional nicotinamide mononucleotide adenylyltransferase (NMNATase) and nicotinamide-adenine dinucleotide pyrophosphatase (Nudix hydrolase). Genes encoding the predicted salvage pathway were cloned and expressed in Escherichia coli , the proteins were purified, and their enzymatic properties were examined. KVP40 NadV NAmPRTase is active in vitro , and a clone complements a Salmonella mutant defective in both the bacterial de novo and salvage pathways. Similar to other NAmPRTases, the KVP40 enzyme displayed ATPase activity indicative of energy coupling in the reaction mechanism. The NatV NMNATase activity was measured in a coupled reaction system demonstrating NAD + biosynthesis from nicotinamide, phosphoribosyl pyrophosphate, and ATP. The NatV Nudix hydrolase domain was also shown to be active, with preferred substrates of ADP-ribose, NAD + , and NADH. Expression analysis using reverse transcription-quantitative PCR (qRT-PCR) and enzyme assays of infected Vibrio parahaemolyticus cells demonstrated nadV and natV transcription during the early and delayed-early periods of infection when other KVP40 genes of nucleotide precursor metabolism are expressed. The distribution and phylogeny of NadV and NatV proteins among several large double-stranded DNA (dsDNA) myophages, and also those from some very large siphophages, suggest broad relevance of pyridine nucleotide scavenging in virus-infected cells. NAD + biosynthesis presents another important metabolic resource control point by large, rapidly replicating dsDNA bacteriophages. IMPORTANCE T4-type bacteriophages enhance DNA precursor synthesis through reductive reactions that use NADH/NADPH as the electron donor and NAD + for ADP-ribosylation of proteins involved in transcribing and translating the phage genome. We show here that phage KVP40 encodes a functional pyridine nucleotide scavenging pathway that is expressed during the metabolic period of the infection cycle. The pathway is conserved in other large, dsDNA phages in which the two genes, nadV and natV , share an evolutionary history in their respective phage-host group. Copyright © 2017 American Society for Microbiology.

EDITORIAL: Annual prizes for best papers

NASA Astrophysics Data System (ADS)

2007-07-01

2006 Roberts Prize The publishers of Physics in Medicine and Biology (PMB) in association with the Institute of Physics and Engineering in Medicine (IPEM) jointly award an annual prize for an article published in PMB during the previous year. The following ten articles, listed below in chronological order, were rated the best of 2006 based on the (two or three) referees' assessments: D W Mundy et al 2006 Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions Phys. Med. Biol. 51 1377-91 Y Yang et al 2006 Investigation of optical coherence tomography as an imaging modality in tissue engineering Phys. Med. Biol. 51 1649-59 M Krämer and M Scholz 2006 Rapid calculation of biological effects in ion radiotherapy Phys. Med. Biol. 51 1959-70 P Crespo et al 2006 On the detector arrangement for in-beam PET for hadron therapy monitoring Phys. Med. Biol. 51 2143-63 R J Senden et al 2006 Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose-response using different monomers Phys. Med. Biol. 51 3301-14 J Wang et al 2006 FDTD calculation of whole-body average SAR in adult and child models for frequencies from 30 MHz to 3 GHz Phys. Med. Biol. 51 4119-27 C A T Van den Berg et al 2006 The use of MR B+1 imaging for validation of FDTD electromagnetic simulations of human anatomies Phys. Med. Biol. 51 4735-46 S Qin and K W Ferrara 2006 Acoustic response of compliable microvessels containing ultrasound contrast agents Phys. Med. Biol. 51 5065-88 R Kramer et al 2006 Skeletal dosimetry in the MAX06 and the FAX06 phantoms for external exposure to photons based on vertebral 3D-microCT images Phys. Med. Biol. 51 6265-89 R Leiderman et al 2006 Coupling between elastic strain and interstitial fluid flow: ramifications for poroelastic imaging Phys. Med. Biol. 51 6291-313 An IPEM college of jurors then assessed and rated these papers in order to choose a winner. We have much pleasure in advising readers that the 2006 Roberts Prize is awarded to: M Krämer and M Scholz 2006 Rapid calculation of biological effects in ion radiotherapy Phys. Med. Biol. 51 1959-70 2007 Prize for the Highest Cited Paper The annual prize for the most highly cited paper is awarded by the journal publishers (IOP Publishing) to the article published in PMB that has received the most citations1 in the previous 5 years (in this case for the period 2002 to 2006 inclusive). We have much pleasure in advising readers that the 2007 prize is awarded to: S S Vedam, P J Keall, V R Kini, H Mostafavi, H P Shukla and R Mohan 2003 Acquiring a four-dimensional computed tomography dataset using an external respiratory signal Phys. Med. Biol. 48 45-62 Simon Harris, Publisher Steve Webb, Editor-in-Chief 1 Figures taken from Thomson/ISI

Mammary Tumor Development: Stromal-Epithelial Interactions in Oncogenesis.

DTIC Science & Technology

1996-09-01

differentiation, prolif- erative preneoplastic lesions, or invasive adenocarcinomas , depending on the promoter con- struct used and the animal’s age when...Zn). Virgin RSV-SGF transgenic mice showed marked preneoplastic MG ductal proliferation by 6 mo. By 8 mo., 1/3 had developed adenocarcinoma . Virgin...fat pRSGF Constitutively expressed Highly abnormal. None Normal Observed at 8 1/3 of mice show months of age invasive secretory adenocarcinoma SGF

First Spectroscopic Identification of Pyrocarbonate for High CO2 Flux Membranes Containing Highly Interconnected Three Dimensional Ionic Channels

DTIC Science & Technology

2013-01-01

Koura, S. Kohara , K. Takeuchi, S. Takahashi, L. A. Curtiss, M. Grimsditch and M.-L. Saboungi, J. Mol. Struct., 1996, 382, 163–169. 49 L.-J. Chen, X...Cheng, C.-J. Lin and C.-M. Huang, Electrochim. Acta, 2002, 47, 1475–1480. 50 S. Kohara , N. Koura, Y. Idemoto, S. Takahashi, M.-L. Saboungi and L. A

Gender and Racial Equity in the U.S. Military Occupational Distribution

DTIC Science & Technology

1988-09-30

suggested here could be operating. Discussion of those cited follows. Structural Discrimination The terms racism , sexism , institutional racism , and struct...a statistically significant level. Specifically, they were consistently underrepresented in the core technical occupations while White males...with Black enlisted men who number 198,000, or 30% of enlisted Army men, and 396,000, or 22% of enlisted men in the DoD Services (Quarterly Statistics

A Toolkit for Designing User Interfaces

DTIC Science & Technology

1990-03-01

as the NPS IB can provide prototyping capability. Interface generators are available commercially for nearly every computing machine on the market ...structure which holds attributes of the message buffer window is shown in Figure 4.2. The variables nlines and nchars hold the number of lines in the...window its appearance of scrolling 46 /* define a type and structure for the message buffer */ struct messbuf( long nlines ; /* number of lines in the

Beam Research Program

DTIC Science & Technology

1984-04-01

wavelengths. A direct application of such a laser is isotope separation. 2. For a brief status report of the Laboratory’s high- explosive flash...operation in the fall of 1982. in a 50-MeV Advanced Test Accelerator Facility (the ATA)1 that we are con- structing at our high- explosives test loca...chemical explosives in target-damage studies. Potential hazards associated with the ATA experiments were considered in choosing our site. LLNL’s

Comparative genomic survey, exon-intron annotation and phylogenetic analysis of NAT-homologous sequences in archaea, protists, fungi, viruses, and invertebrates

USDA-ARS?s Scientific Manuscript database

We have previously published extensive genomic surveys [1-3], reporting NAT-homologous sequences in hundreds of sequenced bacterial, fungal and vertebrate genomes. We present here the results of our latest search of 2445 genomes, representing 1532 (70 archaeal, 1210 bacterial, 43 protist, 97 fungal,...

75 FR 3739 - Agency Information Collection Activities: Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-22

... Traineeship Database for the two nursing traineeship programs. The AENT and NAT tables are used annually by... as the number of enrollees, projected data on enrollees and graduates for the following academic year... and/or NAT grant application(s). The tables are also used in the Nurse Traineeship Database which is...

76 FR 72950 - Draft Guidance for Industry: Use of Nucleic Acid Tests on Pooled and Individual Samples From...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-28

... Hepatitis B Virus AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug... Risk of Transmission of Hepatitis B Virus (HBV), and Requalification of Donors Who Test HBV NAT...-licensed nucleic acid tests (NAT) to screen blood donors for hepatitis B virus (HBV) deoxyribonucleic acid...

Acetylation of aromatic cysteine conjugates by recombinant human N-acetyltransferase 8.

PubMed

Deol, Reema; Josephy, P David

2017-03-01

1. The mercapturic acid (MA) pathway is a metabolic route for the processing of glutathione conjugates to MA (N-acetylcysteine conjugates). An N-acetyltransferase enzyme, NAT8, catalyzes the transfer of an acetyl group from acetyl-CoA to the cysteine amino group, producing a MA, which is excreted in the urine. We expressed human NAT8 in HEK293T cells and developed an HPLC-MS method for the quantitation of the S-aryl-substituted cysteine conjugates and their MA. 2. We measured the activity of the enzyme for acetylation of benzyl-, 4-nitrobenzyl-, and 1-menaphthylcysteine substrates. 3. NAT8 catalyzed the acetylation of all three cysteine conjugates with similar Michaelis-Menten kinetics.

Measurement of neutron energy spectra for Eg=23.1 and 26.6 MeV mono-energetic photon induced reaction on natC using laser electron photon beam at NewSUBARU

NASA Astrophysics Data System (ADS)

Itoga, Toshiro; Nakashima, Hiroshi; Sanami, Toshiya; Namito, Yoshihito; Kirihara, Yoichi; Miyamoto, Shuji; Takemoto, Akinori; Yamaguchi, Masashi; Asano, Yoshihiro

2017-09-01

Photo-neutron energy spectra for Eg=23.1 and 26.6 MeV mono-energetic photons on natC were measured using laser Compton scattering facility at NewSUBARU BL01. The photon energy spectra were evaluated through measurements and simulations with collimator sizes and arrangements for the laser electron photon. The neutron energy spectra for the natC(g,xn) reaction were measured at 60 degrees in horizontal and 90 degrees in horizontal and vertical with respect to incident photon. The spectra show almost isotropic angular distribution and flat energy distribution from detection threshold to upper limit defined by reaction Q-value.

Formation of model polar stratospheric cloud films

NASA Technical Reports Server (NTRS)

Middlebrook, Ann M.; Koehler, Birgit G.; Mcneill, Laurie S.; Tolbert, Margaret A.

1992-01-01

Fourier transform infrared spectroscopy was used to examine the competitive growth of films representative of polar stratospheric clouds. These experiments show that either crystalline nitric acid trihydrate (beta-NAT) or amorphous films with H2O:HNO3 ratios close to 3:1 formed at temperatures 3-7 K warmer than the ice frost point under stratospheric pressure conditions. In addition, with higher HNO3 pressure, we observed nitric acid dihydrate (NAD) formation at temperatures warmer than ice formation. However, our experiments also show that NAD surfaces converted to beta-NAT upon exposure to stratospheric water pressures. Finally, we determined that the net uptake coefficient for HNO3 on beta-NAT is close to unity, whereas the net uptake coefficient for H2O is much less.

Detection of spallation neutrons and protons using the (nat)Cd activation technique in transmutation experiments at Dubna.

PubMed

Manolopoulou, M; Stoulos, S; Fragopoulou, M; Brandt, R; Westmeier, W; Krivopustov, M; Sosnin, A; Zamani, M

2006-07-01

Various spallation sources have been used to transmute long-lived radioactive waste, mostly making use of the wide energy neutron fluence. In addition to neutrons, a large number of protons and gamma rays are also emitted from these sources. In this paper (nat)Cd is proved to be a useful activation detector for determining both thermal-epithermal neutron as well as secondary proton fluences. The fluences measured with (nat)Cd compared with other experimental data and calculations of DCM-DEM code were found to be in reasonable agreement. An accumulation of thermal-epithermal neutrons around the center of the target (i.e. after approx. 10 cm) and of secondary protons towards the end of the target is observed.

Evaluating fossil calibrations for dating phylogenies in light of rates of molecular evolution: a comparison of three approaches.

PubMed

Lukoschek, Vimoksalehi; Scott Keogh, J; Avise, John C

2012-01-01

Evolutionary and biogeographic studies increasingly rely on calibrated molecular clocks to date key events. Although there has been significant recent progress in development of the techniques used for molecular dating, many issues remain. In particular, controversies abound over the appropriate use and placement of fossils for calibrating molecular clocks. Several methods have been proposed for evaluating candidate fossils; however, few studies have compared the results obtained by different approaches. Moreover, no previous study has incorporated the effects of nucleotide saturation from different data types in the evaluation of candidate fossils. In order to address these issues, we compared three approaches for evaluating fossil calibrations: the single-fossil cross-validation method of Near, Meylan, and Shaffer (2005. Assessing concordance of fossil calibration points in molecular clock studies: an example using turtles. Am. Nat. 165:137-146), the empirical fossil coverage method of Marshall (2008. A simple method for bracketing absolute divergence times on molecular phylogenies using multiple fossil calibration points. Am. Nat. 171:726-742), and the Bayesian multicalibration method of Sanders and Lee (2007. Evaluating molecular clock calibrations using Bayesian analyses with soft and hard bounds. Biol. Lett. 3:275-279) and explicitly incorporate the effects of data type (nuclear vs. mitochondrial DNA) for identifying the most reliable or congruent fossil calibrations. We used advanced (Caenophidian) snakes as a case study; however, our results are applicable to any taxonomic group with multiple candidate fossils, provided appropriate taxon sampling and sufficient molecular sequence data are available. We found that data type strongly influenced which fossil calibrations were identified as outliers, regardless of which method was used. Despite the use of complex partitioned models of sequence evolution and multiple calibrations throughout the tree, saturation severely compressed basal branch lengths obtained from mitochondrial DNA compared with nuclear DNA. The effects of mitochondrial saturation were not ameliorated by analyzing a combined nuclear and mitochondrial data set. Although removing the third codon positions from the mitochondrial coding regions did not ameliorate saturation effects in the single-fossil cross-validations, it did in the Bayesian multicalibration analyses. Saturation significantly influenced the fossils that were selected as most reliable for all three methods evaluated. Our findings highlight the need to critically evaluate the fossils selected by data with different rates of nucleotide substitution and how data with different evolutionary rates affect the results of each method for evaluating fossils. Our empirical evaluation demonstrates that the advantages of using multiple independent fossil calibrations significantly outweigh any disadvantages.

Studies of a Ras Antagonist in Breast Cancer

DTIC Science & Technology

2005-05-01

growth by Farensylthiosalicylic acid. J Biol Chem 1995; 270: 22268- 22270 . [19] Egozi Y, Weisz B, Gana-Weisz M, Ben-Baruch G, and Kloog Y, Growth...growth by Farensylthiosalisylic acid. J Biol Chem 270(35) (1995) 22268- 22270 . [71] Y. Egozi, B. Weisz, M. Gana-Weisz, G. Ben-Baruch, and Y. Kloog, Growth...G, Marciano D, Egozi Y, Kloog Y 1995 Selective inhibition of Ras- dependent cell growth by farnesylthiosalisylic acid. J Biol Chem 270:22263- 22270 40

Phenological series in Bologna (Northern Italy): temporal trends and spatial pattern of greening

NASA Astrophysics Data System (ADS)

Puppi, Giovanna; Zanotti, Anna Letizia

2010-05-01

In Europe, in the last thirty years, the onset of spring has advanced (Estrella et al. 2009 Clim Res. 39). However the phenological shifts vary from one country to another and long time series are scanty in Southern Europe (Peňuelas et. al. 2002, Glob. Change Biol.; Črepinšek et Kajfež 2003, Ann.Ser.Hist.Nat.13): for this reason we analyzed the data on leafing of some woody species recorded during the last 3 decades (1977-2009) in the city of Bologna (Emilia-Romagna, Northern Italy) and in several hillside stations in the neighbourhood of the town. As BGS index, the average day of "first leaf unfolding" (GFI=V4, BBCH=11) of a group of common woody species was chosen: the BGS days were analysed in relation with time and temperature changes. The BGS happens on average at the end of March. The species observed display a negative trend along the period (about 2 days of advance per decade) and the BGS days show a significant correlation with the mean temperature of the period January-March (about 3 and a half days of earlier start per degree of increasing temperature). Since an increase in winter temperatures has been predicted in the Emilia-Romagna region in the next decades (Tomozeiu et al. 2007, Theor. Appl. Climatol. 90), the growing season in our region is probably going to extend. Phenological spatial patterns of the neighbourhood of the city are also analysed: greening generally starts on southfacing hills between 100 and 300 m asl.

Zfp206 regulates ES cell gene expression and differentiation.

PubMed

Zhang, Wen; Walker, Emily; Tamplin, Owen J; Rossant, Janet; Stanford, William L; Hughes, Timothy R

2006-01-01

Understanding transcriptional regulation in early developmental stages is fundamental to understanding mammalian development and embryonic stem (ES) cell properties. Expression surveys suggest that the putative SCAN-Zinc finger transcription factor Zfp206 is expressed specifically in ES cells [Zhang,W., Morris,Q.D., Chang,R., Shai,O., Bakowski,M.A., Mitsakakis,N., Mohammad,N., Robinson,M.D., Zirngibl,R., Somogyi,E. et al., (2004) J. Biol., 3, 21; Brandenberger,R., Wei,H., Zhang,S., Lei,S., Murage,J., Fisk,G.J., Li,Y., Xu,C., Fang,R., Guegler,K. et al., (2004) Nat. Biotechnol., 22, 707-716]. Here, we confirm this observation, and we show that ZFP206 expression decreases rapidly upon differentiation of cultured mouse ES cells, and during development of mouse embryos. We find that there are at least six isoforms of the ZFP206 transcript, the longest being predominant. Overexpression and depletion experiments show that Zfp206 promotes formation of undifferentiated ES cell clones, and positively regulates abundance of a very small set of transcripts whose expression is also specific to ES cells and the two- to four-cell stages of preimplantation embryos. This set includes members of the Zscan4, Thoc4, Tcstv1 and eIF-1A gene families, none of which have been functionally characterized in vivo but whose members include apparent transcription factors, RNA-binding proteins and translation factors. Together, these data indicate that Zfp206 is a regulator of ES cell differentiation that controls a set of genes expressed very early in development, most of which themselves appear to be regulators.

Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism.

PubMed

Riveline, D; Zamir, E; Balaban, N Q; Schwarz, U S; Ishizaki, T; Narumiya, S; Kam, Z; Geiger, B; Bershadsky, A D

2001-06-11

The transition of cell-matrix adhesions from the initial punctate focal complexes into the mature elongated form, known as focal contacts, requires GTPase Rho activity. In particular, activation of myosin II-driven contractility by a Rho target known as Rho-associated kinase (ROCK) was shown to be essential for focal contact formation. To dissect the mechanism of Rho-dependent induction of focal contacts and to elucidate the role of cell contractility, we applied mechanical force to vinculin-containing dot-like adhesions at the cell edge using a micropipette. Local centripetal pulling led to local assembly and elongation of these structures and to their development into streak-like focal contacts, as revealed by the dynamics of green fluorescent protein-tagged vinculin or paxillin and interference reflection microscopy. Inhibition of Rho activity by C3 transferase suppressed this force-induced focal contact formation. However, constitutively active mutants of another Rho target, the formin homology protein mDia1 (Watanabe, N., T. Kato, A. Fujita, T. Ishizaki, and S. Narumiya. 1999. Nat. Cell Biol. 1:136-143), were sufficient to restore force-induced focal contact formation in C3 transferase-treated cells. Force-induced formation of the focal contacts still occurred in cells subjected to myosin II and ROCK inhibition. Thus, as long as mDia1 is active, external tension force bypasses the requirement for ROCK-mediated myosin II contractility in the induction of focal contacts. Our experiments show that integrin-containing focal complexes behave as individual mechanosensors exhibiting directional assembly in response to local force.

Differential association for N-acetyltransferase 2 genotype and phenotype with bladder cancer risk in Chinese population.

PubMed

Quan, Lei; Chattopadhyay, Koushik; Nelson, Heather H; Chan, Kenneth K; Xiang, Yong-Bing; Zhang, Wei; Wang, Renwei; Gao, Yu-Tang; Yuan, Jian-Min

2016-06-28

N-acetyltransferase 2 (NAT2) is involved in both carcinogen detoxification through hepatic N-acetylation and carcinogen activation through local O-acetylation. NAT2 slow acetylation status is significantly associated with increased bladder cancer risk among European populations, but its association in Asian populations is inconclusive. NAT2 acetylation status was determined by both single nucleotide polymorphisms (SNPs) and caffeine metabolic ratio (CMR), in a population-based study of 494 bladder cancer patients and 507 control subjects in Shanghai, China. The CMR, a functional measure of hepatic N-acetylation, was significantly reduced in a dose-dependent manner among both cases and controls possessing the SNP-inferred NAT2 slow acetylation status (all P-values<5.0×10-10). The CMR-determined slow N-acetylation status (CMR<0.34) was significantly associated with a 50% increased risk of bladder cancer (odds ratio = 1.50, 95% confidence interval = 1.10-2.06) whereas the SNP-inferred slow acetylation statuses were significantly associated with an approximately 50% decreased risk of bladder cancer. The genotype-disease association was strengthened after the adjustment for CMR and was primarily observed among never smokers. The apparent differential associations for phenotypic and genetic measures of acetylation statuses with bladder cancer risk may reflect dual functions of NAT2 in bladder carcinogenesis because the former only measures the capacity of carcinogen detoxification pathway while the latter represents both carcinogen activation and detoxification pathways. Future studies are warranted to ascertain the specific role of N- and O-acetylation in bladder carcinogenesis, particularly in populations exposed to different types of bladder carcinogens.

Structures of the N-acetyltransferase domain of Xylella fastidiosa N-acetyl-L-glutamate synthase/kinase with and without a His tag bound to N-acetyl-L-glutamate.

PubMed

Zhao, Gengxiang; Jin, Zhongmin; Allewell, Norma M; Tuchman, Mendel; Shi, Dashuang

2015-01-01

Structures of the catalytic N-acetyltransferase (NAT) domain of the bifunctional N-acetyl-L-glutamate synthase/kinase (NAGS/K) from Xylella fastidiosa bound to N-acetyl-L-glutamate (NAG) with and without an N-terminal His tag have been solved and refined at 1.7 and 1.4 Å resolution, respectively. The NAT domain with an N-terminal His tag crystallized in space group P4(1)2(1)2, with unit-cell parameters a=b=51.72, c=242.31 Å. Two subunits form a molecular dimer in the asymmetric unit, which contains ∼41% solvent. The NAT domain without an N-terminal His tag crystallized in space group P21, with unit-cell parameters a=63.48, b=122.34, c=75.88 Å, β=107.6°. Eight subunits, which form four molecular dimers, were identified in the asymmetric unit, which contains ∼38% solvent. The structures with and without the N-terminal His tag provide an opportunity to evaluate how the His tag affects structure and function. Furthermore, multiple subunits in different packing environments allow an assessment of the plasticity of the NAG binding site, which might be relevant to substrate binding and product release. The dimeric structure of the X. fastidiosa N-acetytransferase (xfNAT) domain is very similar to that of human N-acetyltransferase (hNAT), reinforcing the notion that mammalian NAGS is evolutionally derived from bifunctional bacterial NAGS/K.

Association between N-acetyltransferase 2 polymorphisms and pancreatic cancer risk: a meta-analysis.

PubMed

Liang, J X; Gao, W; Liang, Y; Zhou, X M

2015-12-17

N-acetyltransferase 2 (NAT2) is an essential phase II enzyme in the metabolism of aromatic and heterocyclic amines and of hydrazines. NAT2 activity can be divided into three phenotypes: rapid, intermediate, and slow. Studies identifying an association between NAT2 polymorphism and the risk of pancreatic cancer have shown conflicting results. In order to assess this relationship comprehensively, we performed a meta-analysis that involved 1607 patients with pancreatic cancer and 1682 controls from six studies, which were selected from a group of ten, identified by a search of PubMed and Embase databases up to July 2014. Relative risks (RRs) with 95% confidence intervals (CIs) were used to evaluate the relationships. In the overall analysis, no significant associations between NAT2 rapid acetylation genotypes and pancreatic cancer risk (RR = 0.93, 95%CI = 0.73-1.19) were found; however, the results showed significant heterogeneity (I2 = 55.0%). The results from subgroup analysis suggested that the rapid genotypes might decrease the risk of pancreatic cancer (RR = 0.56, 95%CI = 0.38-0.84) in Turkey, although the association was not significant in the United States population (RR = 0.97, 95%CI = 0.71-1.34) or in the multi-center studies (RR = 1.10, 95%CI = 0.90-1.34). Analysis of the slow acetylation genotypes demonstrated the converse outcomes. In conclusion, the results of our study suggested that the NAT2 slow acetylation genotypes might increase the susceptibility to pancreatic cancer in Europe but that these have no significant effects in the United States and multi-center populations.

N-acetyltransferase 2 polymorphism and breast cancer risk with smoking: a case control study in Japanese women.

PubMed

Hara, Akio; Taira, Naruto; Mizoo, Taeko; Nishiyama, Keiko; Nogami, Tomohiro; Iwamoto, Takayuki; Motoki, Takayuki; Shien, Tadahiko; Matsuoka, Junji; Doihara, Hiroyoshi; Ishihara, Setsuko; Kawai, Hiroshi; Kawasaki, Kensuke; Ishibe, Youichi; Ogasawara, Yutaka; Miyoshi, Shinichiro

2017-03-01

Recent studies have suggested that the association between smoking and breast cancer risk might be modified by polymorphisms in the N-acetyltransferase 2 gene (NAT2). Most of these studies were conducted in Western countries, with few reports from East Asia. We conducted a case-control study of 511 breast cancer cases and 527 unmatched healthy controls from December 2010 to November 2011 in Japan. Unconditional logistic regression was used to analyze the association of smoking with breast cancer risk stratified by NAT2 phenotype. In this population, 11 % of the cases and 10 % of the controls were classified as a slow acetylator phenotype. Compared to never smokers, current smokers had an increased breast cancer risk in multivariate analysis [odds ratio (OR) = 2.27, 95 % confidence interval (95 %CI) = 1.38-3.82]. Subgroup analyses of menopausal status indicated the same tendency. Subgroup analyses of NAT2 phenotype, the ORs in both of rapid and slow acetylator phenotype subgroups were comparable, and no interactions were observed between smoking status and NAT2 phenotype (p = 0.97). A dose-dependent effect of smoking on breast cancer risk was seen for the rapid acetylator phenotype, but not for the slow acetylator phenotype. Given the high frequency of the rapid acetylator phenotype, these results show that smoking is a risk factor for breast cancer among most Japanese women. It may be of little significance to identify the NAT2 phenotype in the Japanese population.

Challenges in hepatitis B detection among blood donors.

PubMed

Allain, Jean-Pierre; Cox, Laura

2011-11-01

The availability of hepatitis B virus (HBV) nucleic acid testing (NAT) for donor blood screening led to its implementation in low prevalence and high prevalence countries. Genomic detection was a substantial addition to HBV surface protein (HBsAg) screening by detecting window period infections and 'occult' HBV infections (OBIs), characterized by undetectable HBsAg, low viral load and presence of serological markers (anti-HBc and/or anti-HBs). OBIs are the result of multiple, poorly understood mechanisms including incomplete immune control mutations of the HBsAg antigenic determinants; abnormal expression of S gene; and inhibition of genome transcription. Infectivity for the recipient is high for window period blood and relatively low for OBIs. The number of cases identified by NAT ranges between 1 : 1000 and 1 : 50 000, depending on epidemiology and assay sensitivity whether NAT is implemented in individual donations or pools of samples. OBI donors are generally older than 45 years except in Africa, carry very low viral load (median 11-25  IU/ml) and have normal alanine transaminase levels. Cases carrying anti-HBc alone are more infectious than those with low level of anti-HBs. Evidence of HBsAg escape mutants that are undetected by commercial assays has been published. Inhibition of HBsAg mRNA production and export are potential mechanisms of OBI occurrence. HBV blood safety is improved by NAT for HBV DNA when applied to individual donations. Until the sensitivity of NAT is improved, both this method and HBsAg screening are needed to eliminate potentially infectious blood donations. Occult HBV characterization clarifies new facets of HBV natural history.

Integrated sample-to-detection chip for nucleic acid test assays.

PubMed

Prakash, R; Pabbaraju, K; Wong, S; Tellier, R; Kaler, K V I S

2016-06-01

Nucleic acid based diagnostic techniques are routinely used for the detection of infectious agents. Most of these assays rely on nucleic acid extraction platforms for the extraction and purification of nucleic acids and a separate real-time PCR platform for quantitative nucleic acid amplification tests (NATs). Several microfluidic lab on chip (LOC) technologies have been developed, where mechanical and chemical methods are used for the extraction and purification of nucleic acids. Microfluidic technologies have also been effectively utilized for chip based real-time PCR assays. However, there are few examples of microfluidic systems which have successfully integrated these two key processes. In this study, we have implemented an electro-actuation based LOC micro-device that leverages multi-frequency actuation of samples and reagents droplets for chip based nucleic acid extraction and real-time, reverse transcription (RT) PCR (qRT-PCR) amplification from clinical samples. Our prototype micro-device combines chemical lysis with electric field assisted isolation of nucleic acid in a four channel parallel processing scheme. Furthermore, a four channel parallel qRT-PCR amplification and detection assay is integrated to deliver the sample-to-detection NAT chip. The NAT chip combines dielectrophoresis and electrostatic/electrowetting actuation methods with resistive micro-heaters and temperature sensors to perform chip based integrated NATs. The two chip modules have been validated using different panels of clinical samples and their performance compared with standard platforms. This study has established that our integrated NAT chip system has a sensitivity and specificity comparable to that of the standard platforms while providing up to 10 fold reduction in sample/reagent volumes.

Changes to anti-JCV antibody levels in a Swedish national MS cohort

PubMed Central

Warnke, Clemens; Ramanujam, Ryan; Plavina, Tatiana; Bergström, Tomas; Goelz, Susan; Subramanyam, Meena; Kockum, Ingrid; Rahbar, Afsar; Kieseier, Bernd C; Holmén, Carolina; Olsson, Tomas; Hillert, Jan; Fogdell-Hahn, Anna

2013-01-01

Background The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). Objective To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. Methods An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. Results Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. Conclusions Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted. PMID:23463870

Changes to anti-JCV antibody levels in a Swedish national MS cohort.

PubMed

Warnke, Clemens; Ramanujam, Ryan; Plavina, Tatiana; Bergström, Tomas; Goelz, Susan; Subramanyam, Meena; Kockum, Ingrid; Rahbar, Afsar; Kieseier, Bernd C; Holmén, Carolina; Olsson, Tomas; Hillert, Jan; Fogdell-Hahn, Anna

2013-11-01

The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.

LIMITED RECOVERY OF PINEAL FUNCTION AFTER REGENERATION OF PREGANGLIONIC SYMPATHETIC AXONS: EVIDENCE FOR LOSS OF GANGLIONIC SYNAPTIC SPECIFICITY

PubMed Central

Lingappa, Jaisri R.; Zigmond, Richard E.

2013-01-01

The cervical sympathetic trunks (CST) contain axons of preganglionic neurons that innervate the superior cervical ganglia (SCG). Since, regeneration of CST fibers can be extensive and can reestablish certain specific patterns of SCG connections, restoration of end organ function would be expected. This expectation was examined with respect to the pineal gland, an organ innervated by the two SCG. The activity of pineal serotonin N-acetyltransferase (NAT) exhibits a large circadian rhythm, with activity high at night, which is dependent on the gland’s sympathetic input. Thirty six hours after the CST were crushed bilaterally, nocturnal NAT was decreased by 99%. Three months later, enzyme activity had recovered only to 15% of control values, a recovery dependent on regeneration of CST fibers. Nevertheless, a small day-night rhythm was present in lesioned animals. Neither the density of the gland’s adrenergic innervation nor the ability of an adrenergic agonist to stimulate NAT activity was reduced in rats with regenerated CST. In addition, stimulation of the regenerated CST at a variety of frequencies was at least as effective in increasing NAT activity as seen with control nerves. These data suggest that the failure of pineal function to recover is not due to a quantitative deficit in the extent of reinnervation or in synaptic efficacy. Rather, we suggest that there is some loss of specificity in the synaptic connections made in the SCG during reinnervation, resulting in a loss of the central neuronal information necessary for directing a normal NAT rhythm and thus normal pineal function. PMID:23486957

Alpha-2 adrenergic activity of bromocriptine and quinpirole in chicken pineal gland. Effects on melatonin synthesis and ( sup 3 H)rauwolscine binding

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

Zawilska, J.; Iuvone, P.M.

In the pineal gland and retina of chickens, serotonin N-acetyl-transferase (NAT) activity and melatonin content are modulated by different receptors, alpha-2 adrenergic receptors in pineal gland and D2-dopamine receptors in retina. The effect of two D2-dopamine receptor agonists, bromocriptine and quinpirole (LY 171555), on melatonin synthesis in these tissues was investigated. Systemic administrations of bromocriptine and quinpirole decreased nocturnal NAT activity and melatonin content of both pineal gland and retina. Bromocriptine was equipotent in the two tissues, whereas quinpirole was approximately 100-fold more potent in retina than in pineal gland. In pineal gland, the suppressive effects of bromocriptine and quinpirolemore » on NAT activity were blocked by yohimbine, a selective alpha-2 adrenergic receptor antagonist, but not by spiperone, a D2-dopamine receptor antagonist. In contrast, bromocriptine- and quinpirole-induced decreases of the enzyme activity in retina were antagonized by spiperone, and not affected by yohimbine. The nocturnal increase of NAT activity of pineal glands in vitro was inhibited with an order of potency clonidine greater than bromocriptine greater than quinpirole. Additionally, bromocriptine and quinpirole displaced the specific binding of (3H)rauwolscine, an alpha-2 adrenergic receptor antagonist, to membranes from chicken pineal gland, with potencies comparable to those observed for inhibition of NAT activity in vitro. It is suggested that bromocriptine and quinpirole, in addition to their D2-dopaminergic activity, can stimulate alpha-2 adrenergic receptors in pineal gland of chicken.« less

Photo-neutron reaction cross-sections for natMo in the bremsstrahlung end-point energies of 12-16 and 45-70 MeV

NASA Astrophysics Data System (ADS)

Naik, H.; Kim, G. N.; Kapote Noy, R.; Schwengner, R.; Kim, K.; Zaman, M.; Shin, S. G.; Gey, Y.; Massarczyk, R.; John, R.; Junghans, A.; Wagner, A.; Cho, M.-H.

2016-07-01

The natMo( γ, xn)90, 91, 99Mo reaction cross-sections were experimentally determined for the bremsstrahlung end-point energies of 12, 14, 16, 45, 50, 55, 60 and 70MeV by activation and off-line γ -ray spectrometric technique and using the 20MeV electron linac (ELBE) at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany, and the 100MeV electron linac at the Pohang Accelerator Laboratory (PAL), Pohang, Korea. The natMo( γ, xn)88, 89, 90, 91, 99Mo reaction cross-sections as a function of photon energy were also calculated using the computer code TALYS 1.6. The flux-weighted average cross-sections were obtained from the literature data and the calculated values of TALYS based on mono-energetic photons and are found to be in general agreement with the present results. The flux-weighted average experimental and theoretical cross-sections for the natMo( γ, xn)88, 89, 90, 91, 99Mo reactions increase with the bremsstrahlung end-point energy, which indicates the role of excitation energy. After a certain energy, the individual natMo( γ, xn) reaction cross-sections decrease with the increase of bremsstrahlung energy due to opening of other reactions, which indicates sharing of energy in different reaction channels. The 100Mo( γ, n) reaction cross-section is important for the production of 99Mo , which is a probable alternative to the 98Mo(n, γ) and 235U(n, f ) reactions.

Urinary bladder cancer risk factors in an area of former coal, iron, and steel industries in Germany.

PubMed

Krech, Eugen; Selinski, Silvia; Blaszkewicz, Meinolf; Bürger, Hannah; Kadhum, Thura; Hengstler, Jan G; Truss, Michael C; Golka, Klaus

2017-01-01

This study was performed to investigate the frequency of bladder cancer in patients with an occupational history such as underground hard coal mining and/or painting after the structural change in the local industry. A total of 206 patients with bladder cancer and 207 controls were enlisted regarding occupational and nonoccupational bladder cancer risk factors by questionnaire. The phase II enzymes N-acetyltransferase 2 (NAT2), glutathione S-transferases M1 (GSTM1), and T1 (GSTT1) and the single nucleotide polymorphism (SNP) rs11892031[A/C] reported to be associated with bladder cancer in genome-wide association studies were genotyped. The bladder cancer risk in varnishers and underground hard coal miners was increased as previously shown in a study in this area performed in the 1980s. The occupation of a car mechanic was associated with a significantly elevated bladder cancer risk and higher in the case of underground hard coal miners even though the mine was closed in 1987. The frequency of GSTM1 negative genotype was comparable in cases and controls (53% versus 54%). In the case of NAT2, the slow NAT2 genotype was more frequent (62% versus 58%) and ultra-slow NAT2 genotype (NAT2*6A and/or *7B alleles only) was 23% versus 15%. An occupational history of a varnisher or an underground hard coal miner remains a risk factor for bladder cancer occurrence. Data indicate that in the case of bladder cancer, GSTM1 is a susceptibility factor related to environmental and/or occupational exposure.

Homology modeling and prediction of the amino acid residues participating in the transfer of acetyl-CoA to arylalkylamine by the N-acetyltransferase from Chryseobacterium sp.

PubMed

Takenaka, Shinji; Ozeki, Takahiro; Tanaka, Kosei; Yoshida, Ken-Ichi

2017-11-01

To predict the amino acid residues playing important roles in acetyl-CoA and substrate binding and to study the acetyl group transfer mechanism of Chryseobacterium sp. 5-3B N-acetyltransferase (5-3B NatA). A 3-dimensional homology model of 5-3B NatA was constructed to compare the theoretical structure of this compound with the structures of previously reported proteins belonging to the bacterial GCN5 N-acetyltransferase family. Homology modeling of the 5-3B NatA structure and a characterization of the enzyme's kinetic parameters identified the essential amino acid residues involved in binding and acetyl-group transfer. 126 Leu, 132 Leu, and 135 Lys were implicated in the binding of phosphopantothenic acid, and 100 Tyr and 131 Lys in that of adenosyl biphosphate. The data supported the participation of 83 Glu and 133 Tyr in catalyzing acetyl-group transfer to L-2-phenylglycine. 5-3B NatA catalyzes the enantioselective N-acetylation of L-2-phenylglycine via a ternary complex comprising the enzyme, acetyl-CoA, and the substrate.

Association between N-Acetyltransferase 2 Polymorphism and Bladder Cancer Risk: a Meta-Analysis in a Single Ethnic Group.

PubMed

Xu, Wan-Jiang; Wen, Li-Ping; Jiang, Xiang-Xin; Ye, Li-Yin; Meng, Fan-Hua; Guan, Sheng; Qian, Ying-Jun; Wei, Jing-Feng

2017-02-01

Many studies have evaluated the correlation between N-acetyltransferase 2 (NAT2) slow acetylation genotype and bladder cancer risk. However, the results are inconsistent and remain to be confirmed in each ethnic group. To assess the effects of NAT2 acetylation status on the risk of bladder cancer in the Chinese population, a meta-analysis was performed. Studies were identified using PubMed and Chinese databases through February 2016. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (CIs). This meta-analysis included 10 studies with 896 bladder cancer cases and 1188 controls. In the overall analysis, NAT2 slow acetylation phenotype was significantly associated with an increased risk of bladder cancer in the Chinese population (OR = 1.68, 95% CI = 1.11 - 2.53). In the subgroup analyses by geographic areas and sources of controls, significant risk was found in Mainland China (OR = 1.83, 95% CI = 1.04 - 3.20) and hospitalbased studies (OR = 1.74, 95% CI = 1.27 - 2.38), but not in Taiwan China. This meta-analysis suggested that the NAT2 slow acetylation genotype is associated with an increased bladder cancer risk in Chinese individuals.

Intrasystem Analysis Program (IAP) Structural Design Study.

DTIC Science & Technology

1981-06-01

accuracy constraints, and user competence . This report is designed to serve as a guide in con- structing procedures and identifying those aspects of the...parameters. 3.3.3 Userability The term "Userability" refers here to the level of competence assumed for an IAP analyst in need of a procedure. There...media the wires pass through is homogeneous along the length of the wires. Under these assumptions the wave propagation is predominantly tranverse

Simulation-Based Military Regional Anesthesia Training System

DTIC Science & Technology

2008-12-01

and Zhang, X.Z., 2006 : Development of an MR-brake-based haptic device, Smart Mater. Struct., 15, 1960-66. Meislin, H., Criss, E. A. et al ., 1997...operations were superficial wounds or wounds to the extremities (Trunkey, 1983; Rush et al ., 2007). This was partly due to the advent of body... et al ., 1997). Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection of information is estimated to

Dynamic Multiaxial Response of a Hot-Pressed Aluminum Nitride

DTIC Science & Technology

2012-01-05

Hutchinson, Adv. Appl . Mech. 29 (1992). [34] H. Ming-Yuan, J.W. Hutchinson, Int. J. Solids Struct. 25 (1989) 1053. [35] J. Salem , L. Ghosn, Int. J...Dynamic Multiaxial Response of a Hot- Pressed Aluminum Nitride by Guangli Hu, C. Q. Chen, K. T. Ramesh, and J. W. McCauley ARL-RP-0487...Laboratory Aberdeen Proving Ground, MD 21005-5066 ARL-RP-0487 June 2014 Dynamic Multiaxial Response of a Hot- Pressed Aluminum Nitride

Excitation functions for 7Be, 22,24Na production in Mg and Al by deuteron irradiations up to 50 MeV.

PubMed

Hermanne, A; Takács, S; Tárkányi, F; Adam-Rebeles, R; Ignatyuk, A

2012-12-01

New experimental data for production of (7)Be and (22,24)Na in deuteron irradiation of (nat)Mg and Al up to 50 MeV are presented. The induced activity, measured with HPGe spectroscopy, allows us to determine excitation functions of (nat)Mg(d,x) and (27)Al(d,x) reactions involved in the activation process with reference to (nat)Ti(d,x)(48)V monitor cross sections. A comparison with experimental literature values and results from updated theoretical codes is discussed. Thick target yields were derived from fits to our cross-sections and integrated personnel dose was calculated for different irradiation cycles and exposure scenarios around high power deuteron accelerator facilities. Copyright © 2012 Elsevier Ltd. All rights reserved.

EDITORIAL: Special section on signal transduction Special section on signal transduction

NASA Astrophysics Data System (ADS)

Shvartsman, Stanislav

2012-08-01

This special section of Physical Biology focuses on multiple aspects of signal transduction, broadly defined as the study of the mechanisms by which cells communicate with their environment. Mechanisms of cell communication involve detection of incoming signals, which can be chemical, mechanical or electromagnetic, relaying these signals to intracellular processes, such as cytoskeletal networks or gene expression systems, and, ultimately, converting these signals to responses such as cell differentiation or death. Given the multiscale nature of signal transduction systems, they must be studied at multiple levels, from the identities and structures of molecules comprising signal detection and interpretation networks, to the systems-level properties of these networks. The 11 papers in this special section illustrate some of the most exciting aspects of signal transduction research. The first two papers, by Marie-Anne Félix [1] and by Efrat Oron and Natalia Ivanova [2], focus on cell-cell interactions in developing tissues, using vulval patterning in worm and cell fate specification in mammalian embryos as prime examples of emergent cell behaviors. Next come two papers from the groups of Julio Saez-Rodriguez [3] and Kevin Janes [4]. These papers discuss how the causal relationships between multiple components of signaling systems can be inferred using multivariable statistical analysis of empirical data. An authoritative review by Zarnitsyna and Zhu [5] presents a detailed discussion of the sequence of signaling events involved in T-cell triggering. Once the structure and components of the signaling systems are determined, they can be modeled using approaches that have been successful in other physical sciences. As two examples of such approaches, reviews by Rubinstein [6] and Kholodenko [7], present reaction-diffusion models of cell polarization and thermodynamics-based models of gene regulation. An important class of models takes the form of enzymatic networks, where a single molecule can participate in multiple types of interactions. Mathematical analysis of these models is discussed in the papers by Del Vecchio [8], Seaton and Krishnan [9], and Hatzimanikatis and colleagues [10]. Finally, all signaling systems are information processing devices. While this point is broadly accepted, there have been only a few attempts to apply information theory to experimental signaling systems. A review by Andre Levchenko and colleagues [11] provides a very clear introduction to information theory and its potential applications to signal transduction in cellular systems. References [1] Félix M-A 2012 Phys. Biol. 9 045001 [2] Oron E and Ivanova N 2012 Phys. Biol. 9 045002 [3] MacNamara A et al 2012 Phys. Biol. 9 045003 [4] Jensen K J and Janes K A 2012 Phys. Biol. 9 045004 [5] Zarnitsyna V and Zhu C 2012 Phys. Biol. 9 045005 [6] Rubinstein B et al 2012 Phys. Biol. 9 045006 [7] Frank T D et al 2012 Phys. Biol. 9 045007 [8] Del Vecchio D et al 2012 Phys. Biol. 9 045008 [9] Seaton D D and Krishnan J 2012 Phys. Biol. 9 045009 [10] Radivojevic A et al 2012 Phys. Biol. 9 045010 [11] Rhee A et al 2012 Phys. Biol. 9 045011

Identification of Epigenetic Changes in Prostate Cancer using Induced Pluripotent Stem Cells

DTIC Science & Technology

2014-04-01

somatic cells in human iPS cells. Nat Cell Bioi, 13: 541, 2011 5. Polo, J. M., Liu, S., Figueroa , M. E. et al.: Cell type of origin influences the...human iPS cells. Nat Cell Bioi 13: 5•1 \\ - 5•19. 18. Poloj:\\ə, Lu S, Figueroa ME, Kulalert W, Eminli S, ct a!. (20 10) Cell type of origin

TrawlerWeb: an online de novo motif discovery tool for next-generation sequencing datasets.

PubMed

Dang, Louis T; Tondl, Markus; Chiu, Man Ho H; Revote, Jerico; Paten, Benedict; Tano, Vincent; Tokolyi, Alex; Besse, Florence; Quaife-Ryan, Greg; Cumming, Helen; Drvodelic, Mark J; Eichenlaub, Michael P; Hallab, Jeannette C; Stolper, Julian S; Rossello, Fernando J; Bogoyevitch, Marie A; Jans, David A; Nim, Hieu T; Porrello, Enzo R; Hudson, James E; Ramialison, Mirana

2018-04-05

A strong focus of the post-genomic era is mining of the non-coding regulatory genome in order to unravel the function of regulatory elements that coordinate gene expression (Nat 489:57-74, 2012; Nat 507:462-70, 2014; Nat 507:455-61, 2014; Nat 518:317-30, 2015). Whole-genome approaches based on next-generation sequencing (NGS) have provided insight into the genomic location of regulatory elements throughout different cell types, organs and organisms. These technologies are now widespread and commonly used in laboratories from various fields of research. This highlights the need for fast and user-friendly software tools dedicated to extracting cis-regulatory information contained in these regulatory regions; for instance transcription factor binding site (TFBS) composition. Ideally, such tools should not require prior programming knowledge to ensure they are accessible for all users. We present TrawlerWeb, a web-based version of the Trawler_standalone tool (Nat Methods 4:563-5, 2007; Nat Protoc 5:323-34, 2010), to allow for the identification of enriched motifs in DNA sequences obtained from next-generation sequencing experiments in order to predict their TFBS composition. TrawlerWeb is designed for online queries with standard options common to web-based motif discovery tools. In addition, TrawlerWeb provides three unique new features: 1) TrawlerWeb allows the input of BED files directly generated from NGS experiments, 2) it automatically generates an input-matched biologically relevant background, and 3) it displays resulting conservation scores for each instance of the motif found in the input sequences, which assists the researcher in prioritising the motifs to validate experimentally. Finally, to date, this web-based version of Trawler_standalone remains the fastest online de novo motif discovery tool compared to other popular web-based software, while generating predictions with high accuracy. TrawlerWeb provides users with a fast, simple and easy-to-use web interface for de novo motif discovery. This will assist in rapidly analysing NGS datasets that are now being routinely generated. TrawlerWeb is freely available and accessible at: http://trawler.erc.monash.edu.au .

Comparison of human immunodeficiency virus assays in window phase and elite controller samples: viral load distribution and implications for transmission risk

PubMed Central

Vermeulen, Marion; Coleman, Charl; Mitchel, Josephine; Reddy, Ravi; van Drimmelen, Harry; Fickett, Tracy; Busch, Michael; Lelie, Nico

2016-01-01

BACKGROUND After 3 years of individual-donation nucleic acid test (ID-NAT) screening by the South African National Blood Service (SANBS), a repository of 73 human immunodeficiency virus antibody (anti-HIV)-negative window period (WP)-yield samples and 28 anti-HIV–positive, HIV-RNA–negative elite controllers (ECs) became available for comparison of a p24 antigen (p24 Ag) assay (Innogenetics), two viral load assays (Siemens branch DNA [bDNA] 3.0 and Abbott real-time polymerase chain reaction [RT-PCR]), and three triplex NAT assays (Novartis Diagnostics Ultrio and Ultrio-Plus and Roche TaqScreen) by replicate testing of dilutions. STUDY DESIGN AND METHODS Viral loads were assessed by bDNA and RT-PCR assays and if below 100 copies (cps)/mL, by Ultrio limiting dilution probit analysis. The probability of virus transmission by WP and EC donations was estimated for different levels of the 50% minimum infectious dose (ID50) using Poisson distribution statistics. RESULTS The equal distribution of WP donations plotted by log HIV-RNA levels indicated a random appearance of donors in the ramp-up phase. The HIV p24 Ag assay detected 45% of WP samples and the cutoff crossing point was estimated at 8140 (bDNA)/ 22,710 (RT-PCR) cps/mL. On replicate retesting of 40 HIV p24 Ag–negative ID-NAT WP-yield samples Ultrio minipool (MP)8, Ultrio-Plus MP8, and TaqScreen MP6 detected 79, 81, and 78%, respectively. Modeling with an estimated ID50 of 31.6 virions/RBC indicated that 15% of p24 Ag–negative ID-NAT WP-yield donations would have transmitted HIV if MP6–8 NAT had been used. Only 2% of RBC transfusions from ECs are estimated to be infectious with a worst-case ID50 estimate of 316 virions. CONCLUSION Our analysis of viremia and infectivity of WP and EC donations enables comparison of the efficacy of NAT options in preventing HIV transmission risk. PMID:23445273

Comparison of human immunodeficiency virus assays in window phase and elite controller samples: viral load distribution and implications for transmission risk.

PubMed

Vermeulen, Marion; Coleman, Charl; Mitchel, Josephine; Reddy, Ravi; van Drimmelen, Harry; Fickett, Tracy; Busch, Michael; Lelie, Nico

2013-10-01

After 3 years of individual-donation nucleic acid test (ID-NAT) screening by the South African National Blood Service (SANBS), a repository of 73 human immunodeficiency virus antibody (anti-HIV)-negative window period (WP)-yield samples and 28 anti-HIV-positive, HIV-RNA-negative elite controllers (ECs) became available for comparison of a p24 antigen (p24 Ag) assay (Innogenetics), two viral load assays (Siemens branch DNA [bDNA] 3.0 and Abbott real-time polymerase chain reaction [RT-PCR]), and three triplex NAT assays (Novartis Diagnostics Ultrio and Ultrio-Plus and Roche TaqScreen) by replicate testing of dilutions. Viral loads were assessed by bDNA and RT-PCR assays and if below 100 copies (cps)/mL, by Ultrio limiting dilution probit analysis. The probability of virus transmission by WP and EC donations was estimated for different levels of the 50% minimum infectious dose (ID50 ) using Poisson distribution statistics. The equal distribution of WP donations plotted by log HIV-RNA levels indicated a random appearance of donors in the ramp-up phase. The HIV p24 Ag assay detected 45% of WP samples and the cutoff crossing point was estimated at 8140 (bDNA)/22,710 (RT-PCR) cps/mL. On replicate retesting of 40 HIV p24 Ag-negative ID-NAT WP-yield samples Ultrio minipool (MP)8, Ultrio-Plus MP8, and TaqScreen MP6 detected 79, 81, and 78%, respectively. Modeling with an estimated ID50 of 31.6 virions/RBC indicated that 15% of p24 Ag-negative ID-NAT WP-yield donations would have transmitted HIV if MP6-8 NAT had been used. Only 2% of RBC transfusions from ECs are estimated to be infectious with a worst-case ID50 estimate of 316 virions. Our analysis of viremia and infectivity of WP and EC donations enables comparison of the efficacy of NAT options in preventing HIV transmission risk. © 2013 American Association of Blood Banks.

Combined MIPAS (airborne/satellite), CALIPSO and in situ study on large potential NAT particles observed in early Arctic winter stratosphere in December 2011

NASA Astrophysics Data System (ADS)

Woiwode, Wolfgang; Höpfner, Michael; Pitts, Michael; Poole, Lamont; Oelhaf, Hermann; Molleker, Sergej; Borrmann, Stephan; Ebersoldt, Andreas; Frey, Wiebke; Gulde, Thomas; Maucher, Guido; Piesch, Christof; Sartorius, Christian; Orphal, Johannes

2015-04-01

The understanding of the characteristics of large HNO3-containing particles (potential 'NAT-rocks') involved in vertical redistribution of HNO3 in the polar winter stratosphere is limited due to the difficult accessibility of these particles by observations. While robust polar stratospheric cloud (PSC) classification schemes exist for observations by the space-borne lidar aboard CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations) as well as for the passive mid-infrared limb observations by MIPAS (Michelson Interferometer for Passive Atmospheric Sounding), these observations are hardly exploited for the detection of large (diameter >10 μm) NAT particles. This is due to the facts that these particles have low overall number densities, resulting in weak detectable signatures, and that the physical characteristics of these particles (i.e. shape, morphology, HNO3-content and optical characteristics) are uncertain. We investigate collocated and complementary observations of a low-density potential large NAT particle field by the space-borne instruments CALIPSO and MIPAS-ENVISAT as well as the airborne observations by the limb-sounder MIPAS-STR and the in situ particle probe FSSP-100 (Forward Scattering Spectrometer Probe 100) aboard the high-altitude aircraft Geophysica. The observations aboard the Geophysica on 11 December 2011 associated to ESSenCe (ESa Sounder Campaign 2011) provided us the unique opportunity to study in detail the lower boundary region of a PSC where large potential NAT particles (>20 μm in diameter) were detected in situ. We analyse the ambient temperatures and gas-phase composition (HNO3 and H2O), the signatures of the observed particles in the CALIPSO and MIPAS observations, the HNO3-content of these particles suggested by the FSSP-100 and MIPAS-STR observations, and focus on the spectral fingerprint of these particles in the MIPAS-STR observations. While the spectral characterisation of the observed particles is subject of ongoing work, our results support that these particles consist of NAT and that the particle shape plays a crucial role.

Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation

PubMed Central

2013-01-01

SUMMARY The negative impact of cytomegalovirus (CMV) infection on transplant outcomes warrants efforts toward improving its prevention, diagnosis, and treatment. During the last 2 decades, significant breakthroughs in diagnostic virology have facilitated remarkable improvements in CMV disease management. During this period, CMV nucleic acid amplification testing (NAT) evolved to become one of the most commonly performed tests in clinical virology laboratories. NAT provides a means for rapid and sensitive diagnosis of CMV infection in transplant recipients. Viral quantification also introduced several principles of CMV disease management. Specifically, viral load has been utilized (i) for prognostication of CMV disease, (ii) to guide preemptive therapy, (iii) to assess the efficacy of antiviral treatment, (iv) to guide the duration of treatment, and (v) to indicate the risk of clinical relapse or antiviral drug resistance. However, there remain important limitations that require further optimization, including the interassay variability in viral load reporting, which has limited the generation of standardized viral load thresholds for various clinical indications. The recent introduction of an international reference standard should advance the major goal of uniform viral load reporting and interpretation. However, it has also become apparent that other aspects of NAT should be standardized, including sample selection, nucleic acid extraction, amplification, detection, and calibration, among others. This review article synthesizes the vast amount of information on CMV NAT and provides a timely review of the clinical utility of viral load testing in the management of CMV in solid organ transplant recipients. Current limitations are highlighted, and avenues for further research are suggested to optimize the clinical application of NAT in the management of CMV after transplantation. PMID:24092851

Investigation of an algorithm for anti HCV EIA reactivity in blood donor screening in Turkey in the absence of nucleic acid amplification screening.

PubMed

Karakoc, Ayse Esra; Berkem, Rukiye; Irmak, Hasan; Demiroz, Ali Pekcan; Yenicesu, Idil; Ertugrul, Nigar; Arslan, Önder; Kemahli, Sabri; Yilmaz, Sevinc; Ozcebe, Osman; Kara, Abdurrahman; Ozet, Gulsum; Acikgoz, Ziya Cibali; Acikgoz, Tulin

2017-10-01

In this study we aimed to propose an algorithm for initial anti HCV EIA reactive blood donations in Turkey where nucleic acid amplification tests are not yet obligatory for donor screening. A total of 416 anti HCV screening test reactive donor samples collected from 13 blood centers from three cities in Turkey were tested in duplicate by Ortho HCV Ab Version 3.0 and Radim HCV Ab. All the repeat reactive samples were tested by INNO-LIA HCV Ab 3.0 or Chiron RIBA HCV 3.0 and Abbott Real Time HCV. Intra-assay correlations were calculated with Pearson r test. ROC analysis was used to study the relationship between EIA tests and the confirmatory tests. The number of repeat reactive results with Ortho EIA were 221 (53.1%) whereas that of microEIA, 62 (14.9%). Confirmed positivity rate was 14.6% (33/226) by RIBA and 10.6% (24/226) by NAT. Reactive PCR results were predicted with 100% sensitivity and 95% specificity with S/CO levels of 8.1 with Ortho EIA and 3.4 with microEIA. Repeat reactivity rates declined with a second HCV antibody assay. Samples repeat reactive with one HCV antibody test and negative with the other were all NAT negative. All the NAT reactive samples were RIBA positive. None of the RIBA indeterminate or negative samples were NAT reactive. Considering the threshold values for EIA kits determined by ROC analysis NAT was decided to be performed for the samples above the threshold value and a validated supplemental HCV antibody test for the samples below. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of cancer chemopreventive isothiocyanates as direct inhibitors of the arylamine N-acetyltransferase-dependent acetylation and bioactivation of aromatic amine carcinogens.

PubMed

Duval, Romain; Xu, Ximing; Bui, Linh-Chi; Mathieu, Cécile; Petit, Emile; Cariou, Kevin; Dodd, Robert H; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2016-02-23

Aromatic amines (AAs) are chemicals of industrial, pharmacological and environmental relevance. Certain AAs, such as 4-aminobiphenyl (4-ABP), are human carcinogens that require enzymatic metabolic activation to reactive chemicals to form genotoxic DNA adducts. Arylamine N-acetyltransferases (NAT) are xenobiotic metabolizing enzymes (XME) that play a major role in this carcinogenic bioactivation process. Isothiocyanates (ITCs), including benzyl-ITC (BITC) and phenethyl-ITC (PEITC), are phytochemicals known to have chemopreventive activity against several aromatic carcinogens. In particular, ITCs have been shown to modify the bioactivation and subsequent mutagenicity of carcinogenic AA chemicals such as 4-ABP. However, the molecular and biochemical mechanisms by which these phytochemicals may modulate AA carcinogens bioactivation and AA-DNA damage remains poorly understood. This manuscript provides evidence indicating that ITCs can decrease the metabolic activation of carcinogenic AAs via the irreversible inhibition of NAT enzymes and subsequent alteration of the acetylation of AAs. We demonstrate that BITC and PEITC react with NAT1 and inhibit readily its acetyltransferase activity (k(i) = 200 M(-1).s(-1) and 66 M(-1).s(-1) for BITC and PEITC, respectively). Chemical labeling, docking approaches and substrate protection assays indicated that inhibition of the acetylation of AAs by NAT1 was due to the chemical modification of the enzyme active site cysteine. Moreover, analyses of AAs acetylation and DNA adducts in cells showed that BITC was able to modulate the endogenous acetylation and bioactivation of 4-ABP. In conclusion, we show that direct inhibition of NAT enzymes may be an important mechanism by which ITCs exert their chemopreventive activity towards AA chemicals.

Association of N-acetyltransferase-2 polymorphism with an increased risk of coronary heart disease in a Chinese population.

PubMed

Sun, J D; Yuan, H; Hu, H Q; Yu, H M

2016-03-04

We investigated the possible correlations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of coronary heart disease (CHD). CHD patients (113) and healthy controls (118) were enrolled from the First People's Hospital of Yuhang between January 2013 and June 2014. The patients were divided into mild CHD (N = 72) and severe CHD (N = 41) subgroups. DNA samples were extracted and the distributions of NAT2 polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Clinical characteristic indexes of severe CHD patients were also examined for relevant statistical analysis. WT, M1, M2, and M3 alleles were observed in both case and control groups. PCR-RFLP identified a wild-type homozygote, WT/WT; a mutant heterozygote, WT/Mx; and a mutant homozygote, Mx/Mx (x = 1, 2, and 3) variant of the NAT2 genotype. Mx/Mx differed significantly between case and control groups (P < 0.05); the frequencies of all four alleles did not differ significantly between case and control groups (P > 0.05). Slow acetylator genotype frequencies were notably higher in the case group than in the control group (P < 0.05). Individuals with the slow acetylator genotype were at 1.97-times higher risk of CHD and also displayed higher triglyceride and lower high-density lipoprotein cholesterol levels than those with the rapid acetylator genotype (P < 0.05). Therefore, the NAT2 polymorphism was believed to be associated with increased risk of CHD, with the NAT2 slow acetylator genotype serving as a risk factor for severe CHD in a Chinese population.

Active cigarette smoking and the risk of breast cancer at the level of N-acetyltransferase 2 (NAT2) gene polymorphisms.

PubMed

Kasajova, Petra; Holubekova, Veronika; Mendelova, Andrea; Lasabova, Zora; Zubor, Pavol; Kudela, Erik; Biskupska-Bodova, Kristina; Danko, Jan

2016-06-01

The aim of our study was to assess the correlation between the tobacco exposure and NAT2 gene (rs1041983 C/T, rs1801280 T/C, rs1799930 G/A) polymorphisms in association with breast cancer development. We wanted to determine the prognostic clinical importance of these polymorphisms in association with smoking and breast cancer. For the detection of possible association between smoking, NAT2 gene polymorphisms, and the risk of breast cancer, we designed a case-controlled study with 198 patients enrolled, 98 breast cancer patients and 100 healthy controls. Ten milliliters of peripheral blood from the cubital vein was withdrawn from every patient. The HRM (high resolution melting) analysis was used for the detection of three abovementioned NAT2 gene polymorphisms. When comparing a group of women smoking more than 5 cigarettes a day with the patients smoking fewer than 5 cigarettes a day, we found out that if women were the carriers of aberrant AA genotype for rs1799930, the first group of women had higher risk of breast carcinoma than the second group. If patients were the carriers of aberrant TT genotype for rs1041983, for rs1801280CC genotype, and rs1799930AA genotype and they smoked more than 5 cigarettes a day, they had higher risk of malignant breast disease than never-smoking women. Our results confirm the hypothesis that NAT2 gene polymorphisms (rs1041983 C/T, rs1801280 T/C, and rs1799930 G/A) in association with long-period active smoking could be the possible individual risk-predicting factors for breast cancer development in the population of Slovak women.

Development of a web-based application and multicountry analysis framework for assessing interdicted infections and cost-utility of screening donated blood for HIV, HCV and HBV.

PubMed

Custer, B; Janssen, M P; Hubben, G; Vermeulen, M; van Hulst, M

2017-08-01

Most countries test donations for HIV, HCV and HBV using serology with or without nucleic acid testing (NAT). Cost-utility analyses provide information on the relative value of different screening options. The aim of this project was to develop an open access risk assessment and cost-utility analysis web-tool for assessing HIV, HCV and HBV screening options (http://www.isbtweb.org/working-parties/transfusion-transmitted-infectious-diseases/). An analysis for six countries (Brazil, Ghana, the Netherlands, South Africa, Thailand and USA) was conducted. Four strategies; (1) antibody assays (Abs) for HIV and HCV + HBsAg, (2) antibody assays that include antigens for HIV and HCV (Combo) + HBsAg, (3) NAT in minipools of variable size (MP NAT) and (4) individual donation (ID) NAT can be evaluated using the tool. Country-specific data on donors, donation testing results, recipient outcomes and costs are entered using the online interface. Results obtained include the number infections interdicted using each screening options, and the (incremental and average) cost-utility of the options. In each of the six countries evaluated, the use of antibody assays is cost effective or even cost saving. NAT has varying cost-utility depending on the setting, and where adopted, the incremental cost-utility exceeds any previously defined or proposed threshold in each country. The web-tool allows an assessment of infectious units interdicted and value for money of different testing strategies. Regardless of gross national income (GNI) per capita, countries appear willing to dedicate healthcare resources to blood supply safety in excess of that for other sectors of health care. © 2017 International Society of Blood Transfusion.

Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.

PubMed

Zaroff, Samantha; Leone, Paola; Markov, Vladimir; Francis, Jeremy S

2015-03-01

N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system. Downreguation of Nat8L is particularly pronounced in the 5xFAD hippocampus, and is preceded by a significant upregulation of oligodendrocytic aspartoacylase (aspa), which encodes for the sole known NAA-catabolizing enzyme in the brain. Reductions in 5xFAD NAA and Nat8L cannot be accounted for by discrepancies in either neuron content or activity of the substrate-providing malate-aspartate shuttle, thereby implicating transcriptional regulation in a coordinated response to pathological energetic crisis. A central role for ASPA in this response is supported by a parallel developmental analysis showing highly significant increases in Nat8L expression in an ASPA-null mouse model during a period of early postnatal development normally punctuated by the transcriptional upregulation of aspa. These results provide preliminary evidence of a signaling mechanism in Alzheimer's disease that involves cross talk between neurons and oligodendrocytes, and suggest that ASPA acts to negatively regulate Nat8L expression. This mechanism is proposed to be a fundamental means by which the brain conserves available substrate during energy crises. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer

PubMed Central

Yuan, Jian-Min; Chan, Kenneth K.; Coetzee, Gerhard A.; Castelao, J.Esteban; Watson, Mary A.; Bell, Douglas A.; Wang, Renwei; Yu, Mimi C.

2008-01-01

Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual’s susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyltransferase (NAT) 1 and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case–control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19–48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 [OR for the null genotype = 1.48, 95% confidence interval (CI) = 1.19–1.83]. When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend = 0.002). OR (95% CI) for one and two or more null/low-activity GST genotypes was 1.42 (1.12–1.81) and 1.71 (1.25–2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR = 2.03, 95% CI = 1.12–3.69, P = 0.02). The effect of NAT2 slow acetylation was even stronger in the presence of two or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype. PMID:18544563

Homogenous Surface Nucleation of Solid Polar Stratospheric Cloud Particles

NASA Technical Reports Server (NTRS)

Tabazadeh, A.; Hamill, P.; Salcedo, D.; Gore, Warren J. (Technical Monitor)

2002-01-01

A general surface nucleation rate theory is presented for the homogeneous freezing of crystalline germs on the surfaces of aqueous particles. While nucleation rates in a standard classical homogeneous freezing rate theory scale with volume, the rates in a surface-based theory scale with surface area. The theory is used to convert volume-based information on laboratory freezing rates (in units of cu cm, seconds) of nitric acid trihydrate (NAT) and nitric acid dihydrate (NAD) aerosols into surface-based values (in units of sq cm, seconds). We show that a surface-based model is capable of reproducing measured nucleation rates of NAT and NAD aerosols from concentrated aqueous HNO3 solutions in the temperature range of 165 to 205 K. Laboratory measured nucleation rates are used to derive free energies for NAT and NAD germ formation in the stratosphere. NAD germ free energies range from about 23 to 26 kcal mole, allowing for fast and efficient homogeneous NAD particle production in the stratosphere. However, NAT germ formation energies are large (greater than 26 kcal mole) enough to prevent efficient NAT particle production in the stratosphere. We show that the atmospheric NAD particle production rates based on the surface rate theory are roughly 2 orders of magnitude larger than those obtained from a standard volume-based rate theory. Atmospheric volume and surface production of NAD particles will nearly cease in the stratosphere when denitrification in the air exceeds 40 and 78%, respectively. We show that a surface-based (volume-based) homogeneous freezing rate theory gives particle production rates, which are (not) consistent with both laboratory and atmospheric data on the nucleation of solid polar stratospheric cloud particles.

The mid-IR Absorption Cross Sections of α- and β-NAT (HNO3 · 3H2O) in the range 170 to 185 K and of metastable NAD (HNO3 · 2H2O) in the range 172 to 182 K

NASA Astrophysics Data System (ADS)

Iannarelli, R.; Rossi, M. J.

2015-11-01

Growth and Fourier transform infrared (FTIR) absorption in transmission of the title nitric acid hydrates have been performed in a stirred flow reactor (SFR) under tight control of the H2O and HNO3 deposition conditions affording a closed mass balance of the binary mixture. The gas and condensed phases have been simultaneously monitored using residual gas mass spectrometry and FTIR absorption spectroscopy, respectively. Barrierless nucleation of the metastable phases of both α-NAT (nitric acid trihydrate) and NAD (nitric acid dihydrate) has been observed when HNO3 was admitted to the SFR in the presence of a macroscopic thin film of pure H2O ice of typically 1 µm thickness. The stable β-NAT phase was spontaneously formed from the precursor α-NAT phase through irreversible thermal rearrangement beginning at 185 K. This facile growth scheme of nitric acid hydrates requires the presence of H2O ice at thicknesses in excess of approximately hundred nanometers. Absolute absorption cross sections in the mid-IR spectral range (700-4000 cm-1) of all three title compounds have been obtained after spectral subtraction of excess pure ice at temperatures characteristic of the upper troposphere/lower stratosphere. Prominent IR absorption frequencies correspond to the antisymmetric nitrate stretch vibration (ν3(NO3-)) in the range 1300 to 1420 cm-1 and the bands of hydrated protons in the range 1670 to 1850 cm-1 in addition to the antisymmetric O-H stretch vibration of bound H2O in the range 3380 to 3430 cm-1 for NAT.

Oligomeric properties and DNA binding specificities of repressor isoforms from the Streptomyces bacteriophage phiC31.

PubMed

Wilson, S E; Smith, M C

1998-05-15

Three protein isoforms (74, 54 and 42 kDa) are expressed from repressor gene c in the Streptomyces temperate bacteriophage phiC31. Because expression of the two smaller isoforms, 54 and 42 kDa, is sufficient for superinfection immunity, the interaction between these isoforms was studied. The native 42 kDa repressor (Nat42) and an N-terminally 6x histidine-tagged 54 kDa isoform (His54) were shown by co-purification on a Ni-NTA column to interact in Streptomyces lividans . In vitro three repressor preparations, containing Nat42, His54 and the native 54 and 42 kDa isoforms expressed together (Nat54&42), were subjected to chemical crosslinking and gel filtration analysis. Homo- and hetero-tetramers were observed. Previous work showed that the smallest isoform bound to 17 bp operators containing aconservedinvertedrepeat (CIR) and that the CIRs were located at 16 loci throughout the phiC31 genome. One of the CIRs (CIR6) is believed to be critical for regulating the lytic pathway. The DNA binding activities of the three repressor preparations were studied using fragments containing CIRs (CIR3-CIR6) from the essential early region as templates for DNase I footprinting. Whereas Nat42 bound to CIR6, poorly to CIR5 but undetectably to CIR3 or CIR4, the Nat54&42 preparation could bind to all CIRs tested, albeit poorly to CIR3 and CIR4. The His54 isoform bound all CIRs tested. Isoforms expressed from the phiC31 repressor gene, like those which are expressed from many eukaryotic transcription factor genes, apparently have different binding specificities.

Effects of acute ethanol administration on nocturnal pineal serotonin N-acetyltransferase activity

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

Creighton, J.A.; Rudeen, P.K.

The effect of acute ethanol administration on pineal serotonin N-acetyltransferase (NAT) activity, norepinephrine and indoleamine content was examined in male rats. When ethanol was administered in two equal doses (2 g/kg body weight) over a 4 hour period during the light phase, the nocturnal rise in NAT activity was delayed by seven hours. The nocturnal pineal norepinephrine content was not altered by ethanol except for a delay in the reduction of NE with the onset of the following light phase. Although ethanol treatment led to a significant reduction in nocturnal levels of pineal serotonin content, there was no significant effectmore » upon pineal content of 5-hydroxyindoleacetic acid (5-HIAA). The data indicate that ethanol delays the onset of the rise of nocturnal pineal NAT activity.« less

The NatCarb geoportal: Linking distributed data from the Carbon Sequestration Regional Partnerships

USGS Publications Warehouse

Carr, T.R.; Rich, P.M.; Bartley, J.D.

2007-01-01

The Department of Energy (DOE) Carbon Sequestration Regional Partnerships are generating the data for a "carbon atlas" of key geospatial data (carbon sources, potential sinks, etc.) required for rapid implementation of carbon sequestration on a broad scale. The NATional CARBon Sequestration Database and Geographic Information System (NatCarb) provides Web-based, nation-wide data access. Distributed computing solutions link partnerships and other publicly accessible repositories of geological, geophysical, natural resource, infrastructure, and environmental data. Data are maintained and enhanced locally, but assembled and accessed through a single geoportal. NatCarb, as a first attempt at a national carbon cyberinfrastructure (NCCI), assembles the data required to address technical and policy challenges of carbon capture and storage. We present a path forward to design and implement a comprehensive and successful NCCI. ?? 2007 The Haworth Press, Inc. All rights reserved.

Metastable Nitric Acid Trihydrate in Ice Clouds.

PubMed

Weiss, Fabian; Kubel, Frank; Gálvez, Óscar; Hoelzel, Markus; Parker, Stewart F; Baloh, Philipp; Iannarelli, Riccardo; Rossi, Michel J; Grothe, Hinrich

2016-03-01

The composition of high-altitude ice clouds is still a matter of intense discussion. The constituents in question are ice and nitric acid hydrates, but the exact phase composition of clouds and its formation mechanisms are still unknown. In this work, conclusive evidence for a long-predicted phase, alpha-nitric acid trihydrate (alpha-NAT), is presented. This phase was characterized by a combination of X-ray and neutron diffraction experiments, allowing a convincing structure solution. Furthermore, vibrational spectra (infrared and inelastic neutron scattering) were recorded and compared with theoretical calculations. A strong interaction between water ice and alpha-NAT was found, which explains the experimental spectra and the phase-transition kinetics. On the basis of these results, we propose a new three-step mechanism for NAT formation in high-altitude ice clouds. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A simple and cost-saving approach to optimize the production of subtilisin NAT by submerged cultivation of Bacillus subtilis natto.

PubMed

Ku, Ting-Wei; Tsai, Ruei-Lan; Pan, Tzu-Ming

2009-01-14

Subtilisin NAT, formerly designated nattokinase or subtilisin BSP, is a potent cardiovascular drug because of its strong fibrinolytic activity and safety. In this study, one Bacillus subtilis natto strain with high fibrinolytic activity was isolated. We further studied the optimal conditions for subtilisin NAT production by submerged cultivation and three variables/three levels of response surface methodology (RSM) using various inoculum densities, glucose concentrations, and defatted soybean concentrations as the three variables. According to the RSM analysis, while culturing by 2.93% defatted soybean, 1.75% glucose, and 4.00% inoculum density, we obtained an activity of 13.78 SU/mL. Processing the batch fermentation with this optimal condition, the activity reached 13.69 SU/mL, which is equal to 99.3% of the predicted value.

Growth of nitric acid hydrates on thin sulfuric acid films

NASA Technical Reports Server (NTRS)

Iraci, Laura T.; Middlebrook, Ann M.; Wilson, Margaret A.; Tolbert, Margaret A.

1994-01-01

Type I polar stratospheric clouds (PSCs) are thought to nucleate and grow on stratospheric sulfate aerosols (SSAs). To model this system, thin sulfuric acid films were exposed to water and nitric acid vapors (1-3 x 10(exp -4) Torr H2O and 1-2.5 x 10(exp -6) Torr HNO3) and subjected to cooling and heating cycles. Fourier Transform Infrared (FTIR) spectroscopy was used to probe the phase of the sulfuric acid and to identify the HNO3/H2O films that condensed. Nitric acid trihydrate (NAT) was observed to grow on crystalline sulfuric acid tetrahydrate (SAT) films. NAT also condensed in/on supercooled H2SO4 films without causing crystallization of the sulfuric acid. This growth is consistent with NAT nucleation from ternary solutions as the first step in PSC formation.

Extension of activation cross section data of long lived products in deuteron induced nuclear reactions on platinum up to 50 MeV

NASA Astrophysics Data System (ADS)

Ditrói, F.; Tárkányi, F.; Takács, S.; Hermanne, A.

2017-06-01

In the frame of a systematical study of light ion induced nuclear reactions on platinum, activation cross sections for deuteron induced reactions were investigated. Excitation functions were measured in the 20.8-49.2 MeV energy range for the natPt(d,xn)191,192,193,194,195,196m2,196g,198g,199Au, natPt(d,x)188,189,191,195m,197m,197gPt and natPt(d,x)189,190,192,194m2Ir reactions by using the stacked foil irradiation technique. The experimental results are compared with previous results from the literature and with the theoretical predictions in the TENDL-2014 and TENDL-2015 libraries. The applicability of the produced radio-tracers for wear measurements has been presented.

Requirements, Technology and Configuration Evaluation for Crash Survivable Flight Data Recording (CSFDR) System

DTIC Science & Technology

1981-03-23

25% Rotational angle - 350 degrees Temperature range - -65°C to + 125°C Vibration - 15 g Shock - 50 g Rotational load life - 25,000,000...structed of multi-layered metal foils, vacuum deposited on thin films of Mylar, Kapton, or similar plastics) slowly outgas and contaminate their own...armor. Intumescent coating is a paint derivative, which swells 5 to 50 times its original thickness when exposed to high temperatures ( 350 ° to 500

Recent Developments in Assessing Microstructure-Sensitive Early Stage Fatigue of Polycrystals (Postprint)

DTIC Science & Technology

2014-04-01

can strongly affect formation of fatigue cracks. El Bartali et al. [7] quantified plastic strain at the grain scale in a duplex stainless steel and mea... Fatigue Fract Eng Mater Struct 2013. [7] El Bartali A, Aubin V, Degallaix S. Fatigue damage analysis in a duplex stainless steel by digital image...S. Surface observation and measurement techniques to study the fatigue damage micromechanisms in a duplex stainless steel . Int J Fatigue 2009;31:2049

WebStruct and VisualStruct: Web interfaces and visualization for Structure software implemented in a cluster environment.

PubMed

Jayashree, B; Rajgopal, S; Hoisington, D; Prasanth, V P; Chandra, S

2008-09-24

Structure, is a widely used software tool to investigate population genetic structure with multi-locus genotyping data. The software uses an iterative algorithm to group individuals into "K" clusters, representing possibly K genetically distinct subpopulations. The serial implementation of this programme is processor-intensive even with small datasets. We describe an implementation of the program within a parallel framework. Speedup was achieved by running different replicates and values of K on each node of the cluster. A web-based user-oriented GUI has been implemented in PHP, through which the user can specify input parameters for the programme. The number of processors to be used can be specified in the background command. A web-based visualization tool "Visualstruct", written in PHP (HTML and Java script embedded), allows for the graphical display of population clusters output from Structure, where each individual may be visualized as a line segment with K colors defining its possible genomic composition with respect to the K genetic sub-populations. The advantage over available programs is in the increased number of individuals that can be visualized. The analyses of real datasets indicate a speedup of up to four, when comparing the speed of execution on clusters of eight processors with the speed of execution on one desktop. The software package is freely available to interested users upon request.

Genetics Home Reference: dyserythropoietic anemia and thrombocytopenia

MedlinePlus

... PubMed Crispino JD. GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol. 2005 Feb;16(1): ... GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol. 2005 Feb;25(4):1215- ...

The Role of Stat3 Activation in Androgen Receptor Signaling and Prostate Cancer

DTIC Science & Technology

2006-07-01

S. C. & Xiao, G. (2003) Cancer Metastasis Rev. 22, 405–422. 10. Karin, M. & Greten , F. R. (2005) Nat. Rev. Immunol. 5, 749–759. 11. Karin, M., Cao, Y... Greten , F. R. & Li, Z. W. (2002) Nat. Rev. Cancer 2, 301–310. 12. Fan, C. M. & Maniatis, T. (1991) Nature 354, 395–398. 13. Betts, J. C. & Nabel, G

The Nuclear Death Domain Protein p84N5; A Candidate Breast Cancer Susceptibility Gene

DTIC Science & Technology

2007-05-01

hallmarks of cancer. Cell 100, 57-70, 2000. 35. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev...D., and Weinberg, R. A. (2000) Cell 100, 57-70 46. Karin, M., Cao, Y., Greten , F. R., and Li, Z. W. (2002) Nat Rev Cancer 2, 301-310 47. Cogswell, P

Developing and theoretically justifying innovative organizational practices in health information assurance

NASA Astrophysics Data System (ADS)

Collmann, Jeff R.

2003-05-01

This paper justifies and explains current efforts in the Military Health System (MHS) to enhance information assurance in light of the sociological debate between "Normal Accident" (NAT) and "High Reliability" (HRT) theorists. NAT argues that complex systems such as enterprise health information systems display multiple, interdependent interactions among diverse parts that potentially manifest unfamiliar, unplanned, or unexpected sequences that operators may not perceive or immediately understand, especially during emergencies. If the system functions rapidly with few breaks in time, space or process development, the effects of single failures ramify before operators understand or gain control of the incident thus producing catastrophic accidents. HRT counters that organizations with strong leadership support, continuous training, redundant safety features and "cultures of high reliability" contain the effects of component failures even in complex, tightly coupled systems. Building highly integrated, enterprise-wide computerized health information management systems risks creating the conditions for catastrophic breaches of data security as argued by NAT. The data security regulations of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) implicitly depend on the premises of High Reliability Theorists. Limitations in HRT thus have implications for both safe program design and compliance efforts. MHS and other health care organizations should consider both NAT and HRT when designing and deploying enterprise-wide computerized health information systems.

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts

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

Bhaiya, Payal; Roychowdhury, Sanjoy; Vyas, Piyush M.

2006-09-01

Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 proteinmore » was detected. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time- and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.« less

Transcriptomes That Confer to Plant Defense against Powdery Mildew Disease in Lagerstroemia indica

PubMed Central

Shi, Weibing; Rinehart, Timothy

2015-01-01

Transcriptome analysis was conducted in two popular Lagerstroemia cultivars: “Natchez” (NAT), a white flower and powdery mildew resistant interspecific hybrid and “Carolina Beauty” (CAB), a red flower and powdery mildew susceptible L. indica cultivar. RNA-seq reads were generated from Erysiphe australiana infected leaves and de novo assembled. A total of 37,035 unigenes from 224,443 assembled contigs in both genotypes were identified. Approximately 85% of these unigenes have known function. Of them, 475 KEGG genes were found significantly different between the two genotypes. Five of the top ten differentially expressed genes (DEGs) involved in the biosynthesis of secondary metabolites (plant defense) and four in flavonoid biosynthesis pathway (antioxidant activities or flower coloration). Furthermore, 5 of the 12 assembled unigenes in benzoxazinoid biosynthesis and 7 of 11 in flavonoid biosynthesis showed higher transcript abundance in NAT. The relative abundance of transcripts for 16 candidate DEGs (9 from CAB and 7 from NAT) detected by qRT-PCR showed general agreement with the abundances of the assembled transcripts in NAT. This study provided the first transcriptome analyses in L. indica. The differential transcript abundance between two genotypes indicates that it is possible to identify candidate genes that are associated with the plant defenses or flower coloration. PMID:26247009

A Room Temperature Low-Threshold Ultraviolet Plasmonic Nanolaser

DTIC Science & Technology

2014-09-23

Here we demonstrate the first strong room temperature ultraviolet (B370 nm) SP polariton laser with an extremely low threshold (B3.5MWcm 2). We find...localized surface plasmon and propagating surface plasmon polariton (SPP), has been demonstrated in metal nanosphere cavities6, metal-cladding...Quantum plasmonics. Nat. Phys. 9, 329–340 (2013). 4. Berini, P. & De Leon, I. Surface plasmon- polariton amplifiers and lasers. Nat. Photon. 6, 16–24 (2012

N-Acetyltransferase 1 Polymorphism and Breast Cancer Risk

DTIC Science & Technology

2011-10-01

reported that cancer risk associated with NAT1*10 is further modulated by exposure to environmental carcinogens found in cigarette smoke, meats cooked...at high temperatures, and the use of hair dye. For example, frequent 7 consumption of red meat in combination with NAT1*10 is associated with an...well- done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 8, 233-239. Zhu, Y., and Hein, D.W. (2008). Functional effects of

Characterization of Bacillus subtilis strains in Thua nao, a traditional fermented soybean food in northern Thailand.

PubMed

Inatsu, Y; Nakamura, N; Yuriko, Y; Fushimi, T; Watanasiritum, L; Kawamoto, S

2006-09-01

To clarify the diversity of Bacillus subtilis strains in Thua nao that produce high concentrations of products useful in food manufacturing and in health-promoting compounds. Production of amylase, protease, subtilisin NAT (nattokinase), and gamma-polyglutamic acid (PGA) by the Bacillus subtilis strains in Thua nao was measured. Productivity of protease NAT by these strains tended to be higher than by Japanese commercial natto-producing strains. Molecular diversity of isolated strains was analysed via randomly amplified polymorphic DNA-PCR fingerprinting. The strains were divided into 19 types, including a type with the same pattern as a Japanese natto-producing strain. B. subtilis strains that could be a resource for effective production of protease, amylase, subtilisin NAT, or PGA were evident in Thua nao produced in various regions in northern Thailand. This study clearly demonstrated the value of Thua nao as a potential resource of food-processing enzymes and health-promoting compounds.

On the distribution of the amplitudes of natural ELF emissions from measurements on the Kola peninsula.

NASA Astrophysics Data System (ADS)

Pchelkin, Vladimir; Beloglazov, Mikhail

The distributions of the amplitudes of natural emissions of electromagnetic field in the Shu-mann resonance frequency range are investigated. From the data of Lovozero observatory daily variations of the number of overshoots of signal amplitude above given thresholds were con-structed. A possibility is discussed of applicability for the considered frequency range a known from the literature formula, which describes analytically the peak distribution of the spherics. We note the influence of magnetic disturbances on amplitude distribution function.

Impacts of Lake Level Regulation on Beaches and Boating Facilities--Lakes Erie and Ontario and Connecting Waterways. Recreation Beaches Inventory.

DTIC Science & Technology

1979-12-18

feet, the crews were in- structed to take additional measurements. At very long beaches, such as at Presque Isle State Park, in Pennsylvania , the...REGULATION ON BEACHES AND BOATING FACILITIES- LAKES ERIE AND) ONTARIO AND CONNECTING WATERWAYS -I RECREATION BEACHES INVENTORY 3 December 18, 1979 Contract...CATALOG NUMBER 4. TITLE (and Subtitle) S. TYPE OF REPORT & PERIOD COVERED Impacts of Lake Level Regulation on Beaches and Boating Facilities--Lake Erie and

An Essential Protein Repair Enzyme: Investigation of the Molecular Recognition Mechanism of Methionine Sulfoxide Reductase A

DTIC Science & Technology

2008-05-01

4 ). The three-dimensional spatial orientation of the atoms for these resolved solution structures (Protein Data Bank accession codes: 2gt3...Crystal structure of the Escherichia coli peptide methionine sulphoxide reductase at 1.9 Å resolution . Struct. Fold. Des. 8: 1167 – 1178. 2 . Brot...sources (8). There is a 67% sequence identity between the E.coli and human MsrA ( 2 ). N-terminus C-terminus Figure 2 . Three-dimensional structure

History of the AFRL/USC DARPA Program on Polynitrogen Chemistry. Volume 2

DTIC Science & Technology

2004-10-01

published by Pyykkoe and Runeberg in 1991 as part of a systematic study of the isoelectronic dicyanamide series, but little emphasis was given to N5+ as...2003, 244, 93. [3] K. O. Christe, R. D. Wilson, W. W. Wilson, R. Bau, S. Sukumar, D. A. Dixon, J. Am. Chem. Soc. 1991 , 113, 1991 . [4] P...Pyykkoe, N. Runeberg, J. Mol. Struct. (Theochem.) 1991 , 234, 279. [5] R. Rawls, Chem. & Eng. News, Jan. 25 issue, 1999, pg. 7. [6] P. Zurer, Chem

OSA Proceedings of the Topical Meeting on Soft-X-Ray Projection Lithography Held in Monterey, California on 10-12 April 1991. Volume 12

DTIC Science & Technology

1992-05-22

Carbide because of its high thermal the mirror on its backside or edge. Shott Zerodur conductivity. Edge cooling causes a larger exceeded the limit by about...Characterization Angstrom-level noncontact profiling of mirrors for soft x-ray lithography............ 134 Paul Glenn Nonspecular Scattering from X-Ray...structed by patterning a Mo/Si Tropel Division of GCA Corporation. multilayer coated silicon wafer. The mirrors were coated at AT&T Bell The multilayer

Annual Report on Electronics Research at The University of Texas at Austin.

DTIC Science & Technology

1982-05-15

Professor, Physics, 471-5747 L. Frommhold, Professor, Physics, 471-5100 J. Keto , Associate Professor, Physics, 471-4151 H.J. Kimble, Assistant Professor...Scattering Cross Section of Argon Diatom," Canad. J. Physics, 59, 1418 (1981). *Michael H. Proffitt, J.W. Keto and Lothar Frommhold, "Col- lision Induced...Elec- tron Diffraction Study of the Structure of Anthraquinone and Anthracene," J. Mol. Struct. 77, 127-138 (1981). J.W. Keto , T.D. Raymond and Chien-Yu

Effect of Riblets on Pressure Recovery in a Straight-Walled Diffuser

DTIC Science & Technology

1990-12-01

in the boundary layer velocity pro - file. As the flow continues to oppose the adverse pressure gradient, the fluid near the wall begins to flow in the...and was 37 inches long. The floor and ceiling of the test section were con - 3 structed of wood and the side panels were made of plexiglass. Both side...the diffuser remained fairly con - stant at 52 percent. The riblet results seem to follow the same trend, providing an approximate 35 percent increase in

Lamb Wave Propagation in a Restricted Geometry Composite PI-Joint Specimen (Preprint)

DTIC Science & Technology

2011-11-01

adhesive, and were located along the length and height of the specimen as depicted in Figure 3. The sensors were 6.35 mm round disks of PZT , with a...in both cases for R1, R2, and R3. 3D Finite Element Model Geometry 200mm length 50mm width 140mm height x z y PZT Actuation Sensor...health monitoring using scanning laser vibrometry: III. Lamb waves for fatigue crack detection”, Smart Mater. Struct., Vol. 14, No. 6, 2005. 16

Avalanche Characteristics of Silicide Schottky Barrier Diodes

DTIC Science & Technology

1988-01-01

respectively. Detectors should be con- structed of materials where a and 0 differ greatly, and then the multiplication should be initiated by the...8217 MASTER OF SCIENCE OSLD r In the Graduate College THE UNIVERSITY OF ARIZONA 1 9 8 7 ale L. STATEMENT BY AUTHOR This thesis has been submitted in...the head of the major department or the Dean of the Graduate College when in his or her judgement the proposed use of the material is in the interests

Efficient Estimation of Mutual Information for Strongly Dependent Variables

DTIC Science & Technology

2015-05-11

the two possibilities: for a fixed dimension d and near- est neighbor parameter k, we find a constant ↵ k,d , such that if V̄ (i)/V (i) < ↵ k,d , then...also compare the results to several baseline estima- tors: KSG (Kraskov et al., 2004), generalized near- est neighbor graph (GNN) (Pál et al., 2010...Amaury Lendasse, and Francesco Corona. A boundary corrected expansion of the moments of near- est neighbor distributions. Random Struct. Algorithms

The Influences of Glycosylation on the Antigenicity, Immunogenicity, and Protective Efficacy of Ebola Virus GP DNA Vaccines

DTIC Science & Technology

2006-11-22

multiple muta- tions were not studied, (iii) a vaccinia virus (VACV)- T7 system was used for transient expression, (iv) pseudotyped retrovi- ruses were used...those studies produced little to no detectable GP1 or GP2 in the transient VACV- T7 expression assays, whereas in our studies with the DNA con- structs...type GP2 was detected in pseudotyped retroviruses, a result seemingly in conflict with these authors’ findings with the VACV- T7 expression. Although

Zebrafish Staufen1 and Staufen2 are required for the survival and migration of primordial germ cells.

PubMed

Ramasamy, Srinivas; Wang, Hui; Quach, Helen Ngoc Bao; Sampath, Karuna

2006-04-15

In sexually reproducing organisms, primordial germ cells (PGCs) give rise to the cells of the germ line, the gametes. In many animals, PGCs are set apart from somatic cells early during embryogenesis. Work in Drosophila, C. elegans, Xenopus, and zebrafish has shown that maternally provided localized cytoplasmic determinants specify the germ line in these organisms (Raz, E., 2003. Primordial germ-cell development: the zebrafish perspective. Nat. Rev., Genet. 4, 690--700; Santos, A.C., Lehmann, R., 2004. Germ cell specification and migration in Drosophila and beyond. Curr. Biol. 14, R578-R589). The Drosophila RNA-binding protein, Staufen is required for germ cell formation, and mutations in stau result in a maternal effect grandchild-less phenotype (Schupbach,T., Weischaus, E., 1989. Female sterile mutations on the second chromosome of Drosophila melanogaster:1. Maternal effect mutations. Genetics 121, 101-17). Here we describe the functions of two zebrafish Staufen-related proteins, Stau1 and Stau2. When Stau1 or Stau2 functions are compromised in embryos by injecting antisense morpholino modified oligonucleotides or dominant-negative Stau peptides, germ layer patterning is not affected. However, expression of the PGC marker vasa is not maintained. Furthermore, expression of a green fluorescent protein (GFP):nanos 3'UTR fusion protein in germ cells shows that PGC migration is aberrant, and the mis-migrating PGCs do not survive in Stau-compromised embryos. Stau2 is also required for survival of neurons in the central nervous system (CNS). These phenotypes are rescued by co-injection of Drosophila stau mRNA. Thus, staufen has an evolutionarily conserved function in germ cells. In addition, we have identified a function for Stau proteins in PGC migration.

Oceanic Area System Improvement Study (OASIS). Volume V. North Atlantic, Central East Pacific, and Caribbean Regions Communication Systems Description.

DTIC Science & Technology

1981-09-01

ommunication (COM), Document is available to the U.S. Oceanic Air Traffic Systems public through the National Technical Information Service...contact with NAT aircraft. Tourism and Transport Reykjavik Provides VHF and HF radio Iceland but fi- contact with northerly NAT air- nanced partly by...Other Techniques to Civil Aviation, Working Group B, Note presented by the Aviation and Marine Comnunications Service, Department of Tourism and

The Evolving Role of Lyophilized Plasma in Remote Damage Control Resuscitation in the French Armed Forces Health Service

DTIC Science & Technology

2013-01-01

severely bleeding combat casualties with the following interventions: tourniquets applied immediately in the field, hemo- static dressings, tranexamic ... acid within the first 3 hours, transfusion of FLYP and RBCs in a 1:1 ratio, fresh whole blood (FWB) use, correction of acidosis with bicarbonate...products: hemoglobin, ABO-Rh-Kell grouping, HIV 1 and 2 antibodies and nucleic acid testing (NAT), HCV antibodies and NAT, hepatitis B virus antigen and

Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by L-arginine.

PubMed

Min, Li; Jin, Zhongmin; Caldovic, Ljubica; Morizono, Hiroki; Allewell, Norma M; Tuchman, Mendel; Shi, Dashuang

2009-02-20

N-Acetylglutamate synthase (NAGS) catalyzes the first committed step in l-arginine biosynthesis in plants and micro-organisms and is subject to feedback inhibition by l-arginine. This study compares the crystal structures of NAGS from Neisseria gonorrhoeae (ngNAGS) in the inactive T-state with l-arginine bound and in the active R-state complexed with CoA and l-glutamate. Under all of the conditions examined, the enzyme consists of two stacked trimers. Each monomer has two domains: an amino acid kinase (AAK) domain with an AAK-like fold but lacking kinase activity and an N-acetyltransferase (NAT) domain homologous to other GCN5-related transferases. Binding of l-arginine to the AAK domain induces a global conformational change that increases the diameter of the hexamer by approximately 10 A and decreases its height by approximately 20A(.) AAK dimers move 5A outward along their 2-fold axes, and their tilt relative to the plane of the hexamer decreases by approximately 4 degrees . The NAT domains rotate approximately 109 degrees relative to AAK domains enabling new interdomain interactions. Interactions between AAK and NAT domains on different subunits also change. Local motions of several loops at the l-arginine-binding site enable the protein to close around the bound ligand, whereas several loops at the NAT active site become disordered, markedly reducing enzymatic specific activity.

Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells

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

Tiang, Jacky M.; Butcher, Neville J., E-mail: n.butcher@uq.edu.au; Minchin, Rodney F.

2010-02-26

Arylamine N-acetyltransferase 1 is a phase II metabolizing enzyme that has been associated with certain breast cancer subtypes. While it has been linked to breast cancer risk because of its role in the metabolic activation and detoxification of carcinogens, recent studies have suggested it may be important in cell growth and survival. To address the possible importance of NAT1 in breast cancer, we have used a novel small molecule inhibitor (Rhod-o-hp) of the enzyme to examine growth and invasion of the breast adenocarcinoma line MDA-MB-231. The inhibitor significantly reduced cell growth by increasing the percent of cells in G2/M phasemore » of the cell cycle. Rhod-o-hp also reduced the ability of the MDA-MB-231 cells to grow in soft agar. Using an in vitro invasion assay, the inhibitor significantly reduced the invasiveness of the cells. To test whether this effect was due to inhibition of NAT1, the enzyme was knocked down using a lentivirus-based shRNA approach and invasion potential was significantly reduced. Taken together, the results of this study demonstrate that NAT1 activity may be important in breast cancer growth and metastasis. The study suggests that NAT1 is a novel target for breast cancer treatment.« less

Mechanism of Allosteric Inhibition of N-Acetyl-L-glutamate Synthase by L-Arginine

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

Min, Li; Jin, Zhongmin; Caldovic, Ljubica

2010-01-07

N-Acetylglutamate synthase (NAGS) catalyzes the first committed step in L-arginine biosynthesis in plants and micro-organisms and is subject to feedback inhibition by L-arginine. This study compares the crystal structures of NAGS from Neisseria gonorrhoeae (ngNAGS) in the inactive T-state with L-arginine bound and in the active R-state complexed with CoA and L-glutamate. Under all of the conditions examined, the enzyme consists of two stacked trimers. Each monomer has two domains: an amino acid kinase (AAK) domain with an AAK-like fold but lacking kinase activity and an N-acetyltransferase (NAT) domain homologous to other GCN5-related transferases. Binding of L-arginine to the AAKmore » domain induces a global conformational change that increases the diameter of the hexamer by {approx}10 {angstrom} and decreases its height by {approx}20{angstrom}. AAK dimers move 5{angstrom} outward along their 2-fold axes, and their tilt relative to the plane of the hexamer decreases by {approx}4{sup o}. The NAT domains rotate {approx}109{sup o} relative to AAK domains enabling new interdomain interactions. Interactions between AAK and NAT domains on different subunits also change. Local motions of several loops at the L-arginine-binding site enable the protein to close around the bound ligand, whereas several loops at the NAT active site become disordered, markedly reducing enzymatic specific activity.« less

Cysteamine effects on somatostatin, catecholamines, pineal NAT and melatonin in rats

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

Webb, S.M.; Champney, T.H.; Steger, R.W.

The thiol reagent cysteamine was administered to adult male rats with the aim of investigating its effect on different neural and pineal components. As expected, immunoreactive somatostatin decreased in the median eminence (ME) (p less than 0.05) and gastric antrum (p less than 0.05) after cysteamine; however, no significant change was observed in the pineal IRS content after drug treatment. A decrease in norepinephrine was observed in the ME (p less than 0.001), hypothalamus (p less than 0.001) and pineal gland (p less than 0.05), together with a rise in ME (p less than 0.005) and hypothalamic dopamine (p lessmore » than 0.005) content; these results are consistent with a dopamine-beta-hydroxylase inhibiting effect of cysteamine. No effect was observed on hypothalamic serotonin and 5-hydroxyindole-acetic acid content. Pineal N-acetyltransferase (NAT) activity was significantly higher (p less than 0.05) after cysteamine than after saline, but no statistically significant effect was observed on pineal melatonin content. The mechanism involved in the NAT rise is presumably not related to the known stimulatory effect of norepinephrine, which fell after cysteamine. It is suggested that cysteamine may act at an intracellular level, inhibiting NAT degradation, an effect demonstrated in vitro and thought to be related to a thiol:disulfide exchange mechanism.« less

Temperature stability of proteins essential for the intracellular survival of Mycobacterium tuberculosis.

PubMed

Lack, Nathan A; Kawamura, Akane; Fullam, Elizabeth; Laurieri, Nicola; Beard, Stacey; Russell, Angela J; Evangelopoulos, Dimitrios; Westwood, Isaac; Sim, Edith

2009-03-01

In Mycobacterium tuberculosis, the genes hsaD (2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid hydrolase) and nat (arylamine N-acetyltransferase) are essential for survival inside of host macrophages. These genes act as an operon and have been suggested to be involved in cholesterol metabolism. However, the role of NAT in this catabolic pathway has not been determined. In an effort to better understand the function of these proteins, we have expressed, purified and characterized TBNAT (NAT from M. tuberculosis) and HsaD (2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid hydrolase) from M. tuberculosis. Both proteins demonstrated remarkable heat stability with TBNAT and HsaD retaining >95% of their activity after incubation at 60 degrees C for 30 min. The first and second domains of TBNAT were demonstrated to be very important to the heat stability of the protein, as the transfer of these domains caused a dramatic reduction in the heat stability. The specific activity of TBNAT was tested against a broad range of acyl-CoA cofactors using hydralazine as a substrate. TBNAT was found to be able to utilize not just acetyl-CoA, but also n-propionyl-CoA and acetoacetyl-CoA, although at a lower rate. As propionyl-CoA is a product of cholesterol catabolism, we propose that NAT could have a role in the utilization of this important cofactor.

Structure and function of human Naa60 (NatF), a Golgi-localized bi-functional acetyltransferase

DOE PAGES

Chen, Ji-Yun; Liu, Liang; Cao, Chun-Ling; ...

2016-08-23

N-terminal acetylation (Nt-acetylation), carried out by N-terminal acetyltransferases (NATs), is a conserved and primary modification of nascent peptide chains. Naa60 (also named NatF) is a recently identified NAT found only in multicellular eukaryotes. This protein was shown to locate on the Golgi apparatus and mainly catalyze the Nt-acetylation of transmembrane proteins, and it also harbors lysine Nε -acetyltransferase (KAT) activity to catalyze the acetylation of lysine ε-amine. Here, we report the crystal structures of human Naa60 (hNaa60) in complex with Acetyl-Coenzyme A (Ac-CoA) or Coenzyme A (CoA). The hNaa60 protein contains an amphipathic helix following its GNAT domain that maymore » contribute to Golgi localization of hNaa60, and the β7-β8 hairpin adopted different conformations in the hNaa60(1-242) and hNaa60(1-199) crystal structures. Remarkably, we found that the side-chain of Phe 34 can influence the position of the coenzyme, indicating a new regulatory mechanism involving enzyme, co-factor and substrates interactions. Moreover, structural comparison and biochemical studies indicated that Tyr 97 and His 138 are key residues for catalytic reaction and that a non-conserved β3-β4 long loop participates in the regulation of hNaa60 activity.« less

Observational Evidence Against Mountain-Wave Generation of Ice Nuclei as a Prerequisite for the Formation of Three Solid Nitric Acid Polar Stratospheric Clouds Observed in the Arctic in Early December 1999

NASA Technical Reports Server (NTRS)

Pagan, Kathy L.; Tabazadeh, Azadeh; Drdla, Katja; Hervig, Mark E.; Eckermann, Stephen D.; Browell, Edward V.; Legg, Marion J.; Foschi, Patricia G.

2004-01-01

A number of recently published papers suggest that mountain-wave activity in the stratosphere, producing ice particles when temperatures drop below the ice frost point, may be the primary source of large NAT particles. In this paper we use measurements from the Advanced Very High Resolution Radiometer (AVHRR) instruments on board the National Oceanic and Atmospheric Administration (NOAA) polar-orbiting satellites to map out regions of ice clouds produced by stratospheric mountain-wave activity inside the Arctic vortex. Lidar observations from three DC-8 flights in early December 1999 show the presence of solid nitric acid (Type Ia or NAT) polar stratospheric clouds (PSCs). By using back trajectories and superimposing the position maps on the AVHRR cloud imagery products, we show that these observed NAT clouds could not have originated at locations of high-amplitude mountain-wave activity. We also show that mountain-wave PSC climatology data and Mountain Wave Forecast Model 2.0 (MWFM-2) raw hemispheric ray and grid box averaged hemispheric wave temperature amplitude hindcast data from the same time period are in agreement with the AVHRR data. Our results show that ice cloud formation in mountain waves cannot explain how at least three large scale NAT clouds were formed in the stratosphere in early December 1999.

Plant Growth under Natural Light Conditions Provides Highly Flexible Short-Term Acclimation Properties toward High Light Stress

PubMed Central

Schumann, Tobias; Paul, Suman; Melzer, Michael; Dörmann, Peter; Jahns, Peter

2017-01-01

Efficient acclimation to different growth light intensities is essential for plant fitness. So far, most studies on light acclimation have been conducted with plants grown under different constant light regimes, but more recent work indicated that acclimation to fluctuating light or field conditions may result in different physiological properties of plants. Thale cress (Arabidopsis thaliana) was grown under three different constant light intensities (LL: 25 μmol photons m−2 s−1; NL: 100 μmol photons m−2 s−1; HL: 500 μmol photons m−2 s−1) and under natural fluctuating light (NatL) conditions. We performed a thorough characterization of the morphological, physiological, and biochemical properties focusing on photo-protective mechanisms. Our analyses corroborated the known properties of LL, NL, and HL plants. NatL plants, however, were found to combine characteristics of both LL and HL grown plants, leading to efficient and unique light utilization capacities. Strikingly, the high energy dissipation capacity of NatL plants correlated with increased dynamics of thylakoid membrane reorganization upon short-term acclimation to excess light. We conclude that the thylakoid membrane organization and particularly the light-dependent and reversible unstacking of grana membranes likely represent key factors that provide the basis for the high acclimation capacity of NatL grown plants to rapidly changing light intensities. PMID:28515734

Development of a highly sensitive PCR/DNA chip method to detect mycoplasmas in a veterinary modified live vaccine.

PubMed

Mbelo, Sylvie; Gay, Virginie; Blanchard, Stephanie; Abachin, Eric; Falque, Stephanie; Lechenet, Jacques; Poulet, Hervé; de Saint-Vis, Blandine

2018-05-09

Mycoplasmas are potential contaminants that introduce undesirable changes in mammalian cell cultures. They frequently contaminate cell substrates and other starting materials used for manufacturing cell-derived biologics, such as vaccines and pharmaceutical products. Mycoplasma purity testing of live vaccines, active ingredients, raw material, and seed lots is required during vaccine production. Previously, testing using a time-consuming, costly 28-day culture assay, which lacks sensitivity for species that do not grow in culture, was required in the European Pharmacopoeia (Ph. Eur). But now nucleic acid amplification techniques (NATs) can be used. NATs provide rapid results and are sensitive. We evaluated the sensitivity and specificity of a commercially-available NAT to detect individual mycoplasma DNA in a veterinary modified live vaccine using five reference strains recommended by the Ph. Eur. Our results showed that this NAT-based method can be used to detect mycoplasma in spiked live vaccine, without interference from the vaccine components, with a limit of detection of 10 CFU/mL, as required by the Ph. Eur. Its specificity was demonstrated since no mycoplasmas were detected in non-spiked vaccine. This method is undergoing validation as a replacement for the conventional culture method in the production of veterinary live vaccines. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Accuracy of Anthropometric Equations for Estimating Body Fat in Professional Male Soccer Players Compared with DXA

PubMed Central

López-Taylor, Juan R.; Jiménez-Alvarado, Juan Antonio; Villegas-Balcázar, Marisol; Jáuregui-Ulloa, Edtna E.; Torres-Naranjo, Francisco

2018-01-01

Background There are several published anthropometric equations to estimate body fat percentage (BF%), and this may prompt uncertainty about their application. Purpose To analyze the accuracy of several anthropometric equations (developed in athletic [AT] and nonathletic [NAT] populations) that estimate BF% comparing them with DXA. Methods We evaluated 131 professional male soccer players (body mass: 73.2 ± 8.0 kg; height: 177.5 ± 5.8 cm; DXA BF% [median, 25th–75th percentile]: 14.0, 11.9–16.4%) aged 18 to 37 years. All subjects were evaluated with anthropometric measurements and a whole body DXA scan. BF% was estimated through 14 AT and 17 NAT anthropometric equations and compared with the measured DXA BF%. Mean differences and 95% limits of agreement were calculated for those anthropometric equations without significant differences with DXA. Results Five AT and seven NAT anthropometric equations did not differ significantly with DXA. From these, Oliver's and Civar's (AT) and Ball's and Wilmore's (NAT) equations showed the highest agreement with DXA. Their 95% limits of agreement ranged from −3.9 to 2.3%, −4.8 to 1.8%, −3.4 to 3.1%, and −3.9 to 3.0%, respectively. Conclusion Oliver's, Ball's, Civar's, and Wilmore's equations were the best to estimate BF% accurately compared with DXA in professional male soccer players. PMID:29736402

Reduction in patient burdens with graphical computerized adaptive testing on the ADL scale: tool development and simulation.

PubMed

Chien, Tsair-Wei; Wu, Hing-Man; Wang, Weng-Chung; Castillo, Roberto Vasquez; Chou, Willy

2009-05-05

The aim of this study was to verify the effectiveness and efficacy of saving time and reducing burden for patients, nurses, and even occupational therapists through computer adaptive testing (CAT). Based on an item bank of the Barthel Index (BI) and the Frenchay Activities Index (FAI) for assessing comprehensive activities of daily living (ADL) function in stroke patients, we developed a visual basic application (VBA)-Excel CAT module, and (1) investigated whether the averaged test length via CAT is shorter than that of the traditional all-item-answered non-adaptive testing (NAT) approach through simulation, (2) illustrated the CAT multimedia on a tablet PC showing data collection and response errors of ADL clinical functional measures in stroke patients, and (3) demonstrated the quality control of endorsing scale with fit statistics to detect responding errors, which will be further immediately reconfirmed by technicians once patient ends the CAT assessment. The results show that endorsed items could be shorter on CAT (M = 13.42) than on NAT (M = 23) at 41.64% efficiency in test length. However, averaged ability estimations reveal insignificant differences between CAT and NAT. This study found that mobile nursing services, placed at the bedsides of patients could, through the programmed VBA-Excel CAT module, reduce the burden to patients and save time, more so than the traditional NAT paper-and-pencil testing appraisals.

Organ utilization from increased infectious risk donors: An observational study.

PubMed

L'Huillier, Arnaud G; Humar, Atul; Payne, Clare; Kumar, Deepali

2017-12-01

Donors with an increased risk of transmitting human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) (increased risk donors [IRDs]) are a potential source of organs for transplant. Organs from IRDs can be utilized with appropriate recipient consent and post-transplant follow-up. We reviewed the characteristics and utilization of IRDs in our Organ Procurement Organization (OPO) over a 2-year period. Donor information from April 1, 2013 to March 31, 2015 was obtained through the OPO database. Only consented donors were included. Donors were categorized as IRDs according to Health Canada/Canadian Standards Association (CSA) criteria. A total of 494 potential donors were identified, of which 92 (18.6%) were IRDs. Of these, at least one organ was transplanted from 76 (82.6%). Risk factors for IRDs included injection drug user (IDU) (12%), men having sex with men (MSM) (7%), commercial sex worker (CSW) (4%), and incarceration (24%). Fifty-nine percent (253/429) of IRD organs were utilized. The most frequently used organ was kidney, followed by liver. Median number of organs recovered per IRD was 3 (interquartile range: 2-5). Nucleic acid testing (NAT) was performed in 18.5% (17/92) of IRDs. Reasons for NAT were IDU (n = 2), MSM (n = 2), CSW (n = 2), and previous incarceration (n = 7). Organ utilization from donors that had NAT was similar to donors who did not (94% vs 80%, P = .29). Follow-up NAT was done in <5% of recipients from IRDs. In our cohort, IRDs comprised a significant proportion of donors. Utilization of IRD organs occurred at a significant rate regardless of pre-transplant NAT. These data suggest that multiple factors contribute to the perception of infectious risk from such organs. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Novel association between the nonsynonymous A803G polymorphism of the N-acetyltransferase 2 gene and impaired glucose homeostasis in obese children and adolescents.

PubMed

Marzuillo, Pierluigi; Di Sessa, Anna; Umano, Giuseppina Rosaria; Nunziata, Luigia; Cirillo, Grazia; Perrone, Laura; Miraglia Del Giudice, Emanuele; Grandone, Anna

2017-09-01

The N-acetyltransferase 2 ( NAT2 ) A803G polymorphism has been associated with decreased insulin sensitivity in a large adult population with the A allele associated with insulin-resistance-related traits. Evaluate the association of this polymorphism with anthropometric and metabolic parameters in obese children and adolescents. A total of 748 obese children and adolescents were enrolled. Anthropometric and laboratory data were collected. During oral glucose tolerance test, the presence of a possible exaggerated plasma glucose excursion at 1 h (1HPG) or impaired glucose tolerance (IGT) was considered. Homeostasis model assessment, oral disposition index (oDI) and insulinogenic index (IDI) were calculated. Patients were genotyped for the NAT2 A803G polymorphism. The prevalence of both IGT and elevated-1HPG was higher in children carrying the A803 allele (P = .02 and P = .03). Moreover, this allele was associated with both oDI and IGI reduction (P = .01). No differences among the NAT2 A803G genotypes for the other parameters were shown. Children homozygous for the A allele presented an odds ratio (OR), to show IGT of 4.9 (P = .01). Children both homozygous and heterozygous for the A allele had higher risk to show elevated-1HPG (OR of 2.7, P = .005; and OR = 2.3, P = .005) compared with patients homozygous for the NAT2 803G allele. NAT2 A803 allele seems to play a role in worsening the destiny of obese children carrying it, predisposing them to elevated-1HPG and IGT and then to a possible future type 2 diabetes mellitus throughout an impairment of pancreatic β-cellular insulin secretion as suggested by oDI and IGI reduction. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

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

Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

1995-09-01

The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had amore » genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.« less

Applying Computerized Adaptive Testing to the Negative Acts Questionnaire-Revised: Rasch Analysis of Workplace Bullying

PubMed Central

Ma, Shu-Ching; Li, Yu-Chi; Yui, Mei-Shu

2014-01-01

Background Workplace bullying is a prevalent problem in contemporary work places that has adverse effects on both the victims of bullying and organizations. With the rapid development of computer technology in recent years, there is an urgent need to prove whether item response theory–based computerized adaptive testing (CAT) can be applied to measure exposure to workplace bullying. Objective The purpose of this study was to evaluate the relative efficiency and measurement precision of a CAT-based test for hospital nurses compared to traditional nonadaptive testing (NAT). Under the preliminary conditions of a single domain derived from the scale, a CAT module bullying scale model with polytomously scored items is provided as an example for evaluation purposes. Methods A total of 300 nurses were recruited and responded to the 22-item Negative Acts Questionnaire-Revised (NAQ-R). All NAT (or CAT-selected) items were calibrated with the Rasch rating scale model and all respondents were randomly selected for a comparison of the advantages of CAT and NAT in efficiency and precision by paired t tests and the area under the receiver operating characteristic curve (AUROC). Results The NAQ-R is a unidimensional construct that can be applied to measure exposure to workplace bullying through CAT-based administration. Nursing measures derived from both tests (CAT and NAT) were highly correlated (r=.97) and their measurement precisions were not statistically different (P=.49) as expected. CAT required fewer items than NAT (an efficiency gain of 32%), suggesting a reduced burden for respondents. There were significant differences in work tenure between the 2 groups (bullied and nonbullied) at a cutoff point of 6 years at 1 worksite. An AUROC of 0.75 (95% CI 0.68-0.79) with logits greater than –4.2 (or >30 in summation) was defined as being highly likely bullied in a workplace. Conclusions With CAT-based administration of the NAQ-R for nurses, their burden was substantially reduced without compromising measurement precision. PMID:24534113

Bioinformatics Analysis of Small RNAs in Pima (Gossypium barbadense L.)

PubMed Central

Hu, Hongtao; Yu, Dazhao; Liu, Hong

2015-01-01

Small RNAs (sRNAs) are ~20 to 24 nucleotide single-stranded RNAs that play crucial roles in regulation of gene expression. In plants, sRNAs are classified into microRNAs (miRNAs), repeat-associated siRNAs (ra-siRNAs), phased siRNAs (pha-siRNAs), cis and trans natural antisense transcript siRNAs (cis- and trans-nat siRNAs). Pima (Gossypium barbadense L.) is one of the most economically important fiber crops, producing the best and longest spinnable fiber. Although some miRNAs are profiled in Pima, little is known about siRNAs, the largest subclass of plant sRNAs. In order to profile these gene regulators in Pima, a comprehensive analysis of sRNAs was conducted by mining publicly available sRNA data, leading to identification of 678 miRNAs, 3,559,126 ra-siRNAs, 627 pha-siRNAs, 136,600 cis-nat siRNAs and 79,994 trans-nat siRNAs. The 678 miRNAs, belonging to 98 conserved and 402 lineage-specific families, were produced from 2,138 precursors, of which 297 arose from introns, exons, or intron/UTR-exon junctions of protein-coding genes. Ra-siRNAs were produced from various repeat loci, while most (97%) were yielded from retrotransposons, especially LTRs (long terminal repeats). The genes encoding auxin-signaling-related proteins, NBS-LRRs and transcription factors were major sources of pha-siRNAs, while two conserved TAS3 homologs were found as well. Most cis-NATs in Pima overlapped in enclosed and convergent orientations, while a few hybridized in divergent and coincided orientations. Most cis- and trans-nat siRNAs were produced from overlapping regions. Additionally, characteristics of length and the 5’-first nucleotide of each sRNA class were analyzed as well. Results in this study created a valuable molecular resource that would facilitate studies on mechanism of controlling gene expression. PMID:25679373

Quantification of phase I / II metabolizing enzyme gene expression and polycyclic aromatic hydrocarbon-DNA adduct levels in human prostate

PubMed Central

John, Kaarthik; Ragavan, Narasimhan; Pratt, M. Margaret; Singh, Paras B.; Al-Buheissi, Salah; Matanhelia, Shyam S.; Phillips, David H.; Poirier, Miriam C.; Martin, Francis L.

2008-01-01

BACKGROUND Studies of migrant populations suggest that dietary and/or environmental factors play a crucial role in the aetiology of prostatic adenocarcinoma (CaP). The human prostate consists of the peripheral zone (PZ), transition zone (TZ) and central zone (CZ); CaP occurs most often in the PZ. METHODS To investigate the notion that an underlying differential expression of phase I/II genes, and/or the presence of polycyclic aromatic hydrocarbon (PAH)-DNA adducts might explain the elevated PZ susceptibility, we examined prostate tissues (matched tissue sets consisting of PZ and TZ) from men undergoing radical retropubic prostatectomy for CaP (n=26) or cystoprostatectomy (n=1). Quantitative gene expression analysis was employed for cytochrome P450 (CYP) isoforms CYP1A1, CYP1B1 and CYP1A2, as well as N-acetyltransferase 1 and 2 (NAT1 and NAT2) and catechol-O-methyl transferase (COMT). RESULTS CYP1B1, NAT1 and COMT were expressed in all tissue sets; levels of CYP1B1 and NAT1 were consistently higher in the PZ compared to TZ. Immunohistochemistry confirmed the presence of CYP1B1 (nuclear-associated and primarily in basal epithelial cells) and NAT1. Tissue sections from 23 of these aforementioned 27 matched tissue sets were analyzed for PAH-DNA adduct levels using antiserum elicited against DNA modified with r7, t8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPDE). PAH-DNA adduct levels were highest in glandular epithelial cells, but a comparison of PZ and TZ showed no significant differences. CONCLUSION Although expression of activating and/or detoxifying enzymes may be higher in the PZ, PAH-DNA adduct levels appear to be similar in both zones. Therefore, factors other than PAH-DNA adducts may be responsible for promotion of tumour formation in the human prostate. PMID:19143007

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N-Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

PubMed Central

Staehli Hodel, Eva Maria; Csajka, Chantal; Ariey, Frédéric; Guidi, Monia; Kabanywanyi, Abdunoor Mulokozi; Duong, Socheat; Decosterd, Laurent Arthur; Olliaro, Piero; Genton, Blaise

2013-01-01

The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisinin-based combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C→T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C→T and 2850C→T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisinin-based combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials. PMID:23229480

Sideband Spectroscopy and Dispersion Measurement in Microcavities

DTIC Science & Technology

2012-11-07

high coherence, Brillouin microcavity laser on silicon ,” Opt. Express 20, 20170–20180, (2012). 12. T. Herr, K. Hartinger, J. Riemensberger, C. Y...ultrahigh-Q wedge- resonator on a silicon chip,” Nat. Photon. 6, 369–373 (2012). 11. J. Li, H. Lee, T. Chen, and K. J. Vahala, “Characterization of a ...microresonators,” Nat. Photon. 6, 480–487 (2012). 13. I. Grudinin, A . Matsko, and L. Maleki, “ Brillouin lasing with a CaF2 whispering gallery mode resonator,” Phys

Electronic and Mechanical Properties of GrapheneGermanium Interfaces Grown by Chemical Vapor Deposition

DTIC Science & Technology

2015-10-27

both surfaces lack order underneath the graphene, quantitative differences exist in their in-plane and out-of plane structure. Relatively sharp in-plane...Meric, I.; Lee, C.; Wang, L.; Sorgenfrei, S.; Watanabe , K.; Taniguchi, T.; Kim, P.; Shepard, K. L. Nat. Nanotechnol. 2010, 5, 722−726. (25) Martin, J...V.; MacDonald, A. H.; Morozov, S. V.; Watanabe , K.; Taniguchi, T.; Ponomarenko, L. A. Nat. Phys. 2012, 8, 896−901. (32) Ponomarenko, L. A

Advances in the Visualization and Analysis of Boundary Layer Flow in Swimming Fish

DTIC Science & Technology

2005-02-01

caudal-fin amputation on the kinematics and metabolic rate of underyearling sockeye salmon ( Oncorhynchus nerka ) at steady swimming speeds. J. Exp. Biol...caudal-fin amputation on the kinematics and metabolic rate of underyearling sockeye salmon ( Oncorhynchus nerka ) at steady swimming speeds. J. Exp. Biol

Effects of beef production system on animal performance and carcass characteristics.

PubMed

Maxwell, C L; Krehbiel, C R; Wilson, B K; Johnson, B T; Bernhard, B C; O'Neill, C F; VanOverbeke, D L; Mafi, G G; Step, D L; Richards, C J

2014-12-01

The objective of this study was to evaluate conventional (CONV) and natural (NAT) beef production systems from annual pasture through finishing through grazing. Beef steers (n=180, initial BW=250±19 kg) were assigned randomly to 2 treatments in the pasture phase. Steers were implanted with 40 mg of trenbolone acetate (TBA), 8 mg estradiol, and 29 mg tylosin tartrate (CONV), or received no implant (NAT). Steers on the 2 treatments grazed wheat or cereal rye for 109 d. Conventional steers had an 18.5% improvement in ADG (1.22 vs. 1.03 kg/d, P<0.01) and a heavier final BW (385 vs. 366 kg, P<0.01) compared with NAT steers. Following the pasture phase, steers (n=160 steers, 5 steers/pen, 8 pens/treatment) were assigned to a 2×2 factorial in the feedlot phase. Production system (NAT vs. CONV) was maintained from the pasture phase, and the second factor was 7 vs. 12% low-quality roughage (DM basis, LOW vs. HIGH). During finishing, CONV steers were given 120 mg of TBA and 24 mg estradiol at processing, fed monensin and tylosin, and fed zilpaterol hydrochloride for the last 20 d of the experiment. There were no program×roughage level interactions (P>0.07). The CONV steers ate 6.9% more feed (11.8 vs. 11.0 kg/d, P<0.01), gained 28.4% faster (1.90 vs. 1.48 kg/d, P<0.01), and were 24.2% more efficient (0.164 vs. 0.132, P<0.01) compared with NAT steers. The LOW steers had greater G:F (0.153 vs. 0.144, P<0.01) compared with HIGH steers. There was a 28.3% improvement in estimated carcass weight gain (1.36 vs. 1.06 kg/d), 18.6% improvement in carcass efficiency (0.115 vs. 0.097, P<0.01), and 21.6% improvement (1.52 vs. 1.25 Mcal/kg, P<0.01) in calculated dietary NEg for CONV compared with NAT steers. Hot carcass weight was increased by 62 kg (424 vs. 362 kg, P<0.01) and LM area was increased by 16.9 cm2 (100.9 vs. 84.0 cm2, P<0.01), decreasing USDA yield grade (YG, 3.09 vs. 3.54, P<0.01) for CONV steers compared with NAT steers. Natural steers had a greater percentage of carcasses in the upper 2/3 of USDA Choice grade (48.7 vs. 18.7%, P<0.01), a greater percentage of YG 4 and 5 carcasses (25.4 vs. 9.3%, P<0.01), and a greater percentage of abscessed livers (39.6 vs. 10.5%, P<0.01) compared with CONV steers. The results show that CONV production results in more rapid and efficient production that resulted in heavier carcasses with superior YG and desirable quality grades with both roughage levels.

EDITORIAL: Roberts Prize for the best paper published in 2010 Roberts Prize for the best paper published in 2010

NASA Astrophysics Data System (ADS)

Webb, Steve; Harris, Simon

2011-08-01

The publishers of Physics in Medicine and Biology (PMB), IOP Publishing, in association with the journal owners, the Institute of Physics and Engineering in Medicine (IPEM), jointly award an annual prize for the best paper published in PMB during the previous year. The procedure for deciding the winner has been made as thorough as possible, to try to ensure that an outstanding paper wins the prize. We started off with a shortlist of the 10 research papers published in 2010 which were rated the best based on the referees' quality assessments. Following the submission of a short 'case for winning' document by each of the shortlisted authors, an IPEM college of jurors of the status of FIPEM assessed and rated these 10 papers in order to choose a winner, which was then endorsed by the Editorial Board. We have much pleasure in advising readers that the Roberts Prize for the best paper published in 2010 is awarded to M M Paulides et al from Erasmus MC, Rotterdam, The Netherlands, for their paper on hyperthermia treatment: The clinical feasibility of deep hyperthermia treatment in the head and neck: new challenges for positioning and temperature measurement M M Paulides, J F Bakker, M Linthorst, J van der Zee, Z Rijnen, E Neufeld, P M T Pattynama, P P Jansen, P C Levendag and G C van Rhoon 2010 Phys. Med. Biol. 55 2465 Our congratulations go to these authors. Of course all of the shortlisted papers were of great merit, and the full top-10 is listed below (in alphabetical order). Steve Webb Editor-in-Chief Simon Harris Publisher References Alonzo-Proulx O, Packard N, Boone J M, Al-Mayah A, Brock K K, Shen S Z and Yaffe M J 2010 Validation of a method for measuring the volumetric breast density from digital mammograms Phys. Med. Biol. 55 3027 Bian J, Siewerdsen J H, Han X, Sidky E Y, Prince J L, Pelizzari C A and Pan X 2010 Evaluation of sparse-view reconstruction from flat-panel-detector cone-beam CT Phys. Med. Biol. 55 6575 Brun M-A, Formanek F, Yasuda A, Sekine M, Ando N and Eishii Y 2010 Terahertz imaging applied to cancer diagnosis Phys. Med. Biol. 55 4615 Eklund K and Ahnesjö A 2010 Modeling silicon diode dose response factors for small photon fields Phys. Med. Biol. 55 7411 Kolb A, Lorenz E, Judenhofer M S, Renker D, Lankes K and Pichler B J 2010 Evaluation of Geiger-mode APDs for PET block detector designs Phys. Med. Biol. 55 1815 Lobo J and Popescu I A 2010 Two new DOSXYZnrc sources for 4D Monte Carlo simulations of continuously variable beam configurations, with applications to RapidArc, VMAT, TomoTherapy and CyberKnife Phys. Med. Biol. 55 4431 Paulides M M, Bakker J F, Linthorst M, van der Zee J, Rijnen Z, Neufeld E, Pattynama P M T, Jansen P P, Levendag P C and van Rhoon G C 2010 The clinical feasibility of deep hyperthermia treatment in the head and neck: new challenges for positioning and temperature measurement Phys. Med. Biol. 55 2465 Rockne R, Rockhill J K, Mrugala M, Spence A M, Kalet I, Hendrickson K, Lai A, Cloughesy T, Alvord E C Jr and Swanson K R 2010 Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach Phys. Med. Biol. 55 3271 Wertz H et al 2010 Fast kilovoltage/megavoltage (kVMV) breathhold cone-beam CT for image-guided radiotherapy of lung cancer Phys. Med. Biol. 55 4203 Zhang B, MacFadden D, Damyanovich A Z, Rieker M, Stainsby J, Bernstein M, Jaffray D A, Mikulis D and Ménard C 2010 Development of a geometrically accurate imaging protocol at 3 Tesla MRI for stereotactic radiosurgery treatment planning Phys. Med. Biol. 55 6601

EDITORIAL: Roberts Prize for the best paper published in 2009 Roberts Prize for the best paper published in 2009

NASA Astrophysics Data System (ADS)

Webb, Steve; Harris, Simon

2010-07-01

The publishers of Physics in Medicine and Biology (PMB), IOP Publishing, in association with the journal owners, the Institute of Physics and Engineering in Medicine (IPEM), jointly award an annual prize for the best paper published in PMB during the previous year. The procedure for deciding the winner has been made as thorough as possible, to try to ensure that an outstanding paper wins the prize. We started off with a shortlist of the 10 research papers published in 2009 which were rated the best based on the referees' quality assessments. Following the submission of a short 'case for winning' document by each of the shortlisted authors, an IPEM college of jurors of the status of FIPEM assessed and rated these 10 papers in order to choose a winner, which was then endorsed by the Editorial Board. We have a clear, and very worthy, winner this year. We have much pleasure in advising readers that the 2009 Roberts Prize is awarded to E Z Zhang et al from University College London for their paper on photoacoustic tomography. In vivo high resolution 3D photoacoustic imaging of superficial vascular anatomy E Z Zhang, J G Laufer, R B Pedley and P C Beard 2009 Phys. Med. Biol. 54 1035-46 Our congratulations go to these authors. Of course all of the shortlisted papers were of great merit, and the full top-10 is listed below (in alphabetical order). Steve Webb Editor-in-Chief Simon Harris Publisher References Cheng Y-C N , Neelavalli J and Haacke E M 2009 Limitations of calculating field distributions and magnetic susceptibilities in MRI using a Fourier based method Phys. Med. Biol. 54 1169-89 Cho S, Ahn S, Li Q and Leahy R M 2009 Exact and approximate Fourier rebinning of PET data from time-of-flight to non time-of-flight 2009 Phys. Med. Biol. 54 467-84 Davidson S R H, Weersink R A, Haider M A, Gertner M R, Bogaards A, Giewercer D, Scherz A, Sherar M D, Elhilali M, Chin J L, Trachtenberg J and Wilson B C 2009 Treatment planning and dose analysis for interstitial photodynamic therapy of prostate cancer Phys. Med. Biol. 54 2293-313 Hand J W, Shaw A, Sadhoo N, Rajagopal S, Dickinson R J and Gavrilov L R 2009 A random phased array device for delivery of high intensity focused ultrasound Phys. Med. Biol. 54 5675-93 Johnson P, Lee C, Johnson K, Siragusa D and Bolch W E 2009 The influence of patient size on dose conversion coefficients: a hybrid phantom study for adult cardiac catheterization Phys. Med. Biol. 54 3613-29 Paganetti H 2009 Dose to water versus dose to medium in proton beam therapy Phys. Med. Biol. 54 4399-421 Pramanik M, Song K H, Swierczewska M, Green D, Sitharaman B and Wang L V 2009 In vivo carbon nanotube-enhanced non-invasive photoacoustic mapping of the sentinel lymph node Phys. Med. Biol. 54 3291-301 Schöndube H, Stierstorfer K and Noo F 2009 Accurate helical cone-beam CT reconstruction with redundant data 2009 Phys. Med. Biol. 54 4625-44 Tang G, Earl M A and Yu C X 2009 Variable dose rate single-arc IMAT delivered with a constant dose rate and variable angular spacing Phys. Med. Biol. 54 6439-56 Zhang E Z, Laufer J G, Pedley R B and Beard P C 2009 In vivo high resolution 3D photoacoustic imaging of superficial vascular anatomy Phys. Med. Biol. 54 1035-46 For more information on this article see medicalphysicsweb.org

Alpha particle induced reactions on natCr up to 39 MeV: Experimental cross-sections, comparison with theoretical calculations and thick target yields for medically relevant 52gFe production

NASA Astrophysics Data System (ADS)

Hermanne, A.; Adam Rebeles, R.; Tárkányi, F.; Takács, S.

2015-08-01

Thin natCr targets were obtained by electroplating, using 23.75 μm Cu foils as backings. In five stacked foil irradiations, followed by high resolution gamma spectroscopy, the cross sections for production of 52gFe, 49,51cumCr, 52cum,54,56cumMn and 48cumV in Cr and 61Cu,68Ga in Cu were measured up to 39 MeV incident α-particle energy. Reduced uncertainty is obtained by simultaneous remeasurement of the natCu(α,x)67,66Ga monitor reactions over the whole energy range. Comparisons with the scarce literature values and results from the TENDL-2013 on-line library, based on the theoretical code family TALYS-1.6, were made. A discussion of the production routes for 52gFe with achievable yields and contamination rates was made.

Experimental results and model calculations of excitation functions relevant to the production of specific radioisotopes for metabolic radiotherapy and for pet

NASA Astrophysics Data System (ADS)

Menapace, E.; Birattari, C.; Bonardi, M. L.; Groppi, F.

2004-10-01

First results are given from the comparison of experimental values and model calculations on accelerator-produced high specific activity radionuclides in no-carrier-added (NCA) form. The relevant radioisotopes are: 64Cu, produced by natZn(d, αxn) and natZn(d,2p) reactions, for simultaneous positron/negatron metabolic radiotherapy and PET imaging; 66Ga high-energy positron emitter (4.2 MeV), produced by natZn(d, xn) reactions, for metabolic radiotherapy and for PET; 186gRe, produced by 186W(p,n) and 186W(d,2n) reactions, for negatron (1.1 MeV) metabolic radiotherapy; 211At/ 211Po, produced by 209Bi( α,2n) reaction (with spike of gamma emitter 210At produced by 209Bi( α,3n) reaction) and 225Ac/ 213Bi/ 213Po, produced by 226Ra(p,2n) reaction, both for high-LET radiotherapy.

Extension of activation cross-section data of deuteron induced nuclear reactions on cadmium up to 50 MeV

NASA Astrophysics Data System (ADS)

Hermanne, A.; Tárkányi, F.; Takács, S.; Ditrói, F.

2016-10-01

The excitation functions for 109,110g,111m+g,113m,114m,115mIn, 107,109,115m,115gCd and 105g,106m,110g,111Ag are presented for stacked foil irradiations on natCd targets in the 49-33 MeV deuteron energy domain. Reduced uncertainty is obtained by determining incident particle flux and energy scale relative to re-measured monitor reactions natAl(d,x)22,24Na. The results were compared to our earlier studies on natCd and on enriched 112Cd targets. The merit of the values predicted by the TALYS 1.6 code (resulting from a weighted combination of reaction cross-section data on all stable Cd isotopes as available in the on-line libraries TENDL-2014 and TENDL-2015) is discussed. Influence on optimal production routes for several radionuclides with practical applications (111In, 114mIn, 115Cd, 109,107Cd….) is reviewed.

Drosophila variable nurse cells encodes Arrest defective 1 (ARD1), the catalytic subunit of the major N-terminal acetyltransferase complex

PubMed Central

Wang, Ying; Mijares, Michelle; Gall, Megan D.; Turan, Tolga; Javier, Anna; Bornemann, Douglas J; Manage, Kevin; Warrior, Rahul

2010-01-01

Mutations in the Drosophila variable nurse cells (vnc) gene result in female sterility and oogenesis defects, including egg chambers with too many or too few nurse cells. We show that vnc corresponds to Arrest Defective1 (Ard1) and encodes the catalytic subunit of NatA, the major N-terminal acetyl-transferase complex. While N-terminal acetylation is one of the most prevalent covalent protein modifications in eukaryotes, analysis of its role in development has been challenging since mutants that compromise NatA activity have not been described in any multicellular animal. Our data show that reduced ARD1 levels result in pleiotropic oogenesis defects including abnormal cyst encapsulation, desynchronized cystocyte division, disrupted nurse cell chromosome dispersion and abnormal chorion patterning, consistent with the wide range of predicted NatA substrates. Further we find that loss of Ard1 affects cell survival/proliferation and is lethal for the animal, providing the first demonstration that this modification is essential in higher eukaryotes. PMID:20882681

Back-thrusting in Lesser Himalaya: Evidences from magnetic fabric studies in parts of Almora crystalline zone, Kumaun Lesser Himalaya

NASA Astrophysics Data System (ADS)

Agarwal, Amar; Agarwal, K. K.; Bali, R.; Prakash, Chandra; Joshi, Gaurav

2016-06-01

The present study aims to understand evolution of the Lesser Himalaya, which consists of (meta) sedimentary and crystalline rocks. Field studies, microscopic and rock magnetic investigations have been carried out on the rocks near the South Almora Thrust (SAT) and the North Almora Thrust (NAT), which separates the Almora Crystalline Zone (ACZ) from the Lesser Himalayan sequences (LHS). The results show that along the South Almora Thrust, the deformation is persistent; however, near the NAT deformation pattern is complex and implies overprinting of original shear sense by a younger deformational event. We attribute this overprinting to late stage back-thrusting along NAT, active after the emplacement of ACZ. During this late stage back-thrusting, rocks of the ACZ and LHS were coupled. Back-thrusts originated below the Lesser Himalayan rocks, probably from the Main Boundary Thrust, and propagated across the sedimentary and crystalline rocks. This study provides new results from multiple investigations, and enhances our understanding of the evolution of the ACZ.

Reduction in patient burdens with graphical computerized adaptive testing on the ADL scale: tool development and simulation

PubMed Central

Chien, Tsair-Wei; Wu, Hing-Man; Wang, Weng-Chung; Castillo, Roberto Vasquez; Chou, Willy

2009-01-01

Background The aim of this study was to verify the effectiveness and efficacy of saving time and reducing burden for patients, nurses, and even occupational therapists through computer adaptive testing (CAT). Methods Based on an item bank of the Barthel Index (BI) and the Frenchay Activities Index (FAI) for assessing comprehensive activities of daily living (ADL) function in stroke patients, we developed a visual basic application (VBA)-Excel CAT module, and (1) investigated whether the averaged test length via CAT is shorter than that of the traditional all-item-answered non-adaptive testing (NAT) approach through simulation, (2) illustrated the CAT multimedia on a tablet PC showing data collection and response errors of ADL clinical functional measures in stroke patients, and (3) demonstrated the quality control of endorsing scale with fit statistics to detect responding errors, which will be further immediately reconfirmed by technicians once patient ends the CAT assessment. Results The results show that endorsed items could be shorter on CAT (M = 13.42) than on NAT (M = 23) at 41.64% efficiency in test length. However, averaged ability estimations reveal insignificant differences between CAT and NAT. Conclusion This study found that mobile nursing services, placed at the bedsides of patients could, through the programmed VBA-Excel CAT module, reduce the burden to patients and save time, more so than the traditional NAT paper-and-pencil testing appraisals. PMID:19416521

Synergism between the N-acetyltransferase 2 gene and oxidant exposure increases the risk of idiopathic male infertility.

PubMed

Yarosh, Sergey L; Kokhtenko, Elena V; Churnosov, Mikhail I; Ataman, Alexander V; Solodilova, Maria A; Polonikov, Alexey V

2014-09-01

N-acetyltransferase (NAT2) is a phase-II xenobiotic-metabolizing enzyme participating in the detoxification of toxic arylamines, aromatic amines and hydrazines. The present study was designed to investigate whether two common single-nucleotide polymorphisms (SNP) of the NAT2 gene (481C>T, rs1799929; 590G>A, rs1799930) are associated with susceptibility to idiopathic male infertility and to assess if the risk is modified by oxidant and antioxidant exposures. A total 430 DNA samples (203 infertile patients and 227 fertile men) were genotyped for the polymorphisms by PCR and restriction fragment length polymorphism. No association was found between the NAT2 polymorphisms and idiopathic male infertility. However, gene-environment interaction analysis revealed that a low-acetylation genotype, 590GA, was significantly associated with increased disease risk in men who had environmental risk factors such as cigarette smoking (OR 1.71, 95% CI 1.02-2.87, P = 0.042), alcohol abuse (OR 2.14, 95% CI 1.08-4.27, P = 0.029) and low fruit/vegetable intake (OR 1.68, 95% CI 1.01-2.79, P = 0.04). This pilot study found, as far as is known for the first time, that the polymorphism 590G>A of NAT2 is a novel genetic marker for susceptibility to idiopathic male infertility, but the risk is potentiated by exposure to various environmental oxidants. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Genetic variation in aryl N-acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4-diaminopyridine) phosphate.

PubMed

Haroldsen, Peter E; Garovoy, Marvin R; Musson, Donald G; Zhou, Huiyu; Tsuruda, Laurie; Hanson, Boyd; O'Neill, Charles A

2015-02-01

The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower C max, AUC, and shorter t 1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.

Small interfering RNAs from bidirectional transcripts of GhMML3_A12 regulate cotton fiber development.

PubMed

Wan, Qun; Guan, Xueying; Yang, Nannan; Wu, Huaitong; Pan, Mengqiao; Liu, Bingliang; Fang, Lei; Yang, Shouping; Hu, Yan; Ye, Wenxue; Zhang, Hua; Ma, Peiyong; Chen, Jiedan; Wang, Qiong; Mei, Gaofu; Cai, Caiping; Yang, Donglei; Wang, Jiawei; Guo, Wangzhen; Zhang, Wenhua; Chen, Xiaoya; Zhang, Tianzhen

2016-06-01

Natural antisense transcripts (NATs) are commonly observed in eukaryotic genomes, but only a limited number of such genes have been identified as being involved in gene regulation in plants. In this research, we investigated the function of small RNA derived from a NAT in fiber cell development. Using a map-based cloning strategy for the first time in tetraploid cotton, we cloned a naked seed mutant gene (N1 ) encoding a MYBMIXTA-like transcription factor 3 (MML3)/GhMYB25-like in chromosome A12, GhMML3_A12, that is associated with fuzz fiber development. The extremely low expression of GhMML3_A12 in N1 is associated with NAT production, driven by its 3' antisense promoter, as indicated by the promoter-driven histochemical staining assay. In addition, small RNA deep sequencing analysis suggested that the bidirectional transcriptions of GhMML3_A12 form double-stranded RNAs and generate 21-22 nt small RNAs. Therefore, in a fiber-specific manner, small RNA derived from the GhMML3_A12 locus can mediate GhMML3_A12 mRNA self-cleavage and result in the production of naked seeds followed by lint fiber inhibition in N1 plants. The present research reports the first observation of gene-mediated NATs and siRNA directly controlling fiber development in cotton. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Denitrification and nitrification in the Arctic stratosphere during the winter of 1996-1997

NASA Astrophysics Data System (ADS)

Kondo, Y.; Irie, H.; Koike, M.; Bodeker, G. E.

2000-02-01

The concentrations of HNO3, N2O, ozone, and aerosol in the lower stratosphere inside the Arctic vortex were observed by the Improved Limb Atmospheric Spectrometer (ILAS) in the winter of 1996-1997. These data demonstrate that irreversible loss of reactive nitrogen by sedimentation of HNO3 containing particles (denitrification) at 18-23 km occurred in mid-late February soon after the Arctic vortex cooled below ice saturation temperature (TICE). Denitrification exceeding 40% was observed only in air masses which experienced temperature below TICE. It occurred within 2 days in some of these air masses. Increases in HNO3 by evaporation of the particles (nitrification) at 13-15 km occurred 0-3 days after denitrification was observed, indicating particle radii of 5-10 µm or larger. It is likely that these particles were composed of nitric acid trihydrate (NAT) or NAT-coated ice particles, given that the temperatures below 16 km were higher than TICE. Continued exposure of air masses below NAT saturation temperature for 1-4 days did not lead to any significant denitrification as long as the temperature did not fall below TICE, indicating that possible nucleation of NAT at these temperatures within 4 days did not play a significant role in causing denitrification. There was little change in the average HNO3 column from February 11 to 28 since HNO3 decreases at 18-23 km were almost completely offset by increases at 12-17 km.

Have Tropical Cyclones Been Feeding More Extreme Rainfall?

NASA Technical Reports Server (NTRS)

Lau, K.-M.; Zhou, Y. P.; Wu, H.-T.

2008-01-01

We have conducted a study of the relationship between tropical cyclone (TC) and extreme rain events using GPCP and TRMM rainfall data, and storm track data for July through November (JASON) in the North Atlantic (NAT) and the western North Pacific (WNP). Extreme rain events are defined in terms of percentile rainrate, and TC-rain by rainfall associated with a named TC. Results show that climatologically, 8% of rain events and 17% of the total rain amount in NAT are accounted by TCs, compared to 9% of rain events and 21% of rain amount in WNP. The fractional contribution of accumulated TC-rain to total rain, Omega, increases nearly linearly as a function of rainrate. Extending the analyses using GPCP pentad data for 1979-2005, and for the post-SSM/I period (1988-2005), we find that while there is no significant trend in the total JASON rainfall over NAT or WNP, there is a positive significant trend in heavy rain over both basins for the 1979-2005 period, but not for the post-SSM/I period. Trend analyses of Omega for both periods indicate that TCs have been feeding increasingly more to rainfall extremes in NAT, where the expansion of the warm pool area can explain slight more than 50% of the change in observed trend in total TC rainfall. In WNP, trend signals for Omega are mixed, and the long-term relationship between TC rain and warm pool areas are strongly influenced by interannual and interdecadal variability.

Noonan syndrome and related disorders: alterations in growth and puberty.

PubMed

Noonan, Jacqueline A

2006-12-01

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.

Sterilization of tumor-positive lymph nodes of esophageal cancer by neo-adjuvant treatment is associated with worse survival compared to tumor-negative lymph nodes treated with surgery first.

PubMed

Mantziari, Styliani; Allemann, Pierre; Winiker, Michael; Sempoux, Christine; Demartines, Nicolas; Schäfer, Markus

2017-09-01

Lymph node (LN) involvement by esophageal cancer is associated with compromised long-term prognosis. This study assessed whether LN downstaging by neoadjuvant treatment (NAT) might offer a survival benefit compared to patients with a priori negative LN. Patients undergoing esophagectomy for cancer between 2005 and 2014 were screened for inclusion. Group 1 included cN0 patients confirmed as pN0 who were treated with surgery first, whereas group 2 included patients initially cN+ and down-staged to ypN0 after NAT. Survival analysis was performed with the Kaplan-Meier and Cox regression methods. Fifty-seven patients were included in our study, 24 in group 1 and 33 in group 2. Group 2 patients had more locally advanced lesions compared to a priori negative patients, and despite complete LN sterilization by NAT they still had worse long-term survival. Overall 3-year survival was 86.8% for a priori LN negative versus 63.3% for downstaged patients (P = 0.013), while disease-free survival was 79.6% and 57.9%, respectively (P = 0.021). Tumor recurrence was also earlier and more disseminated for the down-staged group. Downstaged LN, despite the systemic effect of NAT, still inherit an increased risk for early tumor recurrence and worse long-term survival compared to a priori negative LN. © 2017 Wiley Periodicals, Inc.

Taxonomic revision of true morels (Morchella) in Canada and the United States

USDA-ARS?s Scientific Manuscript database

Recent molecular phylogenetic studies by Taskin et al. (Fungal Genet. Biol. 47:672-682. 2010; Mycologia [in press]) and O'Donnell et al. (Fungal Genet. Biol. 48:252-265. 2011) revealed the existence of at least 50 species of Morchella worldwide and demonstrated a high degree of continental endemism ...

Isolation and structures of glycoprotein-derived free oligosaccharides from the unfertilized eggs of Scyliorhinus caniculus. Characterization of the sequences galactose(alpha 1-4)galactose(beta 1-3)-N-acetylglucosamine and N-acetylneuraminic acid(alpha 2-6)galactose(beta 1-3)-N-acetylglucosamine.

PubMed

Plancke, Y; Delplace, F; Wieruszeski, J M; Maes, E; Strecker, G

1996-01-15

As previously reported [Ishii, K., Iwasaki, M., Inoue, S., Kenny, P. T. M., Komura, H. & Inoue, Y. (1989) J. Biol. Chem. 264, 1623-1630; Inoue, S., Iwasaki, M., Ishii, K., Kitajima, K. & Inoue, Y. (1989) J. Biol. Chem. 264, 18520-185261, the unfertilized eggs of two different species of fresh-water fish, Plecoglossus altivelis and Tribodolon hakonensis, contain relatively large amounts of free sialooligosaccharides. These oligosaccharides were found to derive from glycophosphoproteins, owing to the activity of a peptide - N4-(N-acetyl-beta-D-glucosaminyl)asparagine amidase [Iwasaki, M., Seko, A., Kitajima, K., Inoue, Y. & Inoue, S. (1992) J. Biol. Chem. 267, 24287-24296; Seko, A., Kitajima, K., Inoue, Y. & Inoue, S. (1991) J. Biol. Chem. 266, 22110-22114]. Here we describe a new type of free oligosaccharides, isolated from unfertilized eggs of Scyliorhinus caniculus. From the structural analysis, based upon 1H-NMR spectroscopy, the following glycan units are proposed.[Formula: see text

Benchmark of neutron production cross sections with Monte Carlo codes

NASA Astrophysics Data System (ADS)

Tsai, Pi-En; Lai, Bo-Lun; Heilbronn, Lawrence H.; Sheu, Rong-Jiun

2018-02-01

Aiming to provide critical information in the fields of heavy ion therapy, radiation shielding in space, and facility design for heavy-ion research accelerators, the physics models in three Monte Carlo simulation codes - PHITS, FLUKA, and MCNP6, were systematically benchmarked with comparisons to fifteen sets of experimental data for neutron production cross sections, which include various combinations of 12C, 20Ne, 40Ar, 84Kr and 132Xe projectiles and natLi, natC, natAl, natCu, and natPb target nuclides at incident energies between 135 MeV/nucleon and 600 MeV/nucleon. For neutron energies above 60% of the specific projectile energy per nucleon, the LAQGMS03.03 in MCNP6, the JQMD/JQMD-2.0 in PHITS, and the RQMD-2.4 in FLUKA all show a better agreement with data in heavy-projectile systems than with light-projectile systems, suggesting that the collective properties of projectile nuclei and nucleon interactions in the nucleus should be considered for light projectiles. For intermediate-energy neutrons whose energies are below the 60% projectile energy per nucleon and above 20 MeV, FLUKA is likely to overestimate the secondary neutron production, while MCNP6 tends towards underestimation. PHITS with JQMD shows a mild tendency for underestimation, but the JQMD-2.0 model with a modified physics description for central collisions generally improves the agreement between data and calculations. For low-energy neutrons (below 20 MeV), which are dominated by the evaporation mechanism, PHITS (which uses GEM linked with JQMD and JQMD-2.0) and FLUKA both tend to overestimate the production cross section, whereas MCNP6 tends to underestimate more systems than to overestimate. For total neutron production cross sections, the trends of the benchmark results over the entire energy range are similar to the trends seen in the dominate energy region. Also, the comparison of GEM coupled with either JQMD or JQMD-2.0 in the PHITS code indicates that the model used to describe the first stage of a nucleus-nucleus collision also affects the low-energy neutron production. Thus, in this case, a proper combination of two physics models is desired to reproduce the measured results. In addition, code users should be aware that certain models consistently produce secondary neutrons within a constant fraction of another model in certain energy regions, which might be correlated to different physics treatments in different models.

Symposium on Turbulent Shear Flows (4th) Held at Karlsruhe University (Germany, F.R.), 12-14 September 1983.

DTIC Science & Technology

1983-09-01

fluctuat- structed for the present purpose and a small amount of ing velocity components. The present experimental data milk was introduced into the...water flow. Finely dis- will also be compared with the nuerical results and the parsed milk droplets serve as the scattering particles._ experimental...correlation coefficient for the radial In the photoultipIler, I.e., f’ a 0.01. The mean mass transport Is 0.3 < Rvf < 0.4 though the momentum concentration

Characterization of Ignition and Combustion Properties of Nanowire-based Energetics

DTIC Science & Technology

2013-07-23

Sannia, A. Cincotti, G. Cao, Chem. Eng. Sci. 54 (15–16) (1999) 3053–3061. [4] C. Rossi, K. Zhang, D. Esteve, P. Alphonse , P. Tailhades, C. Vahlas, J...94 (5) (2003) 2923–2929. [30] K. Zhang, C. Rossi, G.A.A. Rodriguez, C. Tenail- leau, P. Alphonse , Appl. Phys. Lett. 91 (11) (2007) 113117/1–113117/3...Pister, Smart Mater. Struct. 10(6), 1145 (2001). 8C. Rossi, K. Zhang, D. Esteve, P. Alphonse , P. Tailhades, and C. Vahlas, J. Microelectromech. Syst. 16

Corrigendum to ;Dipole moment and solvatochromism of benzoic acid liquid crystals: Tuning the dipole moment and molecular orbital energies by substituted Au under external electric field; [J. Mol. Struct. 1137 (2017) 440-452

NASA Astrophysics Data System (ADS)

Sıdır, Yadigar Gülseven; Sıdır, İsa; Demiray, Ferhat

2017-08-01

The authors regret to inform that three references in the article titled ;Dipole moment and solvatochromism of benzoic acid liquid crystals: Tuning the dipole moment and molecular orbital energies by substituted Au under external electric field; are not given in the manuscript. This is purely an oversight mistake. The references are as shown in this correction. The authors would like to apologize for any inconvenience caused.

Corrigendum to "Synthesis, structural features, and methyl methacrylate polymerisation of binuclear zinc(II) complexes with tetradentate pyrazolyl ligands" [J. Mol. Struct. 1063 (2014) 70-76

NASA Astrophysics Data System (ADS)

Kim, Sunghoon; Kim, Dongil; Lee, Ha-Jin; Lee, Hyosun

2015-05-01

The authors regret to inform that 4,4‧-bis-(N,N-di(1H-pyrazolyl-1-methyl)phenyl)methane (L2) and its binuclear 4,4‧-bis-(N,N-di-(1H-pyrazolyl-1-methyl)phenyl)methane(dichloro)Zn(II) complex, namely, [L2Zn2Cl4] in the paper were published as the thesis for the degree of master in the Department of Chemistry at Kyungpook National University in 2003.

Advanced Numerical Methods for Simulating Nonlinear Multirate Lumped Parameter Models

DTIC Science & Technology

1991-05-01

defining a Waveform: typedef struct Waveform char *name; /* character string of the name of the variable */ double tn; /* time of the beginning of the...A State-Space Approach, Reprinted from Proc. Third Ann. Allerton Conf. Circuits and Systems Thoery , 659-668, in Computer-Aided Circuit Design...kg/n 3) 1025.9 kg/m3 @ 15* C. v Kinematic Viscosity of Water (m2/sec) 1.19x10-6 m2/sec @ 15* C. G Acceleration of Gravity (m/sec2) 9.80665 m/sec 2 L

Investigation of Metastatic Breast Tumor Heterogeneity and Progression Using Dual Optical/SPECT Imaging. Addendum

DTIC Science & Technology

2008-05-01

2(b) is again 1.0 mm but has been reduced by an order of magnitude to 0.5 mm. It can be seen that the geometric resolution is now the limiting term...activity) of the system. The on-axis geometric efficiency for a pinhole is given by: (2) and represents the fraction of emitted photons that pass through...0.96 mm. The slight increase in the recon- structed diameter is due to the total resolution of the setup being limited by the geometric resolution which

The Role of Microstructural Variability on the Very High-Cycle Fatigue Behavior of Discontinuously-Reinforced Aluminum Metal Matrix Composites using Ultrasonic Fatigue (Preprint)

DTIC Science & Technology

2008-05-01

controlled processing. Bhanu-Prasad et al .37 conducted a systematic study of PM-processed 2124/SiC/30p aluminum composites 4 5 in which matrix alloy...Mater., 27, 173-178. [5] Wang A, Rack HJ (1991). Transition wear behavior of SiC-particulate- and SiC- whisker-reinforced 7091 Al metal matrix...modeling of particle distribution effects on fatigue in Al -SiCp composites. Mater. Sci. Eng. A, Struct. Mater. Prop. Microstruct. Process., 300, 113-124

Removal of pharmaceutical and personal care products (PPCPs) under nitrifying and denitrifying conditions.

PubMed

Suarez, Sonia; Lema, Juan M; Omil, Francisco

2010-05-01

The contribution of volatilization, sorption and transformation to the removal of 16 Pharmaceutical and Personal Care Products (PPCPs) in two lab-scale conventional activated sludge reactors, working under nitrifying (aerobic) and denitrifying (anoxic) conditions for more than 1.5 years, have been assessed. Pseudo-first order biological degradation rate constants (k(biol)) were calculated for the selected compounds in both reactors. Faster degradation kinetics were measured in the nitrifying reactor compared to the denitrifying system for the majority of PPCPs. Compounds could be classified according to their k(biol) into very highly (k(biol)>5Lg(SS)(-1)d(-1)), highly (175%) and anoxic (>65%) conditions, whereas naproxen (NPX), ethinylestradiol (EE2), roxithromycin (ROX) and erythromycin (ERY) were only significantly transformed in the aerobic reactor (>80%). The anti-depressant citalopram (CTL) was moderately biotransformed under both, aerobic and anoxic conditions (>60% and >40%, respectively). Some compounds, as carbamazepine (CBZ), diazepam (DZP), sulfamethoxazole (SMX) and trimethoprim (TMP), manifested high resistance to biological transformation. Solids Retention Time (SRT(aerobic) >50d and <50d; SRT(anoxic) >20d and <20d) had a slightly positive effect on the removal of FLX, NPX, CTL, EE2 and natural estrogens (increase in removal efficiencies <10%). Removal of diclofenac (DCF) in the aerobic reactor was positively affected by the development of nitrifying biomass and increased from 0% up to 74%. Similarly, efficient anoxic transformation of ibuprofen (75%) was observed after an adaptation period of 340d. Temperature (16-26 degrees C) only had a slight effect on the removal of CTL which increased in 4%.

Measurement of excitation function of {sup nat}B(p,x){sup 7}Be nuclear reaction

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

Ditroi, F.; Fenyvesi, A.; Takacs, S.

1994-12-31

Boron of natural composition was irradiated to measure the cross section function of the {sup nat}B(p,x){sup 7}Be nuclear reaction. The reaction is very important from the point of view of Thin Layer Activation (TLA) technique to monitor the wear of boron containing superhard materials (e.g. BN). The aim was to determine the cross section of above reaction in the energy region used in wear measurements because practically there is no cross section data available below 10 MeV.

Molecular Differentiation of Risk for Disease Progression: Delineating Stage-Specific Therapeutic Targets for Disease Management in Breast Cancer

DTIC Science & Technology

2006-07-01

Jeffrey S. S., Botstein D ., Brown P . O. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat. Genet., 23: 41-46, 1999 3...Duggan D . J., Bittner M., Chen Y., Meltzer P ., Trent J. M. Expression profiling using cDNA microarrays. Nat. Genet., 21: 10-14, 1999 4. Oh J. M...1999 5. Golub T. R., Slonim D . K., Tamayo P ., Huard C., Gaasenbeek M., Mesirov J. P ., Coller H., Loh M. L., Downing J. R., Caligiuri M. A

Activation cross sections of α-induced reactions on natZn for Ge and Ga production

NASA Astrophysics Data System (ADS)

Aikawa, M.; Saito, M.; Ebata, S.; Komori, Y.; Haba, H.

2018-07-01

The production cross sections of 68,69Ge and 66,67Ga by α-induced reactions on natZn have been measured using the stacked-foil activation method and off-line γ-ray spectrometry from their threshold energies to 50.7 MeV. The derived cross sections were compared with the previous experimental data and the calculated values in the TENLD-2017 library. Our result shows a slightly larger amplitude than the previous data at the peak, though the peak energy is consistent with them.

Studies to Control Endemic Typhoid Fever in Chile

DTIC Science & Technology

1984-07-14

Malmaceda PGP, Acosta JJV, Arrasco VG. La fiebre tifoidea en el nino senor de dos anos. Biol. Ned. Hosp. Inf. Rex. 38:473, 1981. 11. Kumate J...Penaloza JL, Llausas’A. La fiebre tifoidea en el primer ano de la vida. Biol. Red. Bosp. Inf. 31:925, 1974. 12. Herrera P, Cuellar A. Samanellosis tifica en

Production Methods for a Mesenchymal Stem Cell Therapeutic as a Medical Defense Countermeasure

DTIC Science & Technology

2012-02-01

differentiation of murine embryonic stem cells into vascular progenitors. BMC Cell Biol. 2008;9:2. 56. Johnson EA, Dao TL, Kan RK. Status epilepticus ...their undifferentiated and multipotent status . BMC Cell Biol. 2011;12:12. 52. Sun Y, Chen L, Hou XG, Hou WK, Dong JJ, Sun L, et al. Differentiation of

Elucidation of neurophysin/bioligand interactions from molecular modeling.

PubMed

Kaźmierkiewicz, R; Czaplewski, C; Ciarkowski, J

1997-01-01

This is a review of our recent modeling work aimed at: (i) development and assessment of techniques for reliable refinement of low-resolution protein structures and (ii) using these techniques, at solving specific problems pertinent to neurophysin-bioligand interactions. Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood. NPs are homologous two-domain, sulphur rich small proteins (93-95 residues, 7 disulphide bridges per monomer), capable of being aggregated. The C2 symmetrical NPI2 and NPII2 homodimers, and the (NPI/OT)2 and (NPII/VP)2 heterotetramers, all believed to be the smallest functional units, were modeled using low-resolution structure information, i.e. the C alpha-carbon coordinates of the homologous NPII/dipeptide complex as a template. The all-atom representations of the models were obtained using the SYBYL suite of programs (by Tripos, Inc.). Subsequently, they were relaxed, using a constrained simulated annealing (CSA) protocol, and submitted to about 100 ps molecular dynamics (MD) in water, using the AMBER 4.1 force field. The (NPI/OT)2 and (NPII/VP)2 structures, averaged after the last 20 ps of MD, were remarkably similar to those recently reported either for NPII/dipeptide or NPII/oxytocin complex in the solid state (Chen et al., 1991, Proc. Natl. Acad. Sci., U.S.A. 88, 4240-4244; Rose et al., 1996, Nature Struct. Biol. 3, 163-169). The results indicate that the 3(10) helices (terminating the amino domains) and the carboxyl domains are more mobile than the remainder of the NP monomers. The hormones become anchored by residues 1-3 and 6 to the host, leaving residues 4-5 and 7-9 exposed on the surface and free to move. A cluster of attractive interactions, extending from the ligand binding site, Tyr-24-Ile-26 of unit 1(2), to the inter-monomer interface Val-36 of unit 1(2), Cys-79 and Ile-72 of unit 2(1), is clearly seen. We suggest that both these interactions as well as the increased mobility of the 3(10) helix and the carboxyl domain may contribute to the allosteric communication between the ligand and the unit1-unit2 interface.

Probing the dynamic interface between trimethylamine dehydrogenase (TMADH) and electron transferring flavoprotein (ETF) in the TMADH-2ETF complex: role of the Arg-alpha237 (ETF) and Tyr-442 (TMADH) residue pair.

PubMed

Burgess, Selena G; Messiha, Hanan Latif; Katona, Gergely; Rigby, Stephen E J; Leys, David; Scrutton, Nigel S

2008-05-06

We have used multiple solution state techniques and crystallographic analysis to investigate the importance of a putative transient interaction formed between Arg-alpha237 in electron transferring flavoprotein (ETF) and Tyr-442 in trimethylamine dehydrogenase (TMADH) in complex assembly, electron transfer, and structural imprinting of ETF by TMADH. We have isolated four mutant forms of ETF altered in the identity of the residue at position 237 (alphaR237A, alphaR237K, alphaR237C, and alphaR237E) and with each form studied electron transfer from TMADH to ETF, investigated the reduction potentials of the bound ETF cofactor, and analyzed complex formation. We show that mutation of Arg-alpha237 substantially destabilizes the semiquinone couple of the bound FAD and impedes electron transfer from TMADH to ETF. Crystallographic structures of the mutant ETF proteins indicate that mutation does not perturb the overall structure of ETF, but leads to disruption of an electrostatic network at an ETF domain boundary that likely affects the dynamic properties of ETF in the crystal and in solution. We show that Arg-alpha237 is required for TMADH to structurally imprint the as-purified semiquinone form of wild-type ETF and that the ability of TMADH to facilitate this structural reorganization is lost following (i) redox cycling of ETF, or simple conversion to the oxidized form, and (ii) mutagenesis of Arg-alpha237. We discuss this result in light of recent apparent conflict in the literature relating to the structural imprinting of wild-type ETF. Our studies support a mechanism of electron transfer by conformational sampling as advanced from our previous analysis of the crystal structure of the TMADH-2ETF complex [Leys, D. , Basran, J. , Sutcliffe, M. J., and Scrutton, N. S. (2003) Nature Struct. Biol. 10, 219-225] and point to a key role for the Tyr-442 (TMADH) and Arg-alpha237 (ETF) residue pair in transiently stabilizing productive electron transfer configurations. Our work also points to the importance of Arg-alpha237 in controlling the thermodynamics of electron transfer, the dynamics of ETF, and the protection of reducing equivalents following disassembly of the TMADH-2ETF complex.

Multiphoton microscopy based cryo-imaging of inflated frozen human lung sections at -60°C in healthy and COPD lungs

NASA Astrophysics Data System (ADS)

Abraham, Thomas; Kayra, Damian; Zhang, Angela; Suzuki, Masaru; McDonough, John; Elliott, W. M.; Cooper, Joel D.; Hogg, James C.

2013-02-01

Lung is a complex gas exchanger with interfacial area (where the gas exchange takes place) is about the size of a tennis court. Respiratory function is linked to the biomechanical stability of the gas exchange or alveolar regions which directly depends on the spatial distributions of the extracellular matrix fibers such fibrillar collagens and elastin fibers. It is very important to visualize and quantify these fibers at their native and inflated conditions to have correct morphometric information on differences between control and diseased states. This can be only achieved in the ex vivo states by imaging directly frozen lung specimens inflated to total lung capacity. Multiphoton microscopy, which uses ultra-short infrared laser pulses as the excitation source, produces multiphoton excitation fluorescence (MPEF) signals from endogenously fluorescent proteins (e.g. elastin) and induces specific second harmonic generation (SHG) signals from non-centrosymmetric proteins such as fibrillar collagens in fresh human lung tissues [J. Struct. Biol. (2010)171,189-196]. Here we report for the first time 3D image data obtained directly from thick frozen inflated lung specimens (~0.7- 1.0 millimeter thick) visualized at -60°C without prior fixation or staining in healthy and diseased states. Lung specimens donated for transplantation and released for research when no appropriate recipient was identified served as controls, and diseased lung specimens donated for research by patients receiving lung transplantation for very severe COPD (n=4) were prepared as previously described [N. Engl. J. Med. (2011) 201, 1567]. Lung slices evenly spaced between apex and base were examined using multiphoton microscopy while maintained at -60°C using a temperature controlled cold stage with a temperature resolution of 0.1°C. Infrared femto-second laser pulses tuned to 880nm, dry microscopic objectives, and non-de-scanned detectors/spectrophotometer located in the reflection geometry were used for generating the 3D images/spectral information. We found that this novel imaging approach can provide spatially resolved 3D images with spectral specificities from frozen inflated lungs that are sensitive enough to identity the micro-structural details of fibrillar collagens and elastin fibers in alveolar walls in both healthy and diseased tissues.

Hepatitis C Core Antigen Testing for Diagnosis of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis.

PubMed

Freiman, J Morgan; Tran, Trang M; Schumacher, Samuel G; White, Laura F; Ongarello, Stefano; Cohn, Jennifer; Easterbrook, Philippa J; Linas, Benjamin P; Denkinger, Claudia M

2016-09-06

Diagnosis of chronic hepatitis C virus (HCV) infection requires both a positive HCV antibody screen and confirmatory nucleic acid testing (NAT). Testing for hepatitis C virus core antigen (HCVcAg) is a potential alternative to NAT. To evaluate the accuracy of diagnosis of active HCV infection among adults and children for 5 HCVcAg tests compared with NAT. EMBASE, PubMed, Web of Science, Scopus, and Cochrane Database of Systematic Reviews from 1990 through 31 March 2016. Case-control, cross-sectional, cohort, or randomized trials that compared any of 5 HCVcAg tests with an NAT reference standard. 2 independent reviewers extracted data and assessed quality using an adapted QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. 44 studies evaluated 5 index tests. Studies for the Abbott ARCHITECT HCV Ag assay had the highest quality, whereas those for the Ortho HCV Ag enzyme-linked immunosorbent assay (ELISA) had the lowest quality. From bivariate analyses, the sensitivity and specificity of the assays were as follows: Abbott ARCHITECT, 93.4% (95% CI, 90.1% to 96.4%) and 98.8% (CI, 97.4% to 99.5%); Ortho ELISA, 93.2% (CI, 81.6% to 97.7%) and 99.2% (CI, 87.9% to 100%); and Hunan Jynda Bioengineering Group HCV Ag ELISA, 59.5% (CI, 46.0% to 71.7%) and 82.9% (CI, 58.6% to 94.3%). Insufficient data were available for a meta-analysis about the Fujirebio Lumipulse Ortho HCV Ag and Eiken Lumispot HCV Ag assays. In 3 quantitative studies using Abbott ARCHITECT, HCVcAg correlated closely with HCV RNA levels greater than 3000 IU/mL. Insufficient data were available on covariates, such as HIV or hepatitis B virus status, for subgroup analyses. Few studies reported genotypes of isolates, and data for genotypes 4, 5, and 6 were scant. Most studies were conducted in high-resource settings and reference laboratories. The HCVcAg assays with signal amplification have high sensitivity, high specificity, and good correlation with HCV RNA levels greater than 3000 IU/mL and have the potential to replace NAT in settings with high HCV prevalence. National Institutes of Health.

The crystal structure of N-acetyl-L-glutamate synthase from Neisseria gonorrhoeae provides insights into mechanisms of catalysis and regulation.

PubMed

Shi, Dashuang; Sagar, Vatsala; Jin, Zhongmin; Yu, Xiaolin; Caldovic, Ljubica; Morizono, Hiroki; Allewell, Norma M; Tuchman, Mendel

2008-03-14

The crystal structures of N-acetylglutamate synthase (NAGS) in the arginine biosynthetic pathway of Neisseria gonorrhoeae complexed with acetyl-CoA and with CoA plus N-acetylglutamate have been determined at 2.5- and 2.6-A resolution, respectively. The monomer consists of two separately folded domains, an amino acid kinase (AAK) domain and an N-acetyltransferase (NAT) domain connected through a 10-A linker. The monomers assemble into a hexameric ring that consists of a trimer of dimers with 32-point symmetry, inner and outer ring diameters of 20 and 100A, respectively, and a height of 110A(.) Each AAK domain interacts with the cognate domains of two adjacent monomers across two 2-fold symmetry axes and with the NAT domain from a second monomer of the adjacent dimer in the ring. The catalytic sites are located within the NAT domains. Three active site residues, Arg316, Arg425, and Ser427, anchor N-acetylglutamate in a position at the active site to form hydrogen bond interactions to the main chain nitrogen atoms of Cys356 and Leu314, and hydrophobic interactions to the side chains of Leu313 and Leu314. The mode of binding of acetyl-CoA and CoA is similar to other NAT family proteins. The AAK domain, although catalytically inactive, appears to bind arginine. This is the first reported crystal structure of any NAGS, and it provides insights into the catalytic function and arginine regulation of NAGS enzymes.

The Crystal Structure of N-Acetyl-L-glutamate Synthase from Neisseria gonorrhoeae Provides Insights into Mechanisms of Catalysis and Regulation

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

Shi, Dashuang; Sagar, Vatsala; Jin, Zhongmin

2010-01-07

The crystal structures of N-acetylglutamate synthase (NAGS) in the arginine biosynthetic pathway of Neisseria gonorrhoeae complexed with acetyl-CoA and with CoA plus N-acetylglutamate have been determined at 2.5- and 2.6-A resolution, respectively. The monomer consists of two separately folded domains, an amino acid kinase (AAK) domain and an N-acetyltransferase (NAT) domain connected through a 10-A linker. The monomers assemble into a hexameric ring that consists of a trimer of dimers with 32-point symmetry, inner and outer ring diameters of 20 and 100A, respectively, and a height of 110A(.) Each AAK domain interacts with the cognate domains of two adjacent monomersmore » across two 2-fold symmetry axes and with the NAT domain from a second monomer of the adjacent dimer in the ring. The catalytic sites are located within the NAT domains. Three active site residues, Arg316, Arg425, and Ser427, anchor N-acetylglutamate in a position at the active site to form hydrogen bond interactions to the main chain nitrogen atoms of Cys356 and Leu314, and hydrophobic interactions to the side chains of Leu313 and Leu314. The mode of binding of acetyl-CoA and CoA is similar to other NAT family proteins. The AAK domain, although catalytically inactive, appears to bind arginine. This is the first reported crystal structure of any NAGS, and it provides insights into the catalytic function and arginine regulation of NAGS enzymes.« less

Association of N-acetyltransferase 1 polymorphism and bladder cancer risk: an updated meta-analysis and trial sequential analysis.

PubMed

Xu, Zicheng; Li, Xiao; Qin, Zhiqiang; Xue, Jianxin; Wang, Jingyuan; Liu, Zhentao; Cai, Hongzhou; Yu, Bin; Xu, Ting; Zou, Qin

2017-07-24

Individual studies of the association between N-acetyltransferase 1 (NAT1)*10 allele and bladder cancer susceptibility have shown inconclusive results. To derive a more precise estimation of any such relationship, we performed this systemic review and updated meta-analysis based on 17 publications. A total of 17 studies were investigated with 4,322 bladder cancer cases and 4,944 controls. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Subgroup analyses were conducted based on ethnicity, sex, source of controls and detecting methods. Then trial sequential analysis was performed to evaluate whether the evidence of the results was sufficient and reduce the risk of type I error. There was no association between NAT1*10 allele and bladder cancer risk in a random-effects model (OR = 0.96, 95% CI, 0.84-1.10) or in a fixed-effects model (OR = 0.95, 95% CI, 0.87-1.03). In addition, no significantly increased risk of bladder cancer was found in any other subgroup analysis. Then, trial sequential analyses demonstrated that the results of our study need to be further verified. Despite its limitations, the results of the present meta-analysis suggested that there was no association between NAT1*10 allele and bladder cancer risk. More importantly, our findings need to be further validated regarding whether being without the NAT1*10 allele could in the future be shown to be a potential marker for the risk of bladder cancer.

Molekulare Diagnostik von Hautinfektionen am Paraffinmaterial - Übersicht und interdisziplinärer Konsensus.

PubMed

Sunderkötter, Cord; Becker, Karsten; Kutzner, Heinz; Meyer, Thomas; Blödorn-Schlicht, Norbert; Reischl, Udo; Nenoff, Pietro; Geißdörfer, Walter; Gräser, Yvonne; Herrmann, Mathias; Kühn, Joachim; Bogdan, Christian

2018-02-01

Nukleinsäure-Amplifikations-Techniken (NAT), wie die PCR, sind hochsensitiv sowie selektiv und stellen in der mikrobiologischen Diagnostik wertvolle Ergänzungen zur kulturellen Anzucht und Serologie dar. Sie bergen aber gerade bei formalinfixiertem und in Paraffin eingebettetem Gewebe ein Risiko für sowohl falsch negative als auch falsch positive Resultate, welches nicht immer richtig eingeschätzt wird. Daher haben Vertreter der Deutschen Gesellschaft für Hygiene und Mikrobiologie (DGHM) und der Deutschen Dermatologischen Gesellschaft (DDG) einen Konsensus in Form einer Übersichtsarbeit erarbeitet, wann eine NAT am Paraffinschnitt angezeigt und sinnvoll ist und welche Punkte dabei in der Präanalytik und Befundinterpretation beachtet werden müssen. Da bei Verdacht auf eine Infektion grundsätzlich Nativgewebe genutzt werden soll, ist die PCR am Paraffinschnitt ein Sonderfall, wenn beispielsweise bei erst nachträglichaufgekommenem Verdacht auf eine Infektion kein Nativmaterial zur Verfügung steht und nicht mehr gewonnen werden kann. Mögliche Indikationen sind der histologisch erhobene Verdacht auf eine Leishmaniose, eine Infektion durch Bartonellen oder Rickettsien, oder ein Ecthyma contagiosum. Nicht sinnvoll ist oder kritisch gesehen wird eine NAT am Paraffinschnitt zum Beispiel bei Infektionen mit Mykobakterien oder RNA-Viren. Die Konstellation für eine NAT aus Paraffingewebe sollte jeweils benannt werden, die erforderliche Prä-Analytik, die jeweiligen Grenzen des Verfahrens und die diagnostischen Alternativen bekannt sein. Der PCR-Befund sollte entsprechend kommentiert werden, um Fehleinschätzungen zu vermeiden. © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Evaluation of Quality of Life Following Placement of Self-Expanding Plastic Stents as a Bridge to Surgery in Patients Receiving Neoadjuvant Therapy for Esophageal Cancer

PubMed Central

Cannon, Robert M.; Brown, Russell E.; Ellis, Susan F.; Williams, Sharon; Scoggins, C.R.; Abbas, Abbas E.

2014-01-01

Purpose. To determine whether self-expanding plastic stent (SEPS) placement significantly improves quality of life and maintains optimal nutrition while allowing full-dose neoadjuvant therapy (NAT) in patients with esophageal cancer. Patients and Methods. A prospective, dual-institution, single-arm, phase II (http://ClinicalTrials.gov: NCT00727376) evaluation of esophageal cancer patients undergoing NAT prior to resection. All patients had a self-expanding polymer stent placed prior to NAT. The European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25, Functional Assessment of Cancer Therapy–Anorexia, and Functional Assessment of Cancer Therapy–General surveys were administered prior to stenting, within 1 week post-stent placement, and at the completion of neoadjuvant therapy. Results. Fifty-two patients were enrolled; 3 (5.8%) had stent migrations requiring replacement. There were no instances of esophageal erosion or perforation. All patients received some form of neoadjuvant therapy. Thirty-six (69%) received chemoradiation; 34 (93%) of these patients received the planned dose of chemotherapy, and 27 (75%) received the full planned dose of radiotherapy. There were 16 (31%) patients receiving chemotherapy alone; 12 (74%) of patients in the chemotherapy-alone group completed the planned dose of therapy. Conclusion. Placement of SEPS appears to provide significant improvement in quality of life related to dysphagia and eating restriction in patients with esophageal cancer undergoing neoadjuvant therapy. Consideration of SEPS instead of percutaneous feeding tube should be initiated as a first line in dysphagia palliation and NAT nutritional support. PMID:24567281

Friction and Wear Behavior of Plasma-Sprayed Al2O3-13 wt.%TiO2 Coatings Under the Lubrication of Liquid Paraffin

NASA Astrophysics Data System (ADS)

Zhao, Xiaoqin; An, Yulong; Hou, Guoliang; Zhou, Huidi; Chen, Jianmin

2014-04-01

Two types of ceramic composite coatings (denoted as N-AT13 coating and M-AT13 coating) were fabricated on 1Cr18Ni9Ti stainless steel substrate from ultra-fine and coarse Al2O3-13%TiO2 feedstocks by air plasma spraying. The friction and wear behavior of as-prepared coatings sliding against Al2O3 and stainless steel balls under the lubrication of liquid paraffin was evaluated with an SRV friction and wear tester (Optimol, Germany). The fractured and worn surfaces of the coatings were observed using a scanning electron microscope and a field-emission scanning electron microscope; and the wear mechanisms of the coatings were discussed based on scanning electron microscopic analysis and energy dispersive spectrometric analysis. Results show that N-AT13 coating possesses a unique microstructure and strong inter-splat bonding, thereby showing increased microhardness and bonding strength as well as much better friction-reduction and wear resistance than M-AT13 coating. Moreover, there exist differences in the wear mechanisms of N-AT13 and M-AT13 coatings which slide against ceramic and stainless steel balls under the lubrication of liquid paraffin. Namely, with the increase of normal load, the burnishing of N-AT13 coating coupled with Al2O3 ball is gradually transformed to grain-abrasion and deformation, while M-AT13 coating is dominated by grain-pullout and brittle fracture in the whole range of tested normal load.