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Sample records for a2 a3 a4

  1. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  2. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  3. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  4. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  5. 47 CFR 80.1093 - Ship radio equipment-Sea areas A1, A2, A3, and A4.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, A3, and... AND SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1093 Ship radio equipment—Sea areas A1,...

  6. Fidelity of binding of the guanidinium nucleic acid (DNG) d(Tg)4-T-azido with short strand DNA oligomers (A5G3A5, GA4G3A4G, G2A3G3A3G2, G2A2G5A2G2). A kinetic and thermodynamic study.

    PubMed

    Blaskó, A; Minyat, E E; Dempcy, R O; Bruice, T C

    1997-06-24

    Short strand DNA oligomers (A5G3A5, GA4G3A4G, G2A3G3A3G2, and G2A2G5A2G2) and the guanidinium (g) linked thymidyl nucleoside d(Tg)4-T-azido associate as triplexes. The melting temperatures, Tm, the association and dissociation kinetic and thermodynamic parameters and activation energies for the triplexes were determined by UV thermal analysis. The hypochromic shift and Tm for triplex formation increases with increase in concentration and decreases with the number of mismatches. The melting temperatures are between 35 and 55 degrees C in the range of ionic strength of 0.06-0.24 and decrease with increase in ionic strength at 100 deg/(ionic strength unit). The melting and cooling curves exhibit hysteresis behavior in the temperature range 5-95 degrees C at 0.2 deg/min thermal rate. From these curves, the rate constants and the energies of activation for association (k(on), E(on)) and dissociation (k(off), E(off)) processes were obtained. The second-order rate constants, k(on), for the triplex formation at 288 K are between 10 and 500 M(-2) s(-1). Values of k(on) increase with the decrease in the ionic strength. The first order rate constants for the dissociation, k(off), at 288 K are between 10(-6) and 40 x 10(-6) s(-1) and increase with increase in ionic strength. The energies of activation for the association and dissociation processes are in the range -22 to -9 kcal/mol and 8 to 29 kcal/mol, respectively. At 6.3 x 10(-5) M/base and at the physiological ionic strength (0.15-0.30) and below, the triplex structures formed with d(Tg)4-T-azido and A5G3A5 and GA4G3A4G have well-defined Tm values. The melting curves with G2A3G3A3G2 and G2A2G5A2G2 are very shallow with small hypochromic shifts denoting negligible binding at physiological ionic strength. Therefore, with the increase in the G content (mismatched base pairs) at a certain concentration (e.g., 6.3 x 10(-5) M/base), discrimination (change in fidelity) occurs in the formation and strength of binding of d(Tg)4-T

  7. Catalytic Properties of Botulinum Neurotoxins Subtypes A3 and A4

    PubMed Central

    Henkel, James S.; Jacobson, Mark; Tepp, William; Pier, Christina; Johnson, Eric A.; Barbieri, Joseph T.

    2009-01-01

    Botulinum toxins (BoNT) are zinc proteases (serotypes A-G) which cause flaccid paralysis through the cleavage of SNARE proteins within motor neurons. BoNT/A was originally organized into two subtypes: BoNT/A1 and BoNT/A2, which are ~ 95 % homologous and possess similar catalytic activities. Subsequently, two additional subtypes were identified; BoNT/A3 (Loch Maree), and BoNT/A4 (657Ba), which have 81 and 88% homology with BoNT/A1, respectively. Alignment studies predicted that BoNT/A3 and BoNT/A4 were sufficiently different to BoNT/A1 to affect SNAP25 binding and cleavage. Recombinant Light Chain (LC) of BoNT/A3 (LC/A3) and BoNT/A4 (LC/A4) were subjected to biochemical analysis. LC/A3 cleaved SNAP25 at 50% the rate of LC/A1, but cleaved SNAPtide® at a faster rate than LC/A1, while LC/A4 cleaved SNAP25 and SNAPtide® at slower rates than LC/A1. LC/A3 and LC/A4 had similar Kms for SNAP25 relative to LC/A1, while the kcat for LC/A4 was 10- fold slower than LC/A1, suggesting a defect in substrate cleavage. Neither LC/A3 nor LC/A4 possessed autocatalytic activity, a property of LC/A1 and LC/A2. Thus, the four subtypes of BoNT/A bind SNAP25 with similar affinity but have different catalytic capacities for SNAP25 cleavage, SNAPtide® cleavage, and autocatalysis. The catalytic properties identified among the subtypes of LC/A may influence strategies for the development of small molecule- or peptide- inhibitors as therapies against botulism. PMID:19256469

  8. Desipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling.

    PubMed

    Tanasic, Sascha; Mattusch, Corinna; Wagner, Eva Maria; Eder, Matthias; Rupprecht, Rainer; Rammes, Gerhard; Di Benedetto, Barbara

    2016-06-01

    Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CA1 field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-positive cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Tricyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biological underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyse a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favoured an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the molecular and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clinical use of DMI. PMID:26785076

  9. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism.

    PubMed

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-01-01

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

  10. Investigation of the fatty acid transporter-encoding genes SLC27A3 and SLC27A4 in autism

    PubMed Central

    Maekawa, Motoko; Iwayama, Yoshimi; Ohnishi, Tetsuo; Toyoshima, Manabu; Shimamoto, Chie; Hisano, Yasuko; Toyota, Tomoko; Balan, Shabeesh; Matsuzaki, Hideo; Iwata, Yasuhide; Takagai, Shu; Yamada, Kohei; Ota, Motonori; Fukuchi, Satoshi; Okada, Yohei; Akamatsu, Wado; Tsujii, Masatsugu; Kojima, Nobuhiko; Owada, Yuji; Okano, Hideyuki; Mori, Norio; Yoshikawa, Takeo

    2015-01-01

    The solute carrier 27A (SLC27A) gene family encodes fatty acid transport proteins (FATPs) and includes 6 members. During fetal and postnatal periods of development, the growing brain requires a reliable supply of fatty acids. Because autism spectrum disorders (ASD) are now recognized as disorders caused by impaired early brain development, it is possible that functional abnormalities of SLC27A genes may contribute to the pathogenesis of ASD. Here, we confirmed the expression of SLC27A3 and SLC27A4 in human neural stem cells derived from human induced pluripotent stem cells, which suggested their involvement in the developmental stage of the central nervous system. Additionally, we resequenced the SLC27A3 and SLC27A4 genes using 267 ASD patient and 1140 control samples and detected 47 (44 novel and 29 nonsynonymous) and 30 (17 novel and 14 nonsynonymous) variants for the SLC27A3 and SLC27A4, respectively, revealing that they are highly polymorphic with multiple rare variants. The SLC27A4 Ser209 allele was more frequently represented in ASD samples. Furthermore, we showed that a SLC27A4 Ser209 mutant resulted in significantly higher fluorescently-labeled fatty acid uptake into bEnd3 cells, a mouse brain capillary-derived endothelial cell line, compared with SLC27A4 Gly209, suggesting that the functional change may contribute to ASD pathophysiology. PMID:26548558

  11. Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis

    PubMed Central

    Malone, Andrew F; Phelan, Paul J; Hall, Gentzon; Cetincelik, Umran; Homstad, Alison; Alonso, Andrea; Jiang, Ruiji; Lindsey, Thomas; Wu, Guanghong; Sparks, Matthew A; Smith, Stephen R; Webb, Nicholas J A; Kalra, Philip; Adeyemo, Adebowale; Shaw, Andrey S; Conlon, Peter J; Jennette, J Charles; Howell, David N; Winn, Michelle P; Gbadegesin, Rasheed A

    2014-01-01

    Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes including inherited genetic defects with significant proteinuria being the predominant clinical finding at presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome, thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane findings. Secondary FSGS is known to develop in classic Alport Syndrome at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical findings at diagnosis were proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin glomerular basement membrane, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes. PMID:25229338

  12. 29 CFR 779.365 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Service Establishments Automotive Tire Establishments § 779.365 May qualify as exempt 13(a)(2) or 13(a)(4... automotive vehicles whereby the establishment undertakes to maintain the tires or tubes for a fleet...

  13. 29 CFR 779.365 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Service Establishments Automotive Tire Establishments § 779.365 May qualify as exempt 13(a)(2) or 13(a)(4... automotive vehicles whereby the establishment undertakes to maintain the tires or tubes for a fleet...

  14. 29 CFR 779.365 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Service Establishments Automotive Tire Establishments § 779.365 May qualify as exempt 13(a)(2) or 13(a)(4... automotive vehicles whereby the establishment undertakes to maintain the tires or tubes for a fleet...

  15. 29 CFR 779.365 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Service Establishments Automotive Tire Establishments § 779.365 May qualify as exempt 13(a)(2) or 13(a)(4... automotive vehicles whereby the establishment undertakes to maintain the tires or tubes for a fleet...

  16. 29 CFR 779.365 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Service Establishments Automotive Tire Establishments § 779.365 May qualify as exempt 13(a)(2) or 13(a)(4... automotive vehicles whereby the establishment undertakes to maintain the tires or tubes for a fleet...

  17. 29 CFR 779.364 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Service Establishments Frozen-Food Locker Plants § 779.364 May qualify as exempt 13(a)(2) or 13(a)(4) establishments. (a) An establishment engaged in providing frozen-food locker service to farmers and other private... section 13(a)(2) of the Act if it meets all the requirements of that exemption. Similarly, a...

  18. 29 CFR 779.364 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Service Establishments Frozen-Food Locker Plants § 779.364 May qualify as exempt 13(a)(2) or 13(a)(4) establishments. (a) An establishment engaged in providing frozen-food locker service to farmers and other private... section 13(a)(2) of the Act if it meets all the requirements of that exemption. Similarly, a...

  19. 29 CFR 779.364 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Service Establishments Frozen-Food Locker Plants § 779.364 May qualify as exempt 13(a)(2) or 13(a)(4) establishments. (a) An establishment engaged in providing frozen-food locker service to farmers and other private... section 13(a)(2) of the Act if it meets all the requirements of that exemption. Similarly, a...

  20. 29 CFR 779.364 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Service Establishments Frozen-Food Locker Plants § 779.364 May qualify as exempt 13(a)(2) or 13(a)(4) establishments. (a) An establishment engaged in providing frozen-food locker service to farmers and other private... section 13(a)(2) of the Act if it meets all the requirements of that exemption. Similarly, a...

  1. 29 CFR 779.364 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Service Establishments Frozen-Food Locker Plants § 779.364 May qualify as exempt 13(a)(2) or 13(a)(4) establishments. (a) An establishment engaged in providing frozen-food locker service to farmers and other private... section 13(a)(2) of the Act if it meets all the requirements of that exemption. Similarly, a...

  2. Identification of Two Metallothioneins as Novel Inhalative Coffee Allergens Cof a 2 and Cof a 3

    PubMed Central

    Peters, Ulrike; Frenzel, Karsten; Brettschneider, Reinhold; Oldenburg, Marcus; Bittner, Cordula

    2015-01-01

    Background Dust of green coffee beans is known to be a relevant cause for occupational allergic disorders in coffee industry workers. Recently, we described the first coffee allergen (Cof a 1) establishing an allergenic potential of green coffee dust. Objective Our aim was to identify allergenic components of green coffee in order to enhance inhalative coffee allergy diagnosis. Methods A Coffea arabica pJuFo cDNA phage display library was created and screened for IgE binding with sera from allergic coffee workers. Two further coffee allergens were identified by sequence analysis, expressed in E. coli, and evaluated by Western blots. The prevalence of sensitization to recombinant Cof a 1, Cof a 2, and Cof a 3 and to commercially available extract was investigated by ELISA (enzyme-linked immunosorbent assay) respectively CAP (capacity test) screening in 18 sera of symptomatic coffee workers. Results In addition to the previously described chitinase Cof a 1, two Coffea arabica cysteine-rich metallothioneins of 9 and 7 kDa were identified and included in the IUIS Allergen Nomenclature as Cof a 2 and Cof a 3. Serum IgE antibodies to at least one of the recombinant allergens were found in 8 out of 18 symptomatic coffee workers (44%). Only 2 of the analysed sera (11%) had reacted previously to the commercial allergy test. Conclusions In addition to the previously described Cof a 1 we have identified two further coffee proteins to be type I coffee allergens (Cof a 2 and Cof a 3) which may have a relevant potential for the specific diagnosis and/or therapy of coffee allergy. PMID:25962169

  3. 40 CFR Table A-4 to Subpart A of... - Source Category List for § 98.2(a)(2)

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 22 2012-07-01 2012-07-01 false Source Category List for § 98.2(a)(2) A Table A-4 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt....

  4. 40 CFR Table A-4 to Subpart A of... - Source Category List for § 98.2(a)(2)

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 21 2011-07-01 2011-07-01 false Source Category List for § 98.2(a)(2) A Table A-4 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt....

  5. 40 CFR Table A-4 to Subpart A of... - Source Category List for § 98.2(a)(2)

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Source Category List for § 98.2(a)(2) A Table A-4 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt....

  6. 40 CFR Table A-4 to Subpart A of... - Source Category List for § 98.2(a)(2)

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Source Category List for § 98.2(a)(2) A Table A-4 to Subpart A of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING General Provision Pt. 98, Subpt....

  7. 29 CFR 779.358 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 false May qualify as exempt 13(a)(2) or 13(a)(4) establishments. 779.358 Section 779.358 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR STATEMENTS OF GENERAL POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS THE FAIR LABOR STANDARDS ACT AS APPLIED...

  8. 29 CFR 779.358 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 false May qualify as exempt 13(a)(2) or 13(a)(4) establishments. 779.358 Section 779.358 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR STATEMENTS OF GENERAL POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS THE FAIR LABOR STANDARDS ACT AS APPLIED...

  9. 75 FR 28188 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-20

    ... 7, 2010 (75 FR 910), we published a final rule AD, FR Doc, E9-30471, in the Federal Register. That... (GE) CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1 turbofan engines. The GE alert service bulletin...

  10. Combined application of plasma mutagenesis and gene engineering leads to 5-oxomilbemycins A3/A4 as main components from Streptomyces bingchenggensis.

    PubMed

    Wang, Hai-Yan; Zhang, Ji; Zhang, Yue-Jing; Zhang, Bo; Liu, Chong-Xi; He, Hai-Rong; Wang, Xiang-Jing; Xiang, Wen-Sheng

    2014-12-01

    Milbemycin oxime has been commercialized as effective anthelmintics in the fields of animal health, agriculture, and human infections. Currently, milbemycin oxime is synthesized by a two-step chemical reaction, which involves the ketonization of milbemycins A3/A4 to yield the intermediates 5-oxomilbemycins A3/A4 using CrO3 as catalyst. Due to the low efficiency and environmental unfriendliness of the ketonization of milbemycins A3/A4, it is imperative to develop alternative strategies to produce 5-oxomilbemycins A3/A4. In this study, the atmospheric and room temperature plasma (ARTP) mutation system was first employed to treat milbemycin-producing strain Streptomyces bingchenggensis, and a mutant strain BC-120-4 producing milbemycins A3, A4, B2, and B3 as main components was obtained, which favors the construction of genetically engineered strains producing 5-oxomilbemycins. Importantly, the milbemycins A3/A4 yield of BC-120-4 reached 3,890 ± 52 g/l, which was approximately two times higher than that of the initial strain BC-109-6 (1,326 ± 37 g/l). The subsequent interruption of the gene milF encoding a C5-ketoreductase responsible for the ketonization of milbemycins led to strain BCJ60 (∆milF) with the production of 5-oxomilbemycins A3/A4 and the elimination of milbemycins A3, A4, B2, and B3. The high 5-oxomilbemycins A3/A4 yield (3,470 ± 147 g/l) and genetic stability of BCJ60 implied the potential use in industry to prepare 5-oxomilbemycins A3/A4 for the semisynthesis of milbemycins oxime. PMID:25081559

  11. Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives

    PubMed Central

    Xin, Bingyue; Zheng, Jinshui; Xu, Ziya; Li, Congzhi; Ruan, Lifang; Peng, Donghai

    2015-01-01

    Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121°C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives. PMID:26231642

  12. Three Novel Lantibiotics, Ticins A1, A3, and A4, Have Extremely Stable Properties and Are Promising Food Biopreservatives.

    PubMed

    Xin, Bingyue; Zheng, Jinshui; Xu, Ziya; Li, Congzhi; Ruan, Lifang; Peng, Donghai; Sun, Ming

    2015-10-01

    Lantibiotics are antimicrobial peptides with potential applications as the next generation of antimicrobials in the food industry and/or the pharmaceutical industry. Nisin has successfully been used as a food preservative for over 40 years, but its major drawback is its limited stability under neutral and alkaline pH conditions. To identify alternatives with better biochemical properties, we screened more than 100 strains of the Bacillus cereus group. Three novel lantibiotics, ticins A1 (4,062.98 Da), A3 (4,048.96 Da), and A4 (4,063.02 Da), which were highly thermostable (121°C for 30 min) and extremely pH tolerant (pH 2.0 to 9.0), were identified in Bacillus thuringiensis BMB3201. They all showed potent antimicrobial activities against all tested Gram-positive bacteria and greater activities than those of nisin A against Bacillus cereus and Listeria monocytogenes, two important foodborne pathogens. These three novel lantibiotics, with their extremely stable properties and potent antimicrobial activities, have the potential for use as biopreservatives. PMID:26231642

  13. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 47 Telecommunication 5 2013-10-01 2013-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  14. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 47 Telecommunication 5 2012-10-01 2012-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  15. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 47 Telecommunication 5 2014-10-01 2014-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System (GMDSS) Equipment Requirements for Ship Stations § 80.1091 Ship radio equipment—Sea areas A1, A2, and A3....

  16. Effects of alkylate fuel on exhaust emissions and secondary aerosol formation of a 2-stroke and a 4-stroke scooter

    NASA Astrophysics Data System (ADS)

    Zardini, Alessandro A.; Platt, Stephen M.; Clairotte, Michael; El Haddad, Imad; Temime-Roussel, Brice; Marchand, Nicolas; Ježek, Irena; Drinovec, Luka; Močnik, Griša; Slowik, Jay G.; Manfredi, Urbano; Prévôt, André S. H.; Baltensperger, Urs; Astorga, Covadonga

    2014-09-01

    Regulated and unregulated emissions from a 2-stroke and a 4-stroke scooter were characterized during a legislative driving cycle in a certified laboratory. Scooter exhaust was analyzed at the tailpipe, in a dilution tunnel, and partly collected in a mobile smog chamber for photochemical ageing. We present evidence that the photochemically aged exhaust from a 2-stroke and a 4-stroke scooter produces considerable amounts of secondary organic aerosol: from 1.5 to 22.0 mg/km, and from 5.5 to 6.6 mg/km, respectively. Tests were repeated after replacing the standard petrol and synthetic lube oil with an alkylate fuel (with low content of aromatic compounds) and ultra-clean lube oil (low ash forming potential). We observed emission reduction (with some exceptions) for several gaseous and particulate phase species, in particular for carbon monoxide (from 8% up to 38% and from 31% to 50%, for the 2-stroke and the 4-stroke scooters, respectively), particulate mass (from 32% up to 75% for the 2-stroke scooter), aromatic compounds (89% and 97% for the 2-stroke and the 4-stroke scooter, respectively), and secondary organic aerosol (from 87% to 100% and 99% for the 2-stroke and the 4-stroke scooters, respectively). We attribute the organic aerosol reduction to the low content of aromatics in the alkylate fuel.

  17. Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

    PubMed

    Nabais Sá, M J; Storey, H; Flinter, F; Nagel, M; Sampaio, S; Castro, R; Araújo, J A; Gaspar, M A; Soares, C; Oliveira, A; Henriques, A C; da Costa, A G; Abreu, C P; Ponce, P; Alves, R; Pinho, L; Silva, S E; de Moura, C P; Mendonça, L; Carvalho, F; Pestana, M; Alves, S; Carvalho, F; Oliveira, J P

    2015-11-01

    Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies. PMID:25307543

  18. Identifying and applying a highly selective probe to simultaneously determine the O-glucuronidation activity of human UGT1A3 and UGT1A4

    PubMed Central

    Jiang, Li; Liang, Si-Cheng; Wang, Chao; Ge, Guang-Bo; Huo, Xiao-Kui; Qi, Xiao-Yi; Deng, Sa; Liu, Ke-Xin; Ma, Xiao-Chi

    2015-01-01

    Glucuronidation mediated by uridine 5′-diphospho (UDP)-glucuronosyltransferase is an important detoxification pathway. However, identifying a selective probe of UDP- glucuronosyltransferase is complicated because of the significant overlapping substrate specificity displayed by the enzyme. In this paper, desacetylcinobufagin (DACB) 3-O- and 16-O-glucuronidation were found to be isoform-specific probe reactions for UGT1A4 and UGT1A3, respectively. DACB was well characterized as a probe for simultaneously determining the catalytic activities of O-glucuronidation mediated by UGT1A3 and UGT1A4 from various enzyme sources, through a sensitive analysis method. PMID:25884245

  19. Is health locus of control a 3-factor or a 2-factor construct?

    PubMed

    Talbot, F; Nouwen, A; Gauthier, J

    1996-09-01

    Although the Multidimensional Health Locus of Control (MHLC) scales are commonly used, uncertainty about their factorial validity still remains. In the present study, confirmatory factor analyses of a French-Canadian adaptation of the Multidimensional Health Locus of Control scales (MHLC) were conducted to compare in a non-clinical group of 224 adults two factor models. Multigroup analyses were also conducted using this group and a clinical group of 132 diabetics to assess the equivalence of the MHLC factor structure across these two groups. A 3-factor model postulating an internal, external, and chance dimension, and accounting for measurement errors provided the best fit to the data. Multigroup analyses failed to support the equivalence of the MHLC factor loadings across the non-clinical and clinical group. These findings suggest that comparisons of MHLC scores across such groups may be problematic. PMID:8877693

  20. Genetic Diversity among Clostridium botulinum Strains Harboring bont/A2 and bont/A3 Genes

    PubMed Central

    Raphael, Brian H.; Joseph, Lavin A.; Meno, Sarah R.; Fernández, Rafael A.; Maslanka, Susan E.

    2012-01-01

    Clostridium botulinum type A strains are known to be genetically diverse and widespread throughout the world. Genetic diversity studies have focused mainly on strains harboring one type A botulinum toxin gene, bont/A1, although all reported bont/A gene variants have been associated with botulism cases. Our study provides insight into the genetic diversity of C. botulinum type A strains, which contain bont/A2 (n = 42) and bont/A3 (n = 4) genes, isolated from diverse samples and geographic origins. Genetic diversity was assessed by using bont nucleotide sequencing, content analysis of the bont gene clusters, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Sequences of bont genes obtained in this study showed 99.9 to 100% identity with other bont/A2 or bont/A3 gene sequences available in public databases. The neurotoxin gene clusters of the subtype A2 and A3 strains analyzed in this study were similar in gene content. C. botulinum strains harboring bont/A2 and bont/A3 genes were divided into six and two MLST profiles, respectively. Four groups of strains shared a similarity of at least 95% by PFGE; the largest group included 21 out of 46 strains. The strains analyzed in this study showed relatively limited genetic diversity using either MLST or PFGE. PMID:23042179

  1. Genetic diversity among Clostridium botulinum strains harboring bont/A2 and bont/A3 genes.

    PubMed

    Lúquez, Carolina; Raphael, Brian H; Joseph, Lavin A; Meno, Sarah R; Fernández, Rafael A; Maslanka, Susan E

    2012-12-01

    Clostridium botulinum type A strains are known to be genetically diverse and widespread throughout the world. Genetic diversity studies have focused mainly on strains harboring one type A botulinum toxin gene, bont/A1, although all reported bont/A gene variants have been associated with botulism cases. Our study provides insight into the genetic diversity of C. botulinum type A strains, which contain bont/A2 (n = 42) and bont/A3 (n = 4) genes, isolated from diverse samples and geographic origins. Genetic diversity was assessed by using bont nucleotide sequencing, content analysis of the bont gene clusters, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Sequences of bont genes obtained in this study showed 99.9 to 100% identity with other bont/A2 or bont/A3 gene sequences available in public databases. The neurotoxin gene clusters of the subtype A2 and A3 strains analyzed in this study were similar in gene content. C. botulinum strains harboring bont/A2 and bont/A3 genes were divided into six and two MLST profiles, respectively. Four groups of strains shared a similarity of at least 95% by PFGE; the largest group included 21 out of 46 strains. The strains analyzed in this study showed relatively limited genetic diversity using either MLST or PFGE. PMID:23042179

  2. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of these standards can be inspected at the Federal... 47 Telecommunication 5 2010-10-01 2010-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System...

  3. 47 CFR 80.1091 - Ship radio equipment-Sea areas A1, A2, and A3.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of these standards can be inspected at the Federal... 47 Telecommunication 5 2011-10-01 2011-10-01 false Ship radio equipment-Sea areas A1, A2, and A3... SPECIAL RADIO SERVICES STATIONS IN THE MARITIME SERVICES Global Maritime Distress and Safety System...

  4. Adenosine A(1), A(2a), A(2b), and A(3) receptors in hematopoiesis. 1. Expression of receptor mRNA in four mouse hematopoietic precursor cells.

    PubMed

    Streitová, D; Sefc, L; Savvulidi, F; Pospísil, M; Holá, J; Hofer, M

    2010-01-01

    Four mouse bone marrow or thymus cell populations, namely granulopoietic/monocytopoietic, erythropoietic, B-lymphopoietic, and T-lymphopoietic precursor cells have been assayed by RT-PCR technique for the presence and relative amounts of adenosine A(1), A(2a), A(2b), and A(3) receptor mRNA. It has been found that (i) all four populations studied express all four adenosine receptor subtypes, (ii) the A(1), receptor is the least expressed in all populations studied, (iii) the A(3) receptor is markedly expressed in the populations of granulopoietic/monocytopoietic and erythropoietic cells, (iv) the A(2a) receptor is markedly expressed in the populations of B-lymphopoietic and T-lymphopoietic cells, and v) the A(2b) receptor does not predominate in any of the precursor cells studied. Our data offer a new possibility for the assessment of the readiness of these cells to respond, by receptor-mediated mechanisms, to adenosine or its analogs present in the tissues as a result of endogenous processes and/or following their administration. PMID:19249907

  5. The functions of the A1A2A3 domains in von Willebrand factor include multimerin 1 binding.

    PubMed

    Parker, D'Andra N; Tasneem, Subia; Farndale, Richard W; Bihan, Dominique; Sadler, J Evan; Sebastian, Silvie; de Groot, Philip G; Hayward, Catherine P M

    2016-07-01

    Multimerin 1 (MMRN1) is a massive, homopolymeric protein that is stored in platelets and endothelial cells for activation-induced release. In vitro, MMRN1 binds to the outer surfaces of activated platelets and endothelial cells, the extracellular matrix (including collagen) and von Willebrand factor (VWF) to support platelet adhesive functions. VWF associates with MMRN1 at high shear, not static conditions, suggesting that shear exposes cryptic sites within VWF that support MMRN1 binding. Modified ELISA and surface plasmon resonance were used to study the structural features of VWF that support MMRN1 binding, and determine the affinities for VWF-MMRN1 binding. High shear microfluidic platelet adhesion assays determined the functional consequences for VWF-MMRN1 binding. VWF binding to MMRN1 was enhanced by shear exposure and ristocetin, and required VWF A1A2A3 region, specifically the A1 and A3 domains. VWF A1A2A3 bound to MMRN1 with a physiologically relevant binding affinity (KD: 2.0 ± 0.4 nM), whereas the individual VWF A1 (KD: 39.3 ± 7.7 nM) and A3 domains (KD: 229 ± 114 nM) bound to MMRN1 with lower affinities. VWF A1A2A3 was also sufficient to support the adhesion of resting platelets to MMRN1 at high shear, by a mechanism dependent on VWF-GPIbα binding. Our study provides new information on the molecular basis of MMRN1 binding to VWF, and its role in supporting platelet adhesion at high shear. We propose that at sites of vessel injury, MMRN1 that is released following activation of platelets and endothelial cells, binds to VWF A1A2A3 region to support platelet adhesion at arterial shear rates. PMID:27052467

  6. In Silico Docking of Ligands to Drug Oxidation Enzymes Cytochrome P450 3A4 and Cytochrome P450 1A2.

    NASA Astrophysics Data System (ADS)

    Smith, David; Guglielmon, Jonathan; Glenn, Marsch; Peter, Guengerich F.

    2009-03-01

    Cytochrome P450 3A4 (CYP3A4) and Cytochrome P450 1A2 (CYP1A2) oxidize most drugs in humans. Protein modeling toolkits from OpenEye Scientific Software were used to examine the interaction of drug substrates with CYP3A4 and CYP1A2. Conformers and partial atomic charges were generated for each drug molecule. User-defined volumes were defined around CYP3A4 and CYP1A2 active sites. Ligands were docked assuming protein and substrates as rigid bodies. To assess rigid docking accuracy, x-ray diffraction coordinates of CYP3A4-erythromycin and CYP3A4-metyrapone complexes were obtained. Rigid re-docking of erythromycin and metyrapone into CYP3A4 yielded poses similar to the crystal structures. Rigid docking revealed two other energetically-favorable CYP3A4-metyrapone poses. The best poses were obtained by using all the Open Eye scoring functions. Optimization of protein-ligand interactions within 5-10 Angstroms of the docked ligand was then performed using the Merck Molecular Force Field in which the protein was assumed to be flexible and the ligand to be rigid. Nearby protein residues pulled slightly closer to the substrate, reducing the volume of the active site.

  7. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    PubMed

    Zhu, X; Walton, R G; Tian, L; Luo, N; Ho, S-R; Fu, Y; Garvey, W T

    2013-03-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  8. Functional studies and polymerization of recombinant hemoglobin Glu-alpha2beta26(A3) --> Val/Glu-7(A4) --> Ala.

    PubMed

    Lesecq, S; Baudin, V; Kister, J; Marden, M C; Poyart, C; Pagnier, J

    1996-07-19

    In hemoglobin (Hb) S the hydrophobic mutated residue Val-beta6(A3) (donor site) closely interacts with the hydrophobic side groups of Phe-beta85(F1) and Leu-beta88(F4) (EF pocket, acceptor site) of a neighboring tetramer, resulting in decreased solubility and polymerization of the deoxy-Hb. The beta6(A3) residue is followed by two charged residues Glu-beta7(A4) and Lys-beta8(A5). This cluster has no attraction for the hydrophobic EF pocket. We have modified the beta7(A4) residue next to the donor site Val-beta6(A3), replacing the charged Glu by a hydrophobic Ala-(rHb betaE6V/E7A). The single mutant Glu-beta7 --> Ala-(rHb betaE7A) was also engineered. Both rHbs exhibit a heat instability and an increased oxygen affinity compared to Hb A and Hb S. There was a concentration dependence of the ligand binding properties (1-300 microM in heme) indicating an increased amount of dimers relative to Hb A. The deoxy form of rHb betaE6V/E7A polymerizes in vitro, with a decreased rate of polymer formation relative to Hb S, while the single mutant betaE7A does not polymerize in the same experimental conditions. The Glu-beta7(A4) --> Ala substitution does not increase the hydrophobic interaction between donor and acceptor site. We speculate that the loss of the normal saline bridge between Glu-beta7(A4) and Lys-beta132(H10) leads to an increased flexibility of the A helix and may account for the difference of the polymerization for this Hb S mutant. PMID:8663330

  9. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 12; Express/T-160 Project Express A2 and A3 Sensors Operations Procedures Document

    NASA Technical Reports Server (NTRS)

    Dunning, John (Technical Monitor); Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 deg. E. and 11 deg. W respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  10. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 11; Express/T-160E Project Express A2 and A3 Data Agreement Document

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.; Dunning, John (Technical Monitor)

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80deg E. and 11deg W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3-99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  11. A1-, A2A- and A3-subtype adenosine receptors modulate intraocular pressure in the mouse

    PubMed Central

    Avila, Marcel Y; Stone, Richard A; Civan, Mortimer M

    2001-01-01

    Despite the potential importance of the mouse in studying the pharmacology of aqueous dynamics, measurement of intraocular pressure (IOP) in its very small eye has been problematic. Utilizing a novel servo-null electrophysiologic approach recently applied to the mouse, we have identified a diversity of adenosine-receptor mechanisms in modulating IOP in this species. We report the first evidence that A3 receptors increase IOP in any species, and verify in the mouse reports with larger mammals that A1 receptors lower and A2A receptors increase IOP. PMID:11564641

  12. Structural studies of CsKBi mixed chlorides relation to the crystal structures of A2BMX6, A3MX6, and A2MX6

    NASA Astrophysics Data System (ADS)

    Benachenhou, Farida; Mairesse, Gaëtan; Nowogrocki, Guy; Thomas, Daniel

    1986-11-01

    The room-temperature crystal structures of Cs 3BiCl 6(I) and CsK 2BiCl 6(II) have been determined from X-ray single-crystal data. These compounds are both monoclinic, space group {C2}/{c}, with eight formula units per cell and cell parameters a = 27.017(17), b = 8.252(8), c = 13.121(10) Å, β = 99.70(11)° (I), a = 25.653(13), b = 7.799(5), c = 12.874(9) Å, β = 99.24(8)° (II). The crystal structures have been refined to final R values of 0.069(I) and 0.044(II) from 1706(I) and 2008(II) independent reflections and 93 variable parameters. The BiCl 6 octahedra are slightly distorted (average dBiCl = 2.699 Å) and the alkaline cations are coordinated with eleven or eight chlorine atoms. These structures are better described using the notion of "layers of close-packed octahedra" and can therefore be easily compared with the A2BMX6 (elpasolite type), A3MX6 (cryolite type), and A2MX6 (K 2PtCl 6 type) crystal structures. In these compounds, the "layers" of isolated octahedral MX6 entities ( X = F, Cl, Br, O) define "tetrahedral" and "octahedral" holes, entirely or partially occupied by the A and/or B cations.

  13. Boric acid increases the expression levels of human anion exchanger genes SLC4A2 and SLC4A3.

    PubMed

    Akbas, F; Aydin, Z

    2012-01-01

    Boron is an important micronutrient in plants and animals. The role of boron in living systems includes coordinated regulation of gene expression, growth and proliferation of higher plants and animals. There are several well-defined genes associated with boron transportation and tolerance in plants and these genes show close homology with human anion exchanger genes. Mutation of these genes also characterizes some genetic disorders. We investigated the toxic effects of boric acid on HEK293 cells and mRNA expression of anion exchanger (SLC4A1, SLC4A2 and SLC4A3) genes. Cytotoxicity of boric acid at different concentrations was tested by using the methylthiazolyldiphenyl-tetrazolium bromide assay. Gene expression profiles were examined using quantitative real-time PCR. In the HEK293 cells, the nontoxic upper concentration of boric acid was 250 μM; more than 500 μM caused cytotoxicity. The 250 μM boric acid concentration increased gene expression level of SLC4A2 up to 8.6-fold and SLC4A3 up to 2.6-fold, after 36-h incubation. There was no significant effect of boric acid on SLC4A1 mRNA expression levels. PMID:22576912

  14. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  15. Chromomycins A2 and A3 from marine actinomycetes with TRAIL resistance-overcoming and Wnt signal inhibitory activities.

    PubMed

    Toume, Kazufumi; Tsukahara, Kentaro; Ito, Hanako; Arai, Midori A; Ishibashi, Masami

    2014-06-01

    A biological screening study of an actinomycetes strain assembly was conducted using a cell-based cytotoxicity assay. The CKK1019 strain was isolated from a sea sand sample. Cytotoxicity-guided fractionation of the CKK1019 strain culture broth, which exhibited cytotoxicity, led to the isolation of chromomycins A2 (1) and A3 (2). 1 and 2 showed potent cytotoxicity against the human gastric adenocarcinoma (AGS) cell line (IC50 1; 1.7 and 2; 22.1 nM), as well as strong inhibitory effects against TCF/β-catenin transcription (IC50 1; 1.8 and 2; 15.9 nM). 2 showed the ability to overcome tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance. To the best of our knowledge, the effects of chromomycins A2 (1) and A3 (2) on TRAIL resistance-overcoming activity, and on the Wnt signaling pathway, have not been reported previously. Thus, 1 and 2 warrant potential drug lead studies in relation to TRAIL-resistant and Wnt signal-related diseases and offer potentially useful chemical probes for investigating TRAIL resistance and the Wnt signaling pathway. PMID:24905484

  16. Echinacea purpurea up-regulates CYP1A2, CYP3A4 and MDR1 gene expression by activation of pregnane X receptor pathway

    PubMed Central

    Awortwe, Charles; Manda, Vamshi K.; Avonto, Cristina; Khan, Shabana I.; Khan, Ikhlas A.; Walker, Larry A.; Bouic, Patrick J.; Rosenkranz, Bernd

    2015-01-01

    This study investigated the mechanism underlying Echinacea-mediated induction of CYP1A2, CYP3A4 and MDR1 in terms of human pregnane X receptor (PXR) activation. Crude extracts and fractions of Echinacea purpurea were tested for PXR activation in HepG2 cells by a reporter gene assay. Quantitative real-time PCR was carried out to determine their effects on CYP1A2 and CYP3A4 mRNA expressions. Capsules and fractions were risk ranked as high, intermediate and remote risk of drug-metabolizing enzymes induction based on EC50 values determined for respective CYPs. Fractions F1, F2 and capsule (2660) strongly activated PXR with 5-, 4- and 3.5-fold increase in activity, respectively. Echinacea preparations potentiated up-regulation of CYP1A2, CYP3A4 and MDR1 via PXR activation. Thus E. purpurea preparations cause herb–drug interaction by up-regulating CYP1A2, CYP3A4 and P-gp via PXR activation. PMID:25377539

  17. Selective oxidative demethylation of veratric acid to vanillic acid by CYP199A4 from Rhodopseudomonas palustris HaA2.

    PubMed

    Bell, Stephen G; Tan, Adrian B H; Johnson, Eachan O D; Wong, Luet-Lok

    2010-01-01

    CYP199A4 (RPB3613) from Rhodopseudomonas palustris HaA2 is a heme monooxygenase that catalyzes the hydroxylation of para-substituted benzoic acids. Monooxygenase activity of CYP199A4 can be reconstituted in a Class I electron transfer chain with an associated [2Fe-2S] ferredoxin, HaPux, (RPB3614) and the flavin-dependent reductase, HaPuR, (RPB3656) that is not associated with a CYP gene. CYP199A4 and the ferredoxin HaPux are produced in greater quantities using recombinant Escherichia coli expression systems when compared to the equivalent proteins in the closely related CYP199A2-Pux-PuR Class I system from R. palustris CGA009. HaPuR and HaPux can also replace PuR and Pux in supporting the CYP199A2 enzyme turnover with high activity. Whole-cell in vivo substrate oxidation systems for CYP199A4 and CYP199A2 with HaPux and HaPuR as the electron transfer proteins have been constructed. These E. coli systems were capable of selectively demethylating veratric acid at the para position to produce vanillic acid at rates of up to 15.3 microM (g-cdw)(-1) min(-1) and yields of up to 1.2 g L(-1). PMID:20024082

  18. cDNA sequences of channel catfish (Ictalurus punctatus Rafinesque, 1818) annexin A2, A4, A5 and A11

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Annexins, a protein superfamily, are ubiquitous, and play many important roles in immuno-physiological processes. In this report, we cloned and sequenced channel catfish orthologs to human annexin A2, A4, A5 and A11. Total RNA from tissues was extracted and cDNA libraries were constructed by the r...

  19. In vitro inhibition of human CYP1A2, CYP2D6, and CYP3A4 by six herbs commonly used in pregnancy.

    PubMed

    Langhammer, Astrid Jordet; Nilsen, Odd Georg

    2014-04-01

    Black elderberry, cranberry, fennel, ginger, horsetail, and raspberry leaf, herbs frequently used in pregnancy, were investigated for their in vitro CYP1A2, 2D6, and 3A4 inhibitory potential. Aqueous or ethanolic extracts were made from commercially available herbal products, and incubations were performed with recombinant cDNA-expressed human CYP enzymes in the presence of positive inhibitory controls. Metabolite formation was determined by validated LCMS/MS or HPLC methodologies. IC50 inhibition constants were estimated from CYP activity inhibition plots using non-linear regression. The most potent inhibition was shown for fennel towards CYP2D6 and 3A4 with respective IC50 constants of 23 ± 2 and 40 ± 4 µg/ml, horsetail towards CYP1A2 with an IC50 constant of 27 ± 1 µg/ml, and raspberry leaf towards CYP1A2, 2D6, and 3A4 with IC50 constants of 44 ± 2, 47 ± 8, and 81 ± 11 µg/ml, respectively. Based on the recommended dosing of the different commercial herbal products, clinically relevant systemic CYP inhibitions could be possible for fennel, horsetail, and raspberry leaf. In addition, fennel and raspberry leaf might cause a clinically relevant inhibition of intestinal CYP3A4. The in vivo inhibitory potential of these herbs towards specific CYP enzymes should be further investigated. PMID:23843424

  20. The effect of powder A2/powder A3 mixing ratio on color and translucency parameters of dental porcelain

    PubMed Central

    Lee, Wan-Sun; Kim, So-Yeon; Kim, Woong-Chul; Kim, Hae-Young

    2015-01-01

    PURPOSE The purpose of this study is to mix dental ceramic powder in varying ratios and evaluate the effect of the mixing ratio on color and translucency. MATERIALS AND METHODS The ceramic powder of shade A3 of the same product was mixed with the shade A2 of three products: IPS e.max Ceram (Ivoclar Vivadent, Schaan, Liechtenstein), Vintage Halo (SHOFU Inc., Kyoto, Japan), and Ceramco 3 (Ceramco-Dentsply, Burlington, NJ, USA) in the following fixed ratios (0 wt%, 25 wt%, 50 wt%, 75 wt%, and 100 wt%) and then fired. A total of 150 specimen of ceramic fired were manufactured in a regular size (W: 8.5 mm, L: 10.5 mm, and H: 1.5 mm). For color and translucency, L*, a*, and b* were measured and Two-way analysis of variance (ANOVA) and One-way analysis of variance (ANOVA) were used for data analysis (α=0.05). RESULTS The higher the mixing ratio was, L*, a*, and b* of IPS e.max Ceram were all increased, and L* of Vintage Halo was reduced and a* and b* were increased. L* and a* of Ceramco3 were reduced and b* of Ceramco3 was increased. Color difference (ΔE*ab) was increased in all three products as the mixing ratio got higher. Increased mixing ratios resulted in decreased translucency parameter (TP) values for IPS e.max Ceram but increased TP values for Vintage Halo and Ceramco3. CONCLUSION In this limited study, CIE L*, a*, and b* were influenced by the mixing ratio of the A3 powders and porcelain powder mixtures represented a various color and translucency. PMID:26576257

  1. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects

    PubMed Central

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A.

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world. PMID:26557993

  2. No Association of BDNF, COMT, MAOA, SLC6A3, and SLC6A4 Genes and Depressive Symptoms in a Sample of Healthy Colombian Subjects.

    PubMed

    González-Giraldo, Yeimy; Camargo, Andrés; López-León, Sandra; Forero, Diego A

    2015-01-01

    Background. Major depressive disorder (MDD) is the second cause of years lived with disability around the world. A large number of studies have been carried out to identify genetic risk factors for MDD and related endophenotypes, mainly in populations of European and Asian descent, with conflicting results. The main aim of the current study was to analyze the possible association of five candidate genes and depressive symptoms in a Colombian sample of healthy subjects. Methods and Materials. The Spanish adaptation of the Hospital Anxiety and Depression Scale (HADS) was applied to one hundred eighty-eight healthy Colombian subjects. Five functional polymorphisms were genotyped using PCR-based assays: BDNF-Val66Met (rs6265), COMT-Val158Met (rs4680), SLC6A4-HTTLPR (rs4795541), MAOA-uVNTR, and SLC6A3-VNTR (rs28363170). Result. We did not find significant associations with scores of depressive symptoms, derived from the HADS, for any of the five candidate genes (nominal p values >0.05). In addition, we did not find evidence of significant gene-gene interactions. Conclusion. This work is one of the first studies of candidate genes for depressive symptoms in a Latin American sample. Study of additional genetic and epigenetic variants, taking into account other pathophysiological theories, will help to identify novel candidates for MDD in populations around the world. PMID:26557993

  3. Pulsed Electromagnetic Fields Increased the Anti-Inflammatory Effect of A2A and A3 Adenosine Receptors in Human T/C-28a2 Chondrocytes and hFOB 1.19 Osteoblasts

    PubMed Central

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Gessi, Stefania; Merighi, Stefania; Setti, Stefania; Cadossi, Ruggero; Goldring, Mary B.; Borea, Pier Andrea; Varani, Katia

    2013-01-01

    Adenosine receptors (ARs) have an important role in the regulation of inflammation and their activation is involved in the inhibition of pro-inflammatory cytokine release. The effects of pulsed electromagnetic fields (PEMFs) on inflammation have been reported and we have demonstrated that PEMFs increased A2A and A3AR density and functionality in different cell lines. Chondrocytes and osteoblasts are two key cell types in the skeletal system that play important role in cartilage and bone metabolism representing an interesting target to study the effect of PEMFs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-inflammatory effect of A2A and/or A3ARs in T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. Immunofluorescence, mRNA analysis and saturation binding assays revealed that PEMF exposure up-regulated A2A and A3AR expression. A2A and A3ARs were able to modulate cAMP production and cell proliferation. The activation of A2A and A3ARs resulted in the decrease of some of the most relevant pro-inflammatory cytokine release such as interleukin (IL)-6 and IL-8, following the treatment with IL-1β as an inflammatory stimuli. In human chondrocyte and osteoblast cell lines, the inhibitory effect of A2A and A3AR stimulation on the release of prostaglandin E2 (PGE2), an important lipid inflammatory mediator, was observed. In addition, in T/C-28a2 cells, the activation of A2A or A3ARs elicited an inhibition of vascular endothelial growth factor (VEGF) secretion. In hFOB 1.19 osteoblasts, PEMF exposure determined an increase of osteoprotegerin (OPG) production. The effect of the A2A or A3AR agonists in the examined cells was enhanced in the presence of PEMFs and completely blocked by using well-known selective antagonists. These results demonstrated that PEMF exposure significantly increase the anti-inflammatory effect of A2A or A3ARs suggesting their potential therapeutic use in the therapy of inflammatory bone and joint disorders

  4. Neurospora crassa mat A-2 and mat A-3 proteins weakly interact in the yeast two-hybrid system and affect yeast growth

    PubMed Central

    2009-01-01

    Mating-type genes control the entry into the sexual cycle, mating identity and sexual development in fungi. The mat A-2 and mat A-3 genes, present in the mat A idiomorph of the filamentous fungus Neurospora crassa, are required for post-fertilization functions but are not essential for mating identity. Their putative roles as transcription factors are based on the similarity of mat A-2 with the Podospora anserina SMR1 gene and an HMG motif present in the mat A-3 gene. In this work the yeast two-hybrid system was used to identify transcriptional activity and protein-protein interaction of N. crassamat A-2 and mat A-3 genes. We observed that the mat A-3 protein alone is capable of weakly activating transcription of yeast reporter genes; it also binds with low specificity to the GAL1 promoter sequence, possibly due to its HMG domain. Our results also indicate that mat A-3 is capable to form homodimers, and interact with mat A-2. Interference on yeast growth was observed on some transformants suggesting a toxic action of the mat A-2 protein. Our data on pattern of interactions of mat proteins contributes towards understanding the control of vegetative and sexual cycles in filamentous fungi. PMID:21637691

  5. Segregation of a 4p16.3 duplication with a characteristic appearance, macrocephaly, speech delay and mild intellectual disability in a 3-generation family.

    PubMed

    Schönewolf-Greulich, Bitten; Ravn, Kirstine; Hamborg-Petersen, Bente; Brøndum-Nielsen, Karen; Tümer, Zeynep

    2013-09-01

    Microscopically visible rearrangements of chromosome 4p includes the two well known abnormalities: partial trisomy 4p, and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR 1 and WHSCR2, respectively), which cause well-defined phenotypes including minor anomalies, and developmental delay/intellectual disability. In contrast small duplications of 4p are rare but with the advent of microarray techniques a few cases have been reported in recent years. Here we describe a 3 Mb duplication at 4p16.3 segregating with a characteristic phenotype, macrocephaly, speech delay and mild intellectual disability in a three generation family. PMID:23894085

  6. Three-dimensional calculations for a 4 kA, 3.5 MV, 2 microsecond injector with asymmetric power feed

    NASA Astrophysics Data System (ADS)

    Hughes, Thomas P.; Clark, Robert E.; Yu, Simon S.

    1999-11-01

    The DARHT-2 accelerator under construction at Los Alamos National Laboratory requires a long flattop (2μs) 2-4 kA, 3.5 MV, low-emittance electron beam source. The injector is being constructed at Lawrence Berkeley National Laboratory and consists of a large-area thermionic cathode mounted atop a vertical column. The 90° bend between the horizontally emitted beam and the column produces dipole and higher-pole fields which must be corrected. In addition, the fast rise of the current flowing into the vacuum tank excites rf modes which cause transverse oscillations of the beam centroid. We have modeled these effects with the 3D electromagnetic code LSP. The code has models for pulsed power transmission lines, space-charge-limited emission and transport of charged particles, externally applied magnetic fields, and frequency-dependent absorption of rf. We calculate the transverse displacement of the beam as a function of time during the current pulse, and the positioning and thickness of ferrite absorber needed to damp the rf modes. The numerical results are compared to analytic calculations.

  7. Adenosine A(1), A(2a), A(2b), and A(3) receptors in hematopoiesis. 2. Expression of receptor mRNA in resting and lipopolysaccharide-activated mouse RAW 264.7 macrophages.

    PubMed

    Streitová, D; Hofer, M; Holá, J; Vacek, A; Pospísil, M

    2010-01-01

    Expression of mRNA for adenosine receptor subtypes A(1), A(2a), A(2b), and A(3) in normal and lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages has been investigated using the method of quantitative real-time polymerase chain reaction. The results have shown a very low, unquantifiable expression of adenosine A(1) receptor mRNA in both normal and LPS-activated macrophages. The other three adenosine receptor mRNAs have been found to be expressed at various but always quantifiable levels. Activation of the macrophages by LPS induced upregulation of the expression of adenosine receptor A(2a) and A(2b) mRNA, whereas the expression of adenosine receptor A(3) mRNA was downregulated. Unstimulated macrophages exhibited a high expression of the A(2b) adenosine receptor mRNA. The findings are discussed from the point of view of the antiinflammatory and hematopoiesis-stimulating roles of the adenosine receptor signaling. PMID:19249906

  8. Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABAA receptors microtransplanted to Xenopus oocytes

    PubMed Central

    Roseti, Cristina; Palma, Eleonora; Martinello, Katiuscia; Fucile, Sergio; Morace, Roberta; Esposito, Vincenzo; Cantore, Gianpaolo; Arcella, Antonietta; Giangaspero, Felice; Aronica, Eleonora; Mascia, Addolorata; Di Gennaro, Giancarlo; Quarato, Pier Paolo; Manfredi, Mario; Cristalli, Gloria; Lambertucci, Catia; Marucci, Gabriella; Volpini, Rosaria; Limatola, Cristina; Eusebi, Fabrizio

    2009-01-01

    We previously found that the endogenous anticonvulsant adenosine, acting through A2A and A3 adenosine receptors (ARs), alters the stability of currents (IGABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of IGABA expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABAA receptors revealed instability, manifested by a large IGABA rundown, which in most of the oocytes (≈70%) was obviously impaired by the new A2A antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A3 receptor antagonist (ANR235) significantly improved IGABA stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered IGABA rundown on ANR94 treatment. Our findings indicate that antagonizing A2A and A3 receptors increases the IGABA stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy. PMID:19721003

  9. A panel of tumor markers, calreticulin, annexin A2, and annexin A3 in upper tract urothelial carcinoma identified by proteomic and immunological analysis

    PubMed Central

    2014-01-01

    Background Upper tract urothelial carcinoma (UTUC) is a tumor with sizable metastases and local recurrence. It has a worse prognosis than bladder cancer. This study was designed to investigate the urinary potential tumor markers of UTUC. Methods Between January 2008 and January 2009, urine was sampled from 13 patients with UTUC and 20 healthy adults. The current study identified biomarkers for UTUC using non-fixed volume stepwise weak anion exchange chromatography for fractionation of urine protein prior to two-dimensional gel electrophoresis. Results Fifty five differential proteins have been determined by comparing with the 2-DE maps of the urine of UTUC patients and those of healthy people. Western blotting analysis and immunohistochemistry of tumor tissues and normal tissues from patients with UTUC were carried out to further verify five possible UTUC biomarkers, including zinc-alpha-2-glycoprotein, calreticulin, annexin A2, annexin A3 and haptoglobin. The data of western blot and immunohistochemical analysis are consistent with the 2-DE data. Combined the experimental data in the urine and in tumor tissues collected from patients with UTUC, the crucial over-expressed proteins are calreticulin, annexin A2, and annexin A3. Conclusions Calreticulin, annexin A2, and annexin A3 are very likely a panel of biomarkers with potential value for UTUC diagnosis. PMID:24884814

  10. Hall Effect Thruster Interactions Data from the Russian Express-A2 and Express-A3 Satellites. Part 5; Acquire Express-A3 SPT?100 Based Propulsion Subsystem and Other Subsystem Flight Operation TM-Data, Task 31

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80deg E. and 11deg W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3-99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  11. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 7; Acquire Express-A3 SPT-100 Based Propulsion Subsystem and Other Subsystem Flight Operation TM-Data, Task 32

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  12. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Acquire Express-A3 SPT 100 Based Propulsion Subsystem and Other Subsystem Flight Operation TM-Data, Task 33

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 deg E and 11 deg W, respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3-99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  13. Frequency of COL4A3/COL4A4 Mutations amongst Families Segregating Glomerular Microscopic Hematuria and Evidence for Activation of the Unfolded Protein Response. Focal and Segmental Glomerulosclerosis Is a Frequent Development during Ageing

    PubMed Central

    Papazachariou, Louiza; Demosthenous, Panayiota; Pieri, Myrtani; Papagregoriou, Gregory; Savva, Isavella; Stavrou, Christoforos; Zavros, Michael; Athanasiou, Yiannis; Ioannou, Kyriakos; Patsias, Charalambos; Panagides, Alexia; Potamitis, Costas; Demetriou, Kyproula; Prikis, Marios; Hadjigavriel, Michael; Kkolou, Maria; Loukaidou, Panayiota; Pastelli, Androulla; Michael, Aristos; Lazarou, Akis; Arsali, Maria; Damianou, Loukas; Goutziamani, Ioanna; Soloukides, Andreas; Yioukas, Lakis; Elia, Avraam; Zouvani, Ioanna; Polycarpou, Polycarpos; Pierides, Alkis; Voskarides, Konstantinos; Deltas, Constantinos

    2014-01-01

    Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. PMID:25514610

  14. Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

    PubMed

    Papazachariou, Louiza; Demosthenous, Panayiota; Pieri, Myrtani; Papagregoriou, Gregory; Savva, Isavella; Stavrou, Christoforos; Zavros, Michael; Athanasiou, Yiannis; Ioannou, Kyriakos; Patsias, Charalambos; Panagides, Alexia; Potamitis, Costas; Demetriou, Kyproula; Prikis, Marios; Hadjigavriel, Michael; Kkolou, Maria; Loukaidou, Panayiota; Pastelli, Androulla; Michael, Aristos; Lazarou, Akis; Arsali, Maria; Damianou, Loukas; Goutziamani, Ioanna; Soloukides, Andreas; Yioukas, Lakis; Elia, Avraam; Zouvani, Ioanna; Polycarpou, Polycarpos; Pierides, Alkis; Voskarides, Konstantinos; Deltas, Constantinos

    2014-01-01

    Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. PMID:25514610

  15. Shear stress–induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region

    PubMed Central

    Chen, Junmei; Gallagher, Ryan; Zheng, Ying; Chung, Dominic W.

    2011-01-01

    VWF is required for platelet adhesion to sites of vessel injury, a process vital for both hemostasis and thrombosis. Enhanced VWF secretion and oxidative stress are both hallmarks of inflammation. We recently showed that the neutrophil oxidant hypochlorous acid (HOCl) inhibits VWF proteolysis by ADAMTS13 by oxidizing VWF methionine 1606 (M1606) in the A2 domain. M1606 was readily oxidized in a substrate peptide, but required urea in multimeric plasma VWF. In the present study, we examined whether shear stress enhances VWF oxidation. With an HOCl-generating system containing myeloperoxidase (MPO) and H2O2, we found that shear stress accelerated M1606 oxidation, with 56% becoming oxidized within 1 hour. Seven other methionine residues in the VWF A1A2A3 region (containing the sites for platelet and collagen binding and ADAMTS13 cleavage) were variably oxidized, one completely. Oxidized methionines accumulated preferentially in the largest VWF multimers. HOCl-oxidized VWF was hyperfunctional, agglutinating platelets at ristocetin concentrations that induced minimal agglutination using unoxidized VWF and binding more of the nanobody AU/VWFa-11, which detects a gain-of-function conformation of the A1 domain. These findings suggest that neutrophil oxidants will both render newly secreted VWF uncleavable and alter the largest plasma VWF forms such that they become hyperfunctional and resistant to proteolysis by ADAMTS13. PMID:21917758

  16. Transpedicular vertebral body augmentation reinforced with pedicle screw fixation in fresh traumatic A2 and A3 lumbar fractures: comparison between two devices and two bone cements.

    PubMed

    Korovessis, Panagiotis; Vardakastanis, Konstantinos; Repantis, Thomas; Vitsas, Vasilios

    2014-07-01

    This retrospective study compares efficacy and safety of balloon kyphoplasty (BK) with calcium phosphate (Group A) versus KIVA implant with PMMA (Group B) reinforced with three vertebrae pedicle screw constructs for A2 and A3 single fresh non-osteoporotic lumbar (L1-L4) fractures in 38 consecutive age- and diagnosis-matched patient populations. Extracanal leakage of both low-viscosity PMMA and calcium phosphate (CP) as well as the following roentgenographic parameters: segmental kyphosis (SKA), anterior (AVBHr) and posterior (PVBHr) vertebral body height ratio, spinal canal encroachment (SCE) clearance, and functional outcome measures: VAS and SF-36, were recorded and compared between the two groups. All patients in both groups were followed for a minimum 26 (Group A) and 25 (Group B) months. Extracanal CP and PMMA leakage was observed in four (18 %) and three (15 %) vertebrae/patients of group A and B, respectively. Hybrid fixation improved AVBHr, SKA, SCE, but PVBHr only in group B. VAS and SF-36 improved postoperatively in the patients of both groups. Short-segment construct with the novel KIVA implant restored better than BK-fractured lumbar vertebral body, but this had no impact in functional outcome. Since there was no leakage difference between PMMA and calcium phosphate and no short-term adverse related to PMMA use were observed, we advice the use of PMMA in fresh traumatic lumbar fractures. PMID:23982115

  17. Comparative membrane interaction study of viscotoxins A3, A2 and B from mistletoe (Viscum album) and connections with their structures.

    PubMed Central

    Coulon, Alexandre; Mosbah, Amor; Lopez, André; Sautereau, Anne-Marie; Schaller, Gerhard; Urech, Konrad; Rougé, Pierre; Darbon, Hervé

    2003-01-01

    Viscotoxins A2 (VA2) and B (VB) are, together with viscotoxin A3 (VA3), among the most abundant viscotoxin isoforms that occur in mistletoe-derived medicines used in anti-cancer therapy. Although these isoforms have a high degree of amino-acid-sequence similarity, they are strikingly different from each other in their in vitro cytotoxic potency towards tumour cells. First, as VA3 is the only viscotoxin whose three-dimensional (3D) structure has been solved to date, we report the NMR determination of the 3D structures of VA2 and VB. Secondly, to account for the in vitro cytotoxicity discrepancy, we carried out a comparative study of the interaction of the three viscotoxins with model membranes. Although the overall 3D structure is highly conserved among the three isoforms, some discrete structural features and associated surface properties readily account for the different affinity and perturbation of model membranes. VA3 and VA2 interact in a similar way, but the weaker hydrophobic character of VA2 is thought to be mainly responsible for the apparent different affinity towards membranes. VB is much less active than the other two viscotoxins and does not insert into model membranes. This could be related to the occurrence of a single residue (Arg25) protruding outside the hydrophobic plane formed by the two amphipathic alpha-helices, through which viscotoxins are supposed to interact with plasma membranes. PMID:12733989

  18. Synthesis, spectroscopic, and cellular properties of α-pegylated cis-A2B2- and A3B-types ZnPcs

    PubMed Central

    Ongarora, Benson G.; Zhou, Zehua; Okoth, Elizabeth A.; Kolesnichenko, Igor; Smith, Kevin M.; Vicente, M. Graça H.

    2015-01-01

    A series of pegylated cis-A2B2- or A3B-type ZnPcs, substituted on the α-positions with tri(ethylene glycol) and hydroxyl groups, were synthesized from a new bis-phthalonitrile. A clamshell-type bis-phthalocyanine was also obtained as a byproduct. The hydroxyl group of one ZnPc was alkylated with 3-dimethylaminopropyl chloride to afford a pegylated ZnPc functionalized with an amine group. All mononuclear ZnPcs were soluble in polar organic solvents, showed intense Q absorptions in DMF, and had fluorescence quantum yields in the range 0.10–0.23. The clamshell-type bis-phthalocyanine adopts mainly open shell conformations in DMF, and closed clamshell conformations in chloroform. All ZnPcs were highly phototoxic to human carcinoma HEp2 cells, particularly the amino-ZnPc mainly protonated under physiological conditions, which showed the highest phototoxicity (IC50 = 0.5 μM at 1.5 J/cm2) and dark cytotoxicity (IC50 = 22 μM), in part due to its high cellular uptake. The ZnPcs localized in multiple organelles, including mitochondria, lysosomes, Golgi and ER. PMID:26064037

  19. Identification and Quantification of Fumonisin A1, A2, and A3 in Corn by High-Resolution Liquid Chromatography-Orbitrap Mass Spectrometry

    PubMed Central

    Tamura, Masayoshi; Mochizuki, Naoki; Nagatomi, Yasushi; Harayama, Koichi; Toriba, Akira; Hayakawa, Kazuichi

    2015-01-01

    Three compounds, hypothesized as fumonisin A1 (FA1), fumonisin A2 (FA2), and fumonisin A3 (FA3), were detected in a corn sample contaminated with mycotoxins by high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS). One of them has been identified as FA1 synthesized by the acetylation of fumonisin B1 (FB1), and established a method for its quantification. Herein, we identified the two remaining compounds as FA2 and FA3, which were acetylated fumonisin B2 (FB2) and fumonisin B3 (FB3), respectively. Moreover, we examined a method for the simultaneous analysis of FA1, FA2, FA3, FB1, FB2, and FB3. The corn samples were prepared by extraction using a QuEChERS kit and purification using a multifunctional cartridge. The linearity, recovery, repeatability, limit of detection, and limit of quantification of the method were >0.99, 82.9%–104.6%, 3.7%–9.5%, 0.02–0.60 μg/kg, and 0.05–1.98 μg/kg, respectively. The simultaneous analysis of the six fumonisins revealed that FA1, FA2, and FA3 were present in all corn samples contaminated with FB1, FB2, and FB3. The results suggested that corn marketed for consumption can be considered as being contaminated with both the fumonisin B-series and with fumonisin A-series. This report presents the first identification and quantification of FA1, FA2, and FA3 in corn samples. PMID:25690692

  20. Detection of cfxA2, cfxA3, and cfxA6 genes in beta-lactamase producing oral anaerobes

    PubMed Central

    BINTA, Buhle; PATEL, Mrudula

    2016-01-01

    ABSTRACT Purpose The aim of this study was to identify β-lactamase-producing oral anaerobic bacteria and screen them for the presence of cfxA and BlaTEM genes that are responsible for β-lactamase production and resistance to β-lactam antibiotics. Material and Methods Periodontal pocket debris samples were collected from 48 patients with chronic periodontitis and anaerobically cultured on blood agar plates with and without β-lactam antibiotics. Presumptive β-lactamase-producing isolates were evaluated for definite β-lactamase production using the nitrocefin slide method and identified using the API Rapid 32A system. Antimicrobial susceptibility was performed using disc diffusion and microbroth dilution tests as described by CLSI Methods. Isolates were screened for the presence of the β-lactamase-TEM (BlaTEM) and β-lactamase-cfxA genes using Polymerase Chain Reaction (PCR). Amplified PCR products were sequenced and the cfxA gene was characterized using Genbank databases. Results Seventy five percent of patients carried two species of β-lactamase-producing anaerobic bacteria that comprised 9.4% of the total number of cultivable bacteria. Fifty one percent of β-lactamase-producing strains mainly Prevotella, Porphyromonas, and Bacteroides carried the cfxA gene, whereas none of them carried blaTEM. Further characterization of the cfxA gene showed that 76.7% of these strains carried the cfxA2 gene, 14% carried cfxA3, and 9.3% carried cfxA6. The cfxA6 gene was present in three Prevotella spp. and in one Porphyromonas spp. Strains containing cfxA genes (56%) were resistant to the β-lactam antibiotics. Conclusion This study indicates that there is a high prevalence of the cfxA gene in β-lactamase-producing anaerobic oral bacteria, which may lead to drug resistance and treatment failure. PMID:27119762

  1. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

    PubMed Central

    Bethke, Lara; Webb, Emily; Sellick, Gabrielle; Rudd, Matthew; Penegar, Stephen; Withey, Laura; Qureshi, Mobshra; Houlston, Richard

    2007-01-01

    Background Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. Methods To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. Results There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03–1.80 and OR = 1.34, 95% CI: 1.00–1.79 respectively). Conclusion This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility. PMID:17615053

  2. PROCEEDINGS: 1991 INTERNATIONAL CONFERENCE ON MUNICIPAL WASTE COMBUSTION - VOLUME 1. SESSIONS P, 0, 1A, 2A, 3A, 4A, 6A, 6B, 9C, AND 10B

    EPA Science Inventory

    The three-volumes document 82 presentations by authors from 15 countries at the Second International Conference on Municipal Waste Combustion (MWC) in Tampa, Florida, April 16-19, 1991. The Conference fostered the exchange of current information on research concerning MWC, ash di...

  3. Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel.

    PubMed

    Shia, Jinru; Tang, Laura H; Vakiani, Efsevia; Guillem, Jose G; Stadler, Zsofia K; Soslow, Robert A; Katabi, Nora; Weiser, Martin R; Paty, Philip B; Temple, Larissa K; Nash, Garrett M; Wong, W Douglas; Offit, Kenneth; Klimstra, David S

    2009-11-01

    The utility of immunohistochemical detection of DNA mismatch repair proteins in screening colorectal cancer for hereditary nonpolyposis colorectal cancer (HNPCC) is being widely investigated. Currently, in both research and clinical settings, a 4-antibody panel that includes the 4 most commonly affected proteins (MLH1, MSH2, MSH6, and PMS2) is being used generally. On the basis of the biochemical properties of these proteins, we hypothesized that a 2-antibody panel, comprising MSH6 and PMS2, would be sufficient to detect abnormalities in all 4 proteins. We tested this hypothesis on a series of 232 colorectal carcinoma samples derived from 2 patient cohorts: (1) a prospectively accrued series of patients who were judged to carry a higher-than-average risk for HNPCC based on the revised Bethesda guidelines (n=190); and (2) a retrospective series of patients who were 40 years of age or younger (n=42). Immunohistochemical stains were regarded as negative (protein lost), when there was no nuclear labeling in tumor cells (with positive internal control). Overall, 70 of the 232 tumors demonstrated loss of at least one protein. The most common abnormality was concurrent loss of MLH1 and PMS2 (observed in 17% of the cases), followed by concurrent loss of MSH2 and MSH6 (6%). All MLH1 and MSH2-abnormal cases were also abnormal for PMS2 and MSH6, respectively, whereas 9 of 50 (18%) PMS2 and 6 of 20 (30%) MSH6-abnormal cases showed only isolated loss of PMS2 or MSH6 (with normal staining for MLH1 and MSH2). As such, our findings provide evidence that a 2-antibody panel (PMS2 and MSH6) is as effective as the current 4-antibody panel in detecting DNA mismatch repair protein abnormalities. Such a cost-effective approach carries significant implication, as immunohistochemistry is being widely used as first-line screening for HNPCC. PMID:19701074

  4. Less invasive reduction and fusion of fresh A2 and A 3 traumatic L 1-L 4 fractures with a novel vertebral body augmentation implant and short pedicle screw fixation and fusion.

    PubMed

    Korovessis, Panagiotis; Vardakastanis, Konstantinos; Repantis, Thomas; Vitsas, Vasilios

    2014-04-01

    The aim of this clinical study was to report on the efficacy in reduction and safety in PMMA leakage of a novel vertebral augmentation technique with PEEK and PMMA, together with pedicle screws in the treatment of fresh vertebral fractures in young adults. Twenty consecutive young adults aged 45 ± 11 years with fresh burst A3/AO or severely compressed A2/AO fractures underwent via a less invasive posterior approach one-staged reduction with a novel augmentation implant and PMMA plus 3-vertebrae pedicle screw fixation and fusion. Radiologic parameters as segmental kyphosis (SKA), anterior (AVBHr) and posterior vertebral body height ratio (PVBHr), spinal canal encroachment (SCE), cement leakage and functional parameters as VAS, SF-36 were measured pre- and post-operatively. Hybrid construct restored AVBHr (P < 0.000), PVBHr (P = 0.02), SKA (P = 0.015), SCE (P = 0.002) without loss of correction at an average follow-up of 17 months. PMMA leakage occurred in 3 patients (3 vertebrae) either anteriorly to the fractured vertebral body or to the adjacent disc, but in no case to the spinal canal. Two pedicle screws were malpositioned (one medially, one laterally to the pedicle at the fracture level) without neurologic sequelae. Solid posterolateral spinal fusion occurred 8-10 months post-operatively. Pre-operative VAS and SF-36 scores improved post-operatively significantly. This study showed that this novel vertebral augmentation technique using PEEK implant and PMMA reduces and stabilizes via less invasive technique A2 and A3 vertebral fractures without loss of correction and leakage to the spinal canal. PMID:24170266

  5. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 3; Acquire Express-A3 SPT-100 Based Propulsion Subsystem and Other Subsystem Flight Operation TM-Data for the Period of June 24, 2000 to and Including September 30, 2000, Task 30

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  6. 7 CFR 1a.4 - Limitations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Limitations. 1a.4 Section 1a.4 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.4 Limitations. The powers granted by §§ 1a.2(a) and 1a.2(b) shall be exercised only when a designated official is engaged in an...

  7. 7 CFR 1a.4 - Limitations.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Limitations. 1a.4 Section 1a.4 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.4 Limitations. The powers granted by §§ 1a.2(a) and 1a.2(b) shall be exercised only when a designated official is engaged in an...

  8. Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration

    PubMed Central

    Koszałka, Patrycja; Gołuńska, Monika; Urban, Aleksandra; Stasiłojć, Grzegorz; Stanisławowski, Marcin; Majewski, Marceli; Składanowski, Andrzej C.; Bigda, Jacek

    2016-01-01

    CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine α,β-methylene 5’-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in

  9. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Acquire Express-A2 SPT-100 Based Propulsion Subsystem and Other Subsystem Flight Operation TM-Data for the Period of March 12, 2000 to and Including June 15, 2000, Task 29

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney s Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  10. Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies.

    PubMed

    Butterfield, Russell J; Foley, A Reghan; Dastgir, Jahannaz; Asman, Stephanie; Dunn, Diane M; Zou, Yaqun; Hu, Ying; Donkervoort, Sandra; Flanigan, Kevin M; Swoboda, Kathryn J; Winder, Thomas L; Weiss, Robert B; Bönnemann, Carsten G

    2013-11-01

    Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. PMID:24038877

  11. Thermally-induced single-crystal-to-single-crystal transformations from a 2D two-fold interpenetrating square lattice layer to a 3D four-fold interpenetrating diamond framework and its application in dye-sensitized solar cells.

    PubMed

    Gao, Song; Fan, Rui Qing; Wang, Xin Ming; Wei, Li Guo; Song, Yang; Du, Xi; Xing, Kai; Wang, Ping; Yang, Yu Lin

    2016-07-28

    In this work, a rare 2D → 3D single-crystal-to-single-crystal transformation (SCSC) is observed in metal-organic coordination complexes, which is triggered by thermal treatment. The 2D two-fold interpenetrating square lattice layer [Cd(IBA)2]n (1) is irreversibly converted into a 3D four-fold interpenetrating diamond framework {[Cd(IBA)2(H2O)]·2.5H2O}n (2) (HIBA = 4-(1H-imidazol-1-yl)benzoic acid). Consideration is given to these two complexes with different interpenetrating structures and dimensionality, and their influence on photovoltaic properties are studied. Encouraged by the UV-visible absorption and HOMO-LUMO energy states matched for sensitizing TiO2, the two complexes are employed in combination with N719 in dye-sensitized solar cells (DSSCs) to compensate absorption in the ultraviolet and blue-violet region, offset competitive visible light absorption of I3(-) and reducing charge the recombination of injected electrons. After co-sensitization with 1 and 2, the device co-sensitized by 1/N719 and 2/N719 to yield overall efficiencies of 7.82% and 8.39%, which are 19.94% and 28.68% higher than that of the device sensitized only by N719 (6.52%). Consequently, high dimensional interpenetrating complexes could serve as excellent co-sensitizers and have application in DSSCs. PMID:27356177

  12. Survey and Interpretation Geophysical of Magnetic Isochrones 4n.2 a 2A.3 (7.9 3.6 Ma) in the Central Part of the Rivera Plate

    NASA Astrophysics Data System (ADS)

    Perez, D. A.; Mortera-Gutierrez, C. A.; Bandy, W. L.; Valle, S.

    2013-05-01

    This study shows the results of six campaigns marine geophysics BABRIP06 in 2006, MAMRIV07 in 2007, MAMRIV08 in 2008, GUAYRIV10 in 2010, BATIBAJA11 in 2011 and MAMRIV12 in 2012, in the abyssal plain in the East Pacific Rise (EPR), on board the UNAM vessel, B/O El Puma. The oceanographic campaigns single beam bathymetric data collected and marine magnetic data. The results allow analyze and study the magnetic texture in the central north of the Rivera plate associated with geological structures and behavior of the seafloor to the isochronous 5A. The systematic survey of the magnetic data provided high resolution on the guidelines of the magnetic anomalies associated with cortical spreading between 7.9 and 3.6 Ma, generated by the northern segment of the East Pacific Rise (EPR), between the Rivera and Tamayo Oceanic Transformants. Multibeam bathymetry data and the acoustic reflectivity of the six campaigns are correlated with the geometry of the magnetic anomalies and seismic reflection profiles to understand the processes that formed the highlight recreational ocean in this area. The main results in this study is the identification of continuous magnetic isochrones 4n.2 to 2A.3, magnetic anomalies associated with seamounts, the geometry of the isochrones associated with a propagator and magnetic anomaly identification of isochronous 3n.3 had not been demonstrated by other oceanographic surveys. Possibly oceanic spreading rate was slower during these epochs and the identification of a cross anomaly was due to a fracture zone that generated the propagator.

  13. Genetic variation in the 3′-UTR of CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7: potential effects on regulation by microRNA and pharmacogenomics relevance

    PubMed Central

    Swart, Marelize; Dandara, Collet

    2014-01-01

    Introduction: Pharmacogenomics research has concentrated on variation in genes coding for drug metabolizing enzymes, transporters and nuclear receptors. However, variation affecting microRNA could also play a role in drug response. This project set out to investigate potential microRNA target sites in 11 genes and the extent of variation in the 3′-UTR of six selected genes; CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7. Methods: Fifteen microRNA target prediction algorithms were used to identify microRNAs predicted to regulate 11 genes. The 3′-UTR of the 6 genes which topped the list of potential microRNA targets was sequenced in 30 black South Africans. In addition, genetic variants within these genes were investigated for interference with mRNA-microRNA interactions. Potential effects of observed variants were determined using in silico prediction tools. Results: The 11 genes coding for DMEs, transporters and nuclear receptors were predicted to be targets of microRNAs with CYP2B6, NR1I2 (PXR), CYP3A4, and CYP1A2, interacting with the most microRNAs. The majority of identified genetic variants were predicted to interfere with microRNA regulation. For example, the variant, rs1054190C in NR1I2 was predicted to result in the presence of a binding site for the microRNA miR-1250-5p, while the variant rs1054191G was predicted to result in the absence of a recognition site for miR-371b-3p, miR-4258 and miR-4707-3p. Fifteen of the seventeen, novel variants occurred within microRNA target sequences. Conclusion: The 3′-UTR harbors variation that is likely to influence regulation of specific genes by microRNA. In silico prediction followed by functional validation could aid in decoding the contribution of variation in the 3′-UTR, to some unexplained heritability that affects drug response. Understanding the specific role of each microRNA may lead to identification of markers for targeted therapy and therefore improve personalized drug treatment. PMID:24926315

  14. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 2; Acquire TM Date for Type B Sensors for "Express-A" Number 2 Satellite for the Period of March 12, 2000 to and Including June 15, 2000, Task 25

    NASA Technical Reports Server (NTRS)

    Dunning, John (Technical Monitor); Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  15. Hall Effect Thruster Interactions Data from the Russian Express-A2 and Express-A3 Satellites. Part 8; Acquire TM-Data for Type A and Type B Sensors for "Express A" Number 3 Satellite for the Period of January 1, 2001 to and Including March 31, 2001, Task 27C

    NASA Technical Reports Server (NTRS)

    Dunning, John (Technical Monitor); Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80deg E. and 11deg W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  16. Hall Effect Thruster Interactions Data from the Russian Express-A2 and Express-A3 Satellites. Part 4; Acquire TM-Data for Type A and Type B Sensors for "Express-A" Number 3 Satellite, Task 27A

    NASA Technical Reports Server (NTRS)

    Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80deg E., and 11deg W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3-99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  17. Hall Effect Thruster Interactions Data From the Russian Express-A2 and Express-A3 Satellites. Part 10; Acquire TM-Data for Type A and Type B Sensors for "Express-A" Number 3 Satellite for the Period of July 1, 2001 to and Including September 30, 2001, Task 27D

    NASA Technical Reports Server (NTRS)

    Dunning, John (Technical Monitor); Sitnikova, N.; Volkov, D.; Maximov, I.; Petrusevich, V.; Allen, D.

    2003-01-01

    This 12-part report documents the data obtained from various sensor measurements taken aboard the Russian Express-A2 and Express-A3 spacecraft in Geosynchronous Earth Orbit (GEO). These GEO communications satellites, which were designed and built by NPO Prikladnoy Mekhaniki (NPO PM) of Zheleznogorsk, Russia, utilize Hall thruster propulsion systems for north-south and east-west stationkeeping and as of June 2002, were still operating at 80 E. and 11 W., respectively. Express-A2 was launched on March 12, 2000, while Express-A3 was launched on June 24, 2000. The diagnostic equipment from which these data were taken includes electric field strength sensors, ion current and energy sensors, and pressure sensors. The diagnostics and the Hall thruster propulsion systems are described in detail along with lists of tabular data from those diagnostics and propulsion system and other satellite systems. Space Power, Inc., now part of Pratt & Whitney's Chemical Systems Division, under contract NAS3 99151 to the NASA Glenn Research Center, obtained these data over several periods from March 12, 2000, through September 30, 2001. Each of the 12 individual reports describe, in detail, the propulsion systems as well as the diagnostic sensors utilized. Finally, parts 11 and 12 include the requirements to which NPO PM prepared and delivered these data.

  18. A-3 Groundbreaking Ceremony

    NASA Technical Reports Server (NTRS)

    2007-01-01

    NASA officials and government leaders participated in a groundbreaking event for a new rocket engine test stand at NASA's Stennis Space Center, Miss. Pictured (left to right) are Deputy Associate Administrator for Exploration Systems Doug Cooke, Pratt & Whitney Rocketdyne President Jim Maser, Stennis Space Center Director Richard Gilbrech, NASA Associate Administrator for Exploration Systems Scott Horowitz, NASA Deputy Administrator Shana Dale, Mississippi Gov. Haley Barbour, Sen. Thad Cochran, Sen. Trent Lott, Rep. Gene Taylor, SSC's Deputy Director Gene Goldman, and SSC's A-3 Project Manager Lonnie Dutreix. Stennis' A-3 Test Stand will provide altitude testing for NASA's developing J-2X engine. That engine will power the upper stages of NASA's Ares I and Ares V rockets. A-3 is the first large test stand to be built at SSC since the site's inception in the 1960s.

  19. A-3 Construction

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Workers erect the first beams of structural steel for the 235-foot tall A-3 Test Stand on Oct. 29, 2008. Ground work for the stand was broken in August 2008 and the final structural steel beam was placed on April 9, 2009.

  20. New triterpene constituents, foliasalacins A(1)-A(4), B(1)-B(3), and C, from the leaves of Salacia chinensis.

    PubMed

    Yoshikawa, Masayuki; Zhang, Yi; Wang, Tao; Nakamura, Seikou; Matsuda, Hisashi

    2008-07-01

    Four dammarane-type, three lupane-type, and an oleanane-type triterpenes named foliasalacins A(1) (1), A(2) (2), A(3) (3), A(4) (4), B(1) (5), B(2) (6), B(3) (7), and C (8) were isolated from the leaves of Salacia chinensis LINN. collected in Thailand. The structures of new triterpene constituents (1-8) were characterized on the basis of chemical and physiochemical evidence. PMID:18591801

  1. 7 CFR 1a.2 - Authorization.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Authorization. 1a.2 Section 1a.2 Agriculture Office of the Secretary of Agriculture LAW ENFORCEMENT AUTHORITIES § 1a.2 Authorization. Any official of the Office of Inspector General who is designated by the Inspector General according to §§ 1a.3 and 1a.5...

  2. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 4 2014-01-01 2014-01-01 false Fees. 261a.4 Section 261a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM (CONTINUED) RULES REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a) Copies of records. We will provide you...

  3. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority to originally classify information as Secret...

  4. 32 CFR 169a.4 - Policy.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Policy. 169a.4 Section 169a.4 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING COMMERCIAL ACTIVITIES PROGRAM PROCEDURES General § 169a.4 Policy. (a) Ensure DoD mission accomplishment. The implementation of this part shall consider the overall...

  5. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  6. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  7. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  8. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  9. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  10. 38 CFR 8a.4 - Coverage.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Coverage. 8a.4 Section 8a.4 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE INSURANCE § 8a.4 Coverage. (a) The amount of VMLI in force on his or her life at any one time shall...

  11. 15 CFR 4a.4 - Classification authority.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Classification authority. 4a.4 Section 4a.4 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.4 Classification authority. Authority...

  12. 7 CFR 15a.4 - Assurance required.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Assurance required. 15a.4 Section 15a.4 Agriculture... FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.4 Assurance required. (a) General. Every application for... contain or be accompanied by an assurance from the applicant or recipient, satisfactory to the...

  13. 12 CFR 269a.4 - Investigator.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Investigator. 269a.4 Section 269a.4 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM DEFINITIONS § 269a.4 Investigator. The term investigator means the officer designated by the panel to investigate...

  14. 29 CFR 1912a.4 - Meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 7 2010-07-01 2010-07-01 false Meetings. 1912a.4 Section 1912a.4 Labor Regulations...) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.4 Meetings. (a) The Committee shall hold no fewer than two meetings during each calendar year and, it is contemplated that no more than...

  15. 32 CFR 383a.4 - Organization.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Organization. 383a.4 Section 383a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.4 Organization. (a) The DeCA is established as an...

  16. Structure–Activity Relationships of N6-Benzyladenosine-5′-uronamides as A3-Selective Adenosine Agonists†

    PubMed Central

    Gallo-Rodriguez, Carola; Ji, Xiao-duo; Melman, Neli; Siegman, Barry D.; Sanders, Lawrence H.; Orlina, Jeraldine; Fischer, Bilha; Pu, Quanlong; Olah, Mark E.; van Galen, Philip J. M.; Stiles, Gary L.; Jacobson, Kenneth A.

    2015-01-01

    Adenosine analogues modified at the 5′-position as uronamides and/or as N6-benzyl derivatives were synthesized. These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A3 adenosine receptor and at rat brain A1 and A2a receptors. 5′-Uronamide substituents favored A3 selectivity in the order N-methyl > N-ethyl ∞ unsubstituted carboxamide > N-cyclopropyl. 5′-(N-Methylcarboxamido)-N6-benzyladenosine was 37–56-fold more selective for A3 receptors. Potency at A3 receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5′-N-Methyluronamides and N6-(3-substituted-benzyl)adenosines are optimal for potency and selectivity at A3 receptors. A series of 3-(halobenzyl)-5′-N-ethyluronamide derivatives showed the order of potency at A1 and A2a receptors of I ~ Br > Cl > F. At A3 receptors the 3-F derivative was weaker than the other halo derivatives. 5′-N-Methyl-N6-(3-iodobenzyl)adenosine displayed a Ki value of 1.1 nM at A3 receptors and selectivity versus A1 and A2a receptors of 50-fold. A series of methoxybenzyl derivatives showed that a 4-methoxy group best favored A3 selectivity. A 4-sulfobenzyl derivative was a specific ligand at A3 receptors of moderate potency. An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking. PMID:8126704

  17. A3 Altitude Test Facility

    NASA Technical Reports Server (NTRS)

    Dulreix, Lionel J.

    2009-01-01

    This slide presentation shows drawings, diagrams and photographs of the A3 Altitude Test Facility. It includes a review of the A3 Facility requirements, and drawings of the various sections of the facility including Engine Deck and Superstructure, Test Cell and Thrust Takeout, Structure and Altitude Support Systems, Chemical Steam generators, and the subscale diffuser. There are also pictures of the construction site, and the facility under construction. A Diagram of the A3 Steam system schematic is also shown

  18. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... TO PERSONAL INFORMATION UNDER THE PRIVACY ACT OF 1974 General Provisions § 261a.4 Fees. (a) Copies of... charged for duplication of records and/or production of computer output under the Board's Rules...

  19. A-3 Construction Time Lapse

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A time lapse from start to finish of steel erection for the 235-foot tall A-3 Test Stand. Ground work for the stand was broken in August 2008 and the final structural steel beam was placed April 9, 2009.

  20. A-3 First Tree Cutting

    NASA Technical Reports Server (NTRS)

    2007-01-01

    Tree clearing for the site of the new A-3 Test Stand at Stennis Space center began June 13. NASA's first new large rocket engine test stand to be built since the site's inception, A-3 construction begins a historic era for America's largest rocket engine test complex. The 300-foot-tall structure is scheduled for completion in August 2010. A-3 will perform altitude tests on the Constellation's J-2X engine that will power the upper stage of the Ares I crew launch vehicle and earth departure stage of the Ares V cargo launch vehicle. The Constellation Program, NASA's plan for carrying out the nation's Vision for Space Exploration, will return humans to the moon and eventually carry them to Mars and beyond.

  1. 26 CFR 1.401(a)-4 - Optional forms of benefit (before 1994).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... forth in section 410(b)(2)(A)(i). The employer need not satisfy the average benefit percentage test in...) Elimination of optional forms—(A) In general. Notwithstanding paragraphs (a)(2)(i) and (a)(2)(ii) of this Q&A...). (3) Effective availability—(i) In general. The requirement of this paragraph (a)(3) is satisfied...

  2. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... at the same cost we charge for duplication of records and/or production of computer output under the Board's Rules Regarding Availability of Information, 12 CFR Part 261. (b) No fee. We will not charge you... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees....

  3. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... at the same cost we charge for duplication of records and/or production of computer output under the Board's Rules Regarding Availability of Information, 12 CFR Part 261. (b) No fee. We will not charge you... REGARDING ACCESS TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees....

  4. 12 CFR 261a.4 - Fees.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... same cost we charge for duplication of records and/or production of computer output under the Board's Rules Regarding Availability of Information, 12 CFR part 261. (b) No fee. We will not charge you a fee... TO PERSONAL INFORMATION UNDER THE PRIVACY ACT 1974 General Provisions § 261a.4 Fees. (a) Copies...

  5. 45 CFR 12a.4 - Suitability determination.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... PROPERTY TO ASSIST THE HOMELESS § 12a.4 Suitability determination. (a) Suitability determination. Within 30... § 12a.6, which properties are suitable for use as facilities to assist the homeless and report its... use as a facility to assist the homeless without regard to any particular use. (c)...

  6. A-3 steel work completed

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Stennis Space Center engineers celebrated a key milestone in construction of the A-3 Test Stand on April 9 - completion of structural steel work. Workers with Lafayette (La.) Steel Erector Inc. placed the last structural steel beam atop the stand during a noon ceremony attended by more than 100 workers and guests.

  7. Vessels installed at A-3

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Construction of the A-3 Test Stand approaches another milestone with delivery and installation of water, isopropyl alcohol (IPA) and liquid oxygen (LOX) tanks. The three LOX tanks shown on the left and the two IPA tanks shown on the right are all 35,000 gallons each. The four water tanks in the center are 39,000 gallons each.

  8. 26 CFR 1.401(a)(4)-1 - Nondiscrimination requirements of section 401(a)(4).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...)(iv) that fail to satisfy the allocation and compensation requirements of § 1.401(k)-2(a)(4)(i... to section 403(b)(12)(A)(i), references in §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 to satisfying... “1.401(k)-2(a)(5)(i)”. However, because of inaccurate amendatory language, this amendment could...

  9. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., 1972, partnership ABC, which makes its returns on the basis of a calendar year, employed WIN employees. Partnership ABC incurred WIN expenses with respect to these employees of $20,000 for the taxable year. Partnership ABC has 10 partners who make their returns on the basis of a calendar year and share...

  10. 26 CFR 1.50A-4 - Exceptions to the application of § 1.50A-3.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... a trade or business) applies. (b) Voluntary termination of employment. A termination of employment... the WIN employees. (g) Mere change in form of conducting a trade or business—(1) General rule. (i) The... in the form of conducting the trade or business in which such employment occurs, provided that...

  11. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... eliminate the effects of: (i) Any depletion with respect to an oil or gas property (other than a gas... royalty or other interest in oil, gas, or other mineral representing any percentage depletion allowance to... assets of which were oil properties was $1,000. The trust's allowable percentage depletion pursuant...

  12. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... eliminate the effects of: (i) Any depletion with respect to an oil or gas property (other than a gas... royalty or other interest in oil, gas, or other mineral representing any percentage depletion allowance to... assets of which were oil properties was $1,000. The trust's allowable percentage depletion pursuant...

  13. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... eliminate the effects of: (i) Any depletion with respect to an oil or gas property (other than a gas... royalty or other interest in oil, gas, or other mineral representing any percentage depletion allowance to... assets of which were oil properties was $1,000. The trust's allowable percentage depletion pursuant...

  14. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... year from A's retail outlets and Corporation M has gross receipts of $4 million from sales of oil for... an operator of a retail outlet merely because C's oil and gas is sold on C's behalf through a retail... retail outlet which sells oil and gas. H, wife, owns producing oil and gas properties. G is not...

  15. 26 CFR 1.613A-4 - Limitations on application of § 1.613A-3 exemption.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... year from A's retail outlets and Corporation M has gross receipts of $4 million from sales of oil for... an operator of a retail outlet merely because C's oil and gas is sold on C's behalf through a retail... retail outlet which sells oil and gas. H, wife, owns producing oil and gas properties. G is not...

  16. Data on the epitope mapping of soybean A2 and A3 glycinin.

    PubMed

    Saeed, Hanaa; Gagnon, Christine; Cober, Elroy; Gleddie, Steve

    2016-09-01

    The data information provided in this article relate to our research article "Using patient serum to epitope map soybean glycinins reveals common epitopes shared with many legumes and tree nuts" (Saeed et al., 2016) [1]. Here we provide western blot detection of glycinin subunits by soy-sensitive human sera, ELISA screens with overlapping synthetic peptides (epitope mapping), and various database/server epitope searches. PMID:27294180

  17. A-3 scientific results - extragalactic

    NASA Technical Reports Server (NTRS)

    Schwartz, D. A.

    1979-01-01

    The results of the HEAO A-3 experiment are summarized. Specific contributions of the experiment to extragalactic astronomy are emphasized. The discovery of relatively condensed X-ray emission in the cores of those clusters of galaxies which are dominated by a giant elliptical or cD galaxy, the discovery of extended X-ray emitting plasma in groups of galaxies, and the demonstration that BL Lac objects are a class of X-ray sources are among the topics discussed.

  18. 26 CFR 1.401(a)(4)-1 - Nondiscrimination requirements of section 401(a)(4).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) includes a safe-harbor testing method for contributions provided under a target benefit plan. (B) Section...)(iv) that fail to satisfy the allocation and compensation requirements of § 1.401(k)-2(a)(4)(i), matching contributions that fail to satisfy § 1.401(m)-2(a)(4)(iii), and qualified...

  19. Simulating a 4-effect absorption chiller

    SciTech Connect

    Grossman, G.; Zaltash, A.; Adcock, P.W.; DeVault, R.C.

    1995-06-01

    Absorption chillers are heat-operated refrigeration machines that operate on one of the earliest known principles of refrigeration. Current absorption chillers typically use either steam or a gas-fired burner as the energy source. All current gas-fired absorption cooling systems are based on the well known single-effect or double-effect cycles. To further improve utilization of the high temperature heat available from natural gas, a variety of triple-effect cycles have been proposed and are being developed that are capable of substantial performance improvement over equivalent double-effect cycles. This article describes a study that investigated the possibility of even further improving utilization of the high temperature heat available from natural gas combustion. During the study, performance simulation was conducted for a 4-effect lithium bromide/water cycle. From an environmental perspective, absorption chillers provide several benefits. They use absorption pairs (such as lithium bromide/water) as the working fluids, rather than chlorofluorocarbons or hydrochlorofluorocarbons, which contribute to ozone depletion and global warming.

  20. Identification and function of adenosine A3 receptor in afferent arterioles.

    PubMed

    Lu, Yan; Zhang, Rui; Ge, Ying; Carlstrom, Mattias; Wang, Shaohui; Fu, Yiling; Cheng, Liang; Wei, Jin; Roman, Richard J; Wang, Lei; Gao, Xichun; Liu, Ruisheng

    2015-05-01

    Adenosine plays an important role in regulation of renal microcirculation. All receptors of adenosine, A1, A2A, A2B, and A3, have been found in the kidney. However, little is known about the location and function of the A3 receptor in the kidney. The present study determined the expression and role of A3 receptors in mediating the afferent arteriole (Af-Art) response and studied the interaction of A3 receptors with angiotensin II (ANG II), A1 and A2 receptors on the Af-Art. We found that the A3 receptor expressed in microdissected isolated Af-Art and the mRNA levels of A3 receptor were 59% of A1. In the isolated microperfused Af-Art, A3 receptor agonist IB-MECA did not have a constrictive effect. Activation of A3 receptor dilated the preconstricted Af-Art by norepinephrine and blunted the vasoconstrictive effect of both adenosine A1 receptor activation and ANG II on the Af-Art, respectively. Selective A2 receptor antagonist (both A2A and A2B) had no effect on A3 receptor agonist-induced vasodilation, indicating that the dilatory effect of A3 receptor activation is not mediated by activation of A2 receptor. We conclude that the A3 receptor is expressed in the Af-Art, and activation of the A3 receptor dilates the Af-Art. PMID:25608966

  1. A(3) adenosine receptor ligands: history and perspectives.

    PubMed

    Baraldi, P G; Cacciari, B; Romagnoli, R; Merighi, S; Varani, K; Borea, P A; Spalluto, G

    2000-03-01

    Adenosine regulates many physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four different adenosine receptors have been identified and classified as A(1), A(2A), A(2B), and A(3). These adenosine receptors are members of the G-protein-coupled receptor family. While adenosine A(1) and A(2A) receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A(3) adenosine receptor subtype is presently under study in order to better understand its physio-pathological functions. Activation of adenosine A(3) receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A(3) adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells. These mediators are responsible for processes such as inflammation and hypotension. It has also been suggested that the A(3) receptor plays an important role in brain ischemia, immunosuppression, and bronchospasm in several animal models. Based on these results, highly selective A(3) adenosine receptor agonists and/or antagonists have been indicated as potential drugs for the treatment of asthma and inflammation, while highly selective agonists have been shown to possess cardioprotective effects. The updated material related to this field of research has been rationalized and arranged in order to offer an overview of the topic. PMID:10723024

  2. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... notice sent to you in conjunction with the community inspection procedure established under 44 CFR 59.30... procedure set forth in National Flood Insurance Program Regulations (44 CFR 59.30). During the several years... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Appendix A(4) to Part 61...

  3. 44 CFR Appendix A(4) to Part 61 - Appendix A(4) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... notice sent to you in conjunction with the community inspection procedure established under 44 CFR 59.30... procedure set forth in National Flood Insurance Program Regulations (44 CFR 59.30). During the several years... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(4) to Part 61...

  4. The A3 adenosine receptor: history and perspectives.

    PubMed

    Borea, Pier Andrea; Varani, Katia; Vincenzi, Fabrizio; Baraldi, Pier Giovanni; Tabrizi, Mojgan Aghazadeh; Merighi, Stefania; Gessi, Stefania

    2015-01-01

    By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein-coupled adenosine receptors (ARs): A(1), A(2)A, A(2)B, and A(3). The A(3) adenosine receptor (A(3)AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A(3)AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A(3) agonists or antagonists would be the best choice. Today, the choice has been made and A(3)AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A(3)AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health. PMID:25387804

  5. 29 CFR 779.363 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... granite slabs or sand-rubbed marble. In such a case the establishments will cut ends, tops, or joints on... semifinished or rough granite or marble or other stone into finished monuments such as the work performed in... receives some semifinished work, including sawed, steeled, or polished granite slabs or sand-rubbed...

  6. 29 CFR 779.363 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... granite slabs or sand-rubbed marble. In such a case the establishments will cut ends, tops, or joints on... semifinished or rough granite or marble or other stone into finished monuments such as the work performed in... receives some semifinished work, including sawed, steeled, or polished granite slabs or sand-rubbed...

  7. 29 CFR 779.363 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... granite slabs or sand-rubbed marble. In such a case the establishments will cut ends, tops, or joints on... semifinished or rough granite or marble or other stone into finished monuments such as the work performed in... receives some semifinished work, including sawed, steeled, or polished granite slabs or sand-rubbed...

  8. 29 CFR 779.363 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... granite slabs or sand-rubbed marble. In such a case the establishments will cut ends, tops, or joints on... semifinished or rough granite or marble or other stone into finished monuments such as the work performed in... receives some semifinished work, including sawed, steeled, or polished granite slabs or sand-rubbed...

  9. 29 CFR 779.363 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... granite slabs or sand-rubbed marble. In such a case the establishments will cut ends, tops, or joints on... semifinished or rough granite or marble or other stone into finished monuments such as the work performed in... receives some semifinished work, including sawed, steeled, or polished granite slabs or sand-rubbed...

  10. 29 CFR 779.358 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... car lots. (4) Sales of ice of a ton or more. (5) Sales of ice at a price comparable to that charged by... comparable to or lower than the prevailing price to dealers in the area. (c) The legislative...

  11. 29 CFR 779.358 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... FAIR LABOR STANDARDS ACT AS APPLIED TO RETAILERS OF GOODS OR SERVICES Exemptions for Certain Retail or...)(4) establishments. (a) An establishment engaged in selling ice may qualify as an exempt retail or... and must be recognized as retail sales in the industry are met, sales of ice which meet all...

  12. 29 CFR 779.358 - May qualify as exempt 13(a)(2) or 13(a)(4) establishments.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... FAIR LABOR STANDARDS ACT AS APPLIED TO RETAILERS OF GOODS OR SERVICES Exemptions for Certain Retail or...)(4) establishments. (a) An establishment engaged in selling ice may qualify as an exempt retail or... and must be recognized as retail sales in the industry are met, sales of ice which meet all...

  13. EphA4 is a prognostic factor in gastric cancer

    PubMed Central

    2013-01-01

    Background Erythropoietin-producing hepatocellular (Eph) receptor, consisting of a family of receptor tyrosine kinases, plays critical roles in tumour development and is considered an attractive target for cancer therapy. Methods Tumour samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy. The expressions of EphA2, EphA4, and ephrinA1 were evaluated immunohistochemically. Results High expressions of EphA2, EphA4, and ephrinA1 significantly correlated with variables related to tumour progression, including the depth of invasion, metastatic lymph nodes, pathological stage, and distant metastasis or recurrent disease. High expressions of EphA2, EphA4, and ephrinA1 were significantly associated with poorer disease-specific survival (DSS; p < 0.001, p < 0.001, p = 0.026). On multivariate analysis, EphA4 was an independent prognostic factor of DSS (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.1-4.8; p = 0.028), and EphA2 tended to be a prognostic factor (HR, 2.4; 95% CI, 1.0-5.8; p = 0.050). In stage II and III cancer, EphA4 and EphA2 were both significantly associated with shorter survival (p = 0.007 and 0.019), but only EphA2 was an independent prognostic factor (HR, 2.6; 95% CI, 1.1-6.3; p = 0.039). Conclusion EphA4 may play important roles in tumor progression and outcomes in patients with gastric cancer. PMID:23738943

  14. Functionalized Congeners of 1,4-Dihydropyridines as Antagonist Molecular Probes for A3 Adenosine Receptors

    PubMed Central

    Li, An-Hu; Chang, Louis; Ji, Xiao-duo; Melman, Neli; Jacobson, Kenneth A.

    2012-01-01

    4-Phenylethynyl-6-phenyl-1,4-dihydropyridine derivatives are selective antagonists at human A3 adenosine receptors, with Ki values in a radioligand binding assay vs [125I]AB-MECA [N6-(4-amino-3-iodobenzyl)-5′-N-methylcarbamoyl-adenosine] in the submicromolar range. In this study, functionalized congeners of 1,4-dihydropyridines were designed as chemically reactive adenosine A3 antagonists, for the purpose of synthesizing molecular probes for this receptor subtype. Selectivity of the new analogues for cloned human A3 adenosine receptors was determined in radioligand binding in comparison to binding at rat brain A1 and A2A receptors. Benzyl ester groups at the 3- and/or 5-positions and phenyl groups at the 2- and/or 6-positions were introduced as potential sites for chain attachment. Structure–activity analysis at A3 adenosine receptors indicated that 3,5-dibenzyl esters, but not 2,6-diphenyl groups, are tolerated in binding. Ring substitution of the 5-benzyl ester with a 4-fluorosulfonyl group provided enhanced A3 receptor affinity resulting in a Ki value of 2.42 nM; however, a long-chain derivative containing terminal amine functionalization at the 4-position of the 5-benzyl ester showed only moderate affinity. This sulfonyl fluoride derivative appeared to bind irreversibly to the human A3 receptor (1 h incubation at 100 nM resulting in the loss of 56% of the specific radioligand binding sites), while the binding of other potent dihydropyridines and other antagonists was generally reversible. At the 3-position of the dihydropyridine ring, an amine-functionalized chain attached at the 4-position of a benzyl ester provided higher A3 receptor affinity than the corresponding 5-position isomer. This amine congener was also used as an intermediate in the synthesis of a biotin conjugate, which bound to A3 receptors with a Ki value of 0.60 μM. PMID:10411465

  15. Pharmacogenetics of the organic anion transporting polypeptide 1A2

    PubMed Central

    Franke, Ryan M; Scherkenbach, Lisa A; Sparreboom, Alex

    2016-01-01

    The solute carrier, human organic anion transporting polypeptide 1A2 (OATP1A2, OATP-A, OATP1 and OATP) is highly expressed in the intestine, kidney, cholangiocytes and the blood–brain barrier. This localization suggests that OATP1A2 may be vitally important in the absorption, distribution and excretion of a broad array of clinically important drugs. Several nonsynonymous polymorphisms have been identified in the gene encoding OATP1A2, SLCO1A2 (SLC21A3), with some of these variants demonstrating functional changes in the transport of OATP1A2 substrates. PMID:19290786

  16. Thermal analysis of a 4m honeycomb telescope primary mirror

    NASA Astrophysics Data System (ADS)

    Zhang, Jun; Xian, Hao

    2012-09-01

    Thermal characteristics of a 4m class honeycomb telescope primary mirror are presented. A 3 dimensional finite elements model of the primary mirror with the varying ambient air temperature as the boundary conditions is used for the numerical simulations. Every night's air temperature profile has been detected in 2009 in Gaomeigu observatory site. Four typical nights' air temperature profiles in different seasons are chose as the boundary conditions in finite element simulation. Temperature difference between primary mirror's optical surface and ambient air is studied, as well as the axial temperature difference inner the mirror blank and radial temperature difference on the optical surface. Primary mirror seeing phenomenon results from the temperature difference between primary mirror's optical surface and the ambient air is discussed. Thermal deformations due to temperature gradient of the primary mirror are analyzed by the finite element model. Axial thermal deformations on the optical surface are discussed in detail. Thermal deformation would induce the optical surface of primary mirror to distort from the normal shape, and lead to large observation image quality degradation. Primary mirror seeing with the turbulence near the optical surface would introduce wavefront aberration and deteriorate the final observation image. In order to reduce mirror seeing and thermal deformation, it is necessary to design a thermal control system for primary mirror. The thermal and structural analysis result will be valuable in designing primary mirror's thermal control system.

  17. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION, AND PUBLIC AVAILABILITY OF NATIONAL SECURITY INFORMATION § 4a.3 Classification levels. Information may be classified as national security...

  18. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  19. 32 CFR 242a.3 - Open meetings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Open meetings. 242a.3 Section 242a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) MISCELLANEOUS PUBLIC MEETING PROCEDURES OF THE BOARD OF REGENTS, UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES § 242a.3 Open meetings. (a) Members shall...

  20. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Definitions. 374a.3 Section 374a.3 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions. Adequate security means (a) a bond, issued by...

  1. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2010-07-01 2010-07-01 false Mission. 383a.3 Section 383a.3 National...

  2. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2014-07-01 2014-07-01 false Mission. 383a.3 Section 383a.3 National...

  3. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2011-07-01 2011-07-01 false Mission. 383a.3 Section 383a.3 National...

  4. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2013-07-01 2013-07-01 false Mission. 383a.3 Section 383a.3 National...

  5. 32 CFR 383a.3 - Mission.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.3 Mission. (a) The mission of the DeCA is to: (1) Provide an... Assistant Secretary of Defense (Production and Logistics) (ASD(P&L)). ... 32 National Defense 2 2012-07-01 2012-07-01 false Mission. 383a.3 Section 383a.3 National...

  6. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  7. 14 CFR 374a.3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Definitions. 374a.3 Section 374a.3... REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.3 Definitions. Adequate... contributions or make expenditures, with a view to bringing about his nomination for election, or election,...

  8. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  9. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  10. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  11. 32 CFR 168a.3 - Definition.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Definition. 168a.3 Section 168a.3 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.3 Definition. Sponsoring Agency. A DoD Component or...

  12. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Lifetime Learning Credit. 1.25A-4 Section 1.25A-4... Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1) Taxable years beginning before January 1, 2003. Subject to the phaseout of the education tax credit described...

  13. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 1 2014-04-01 2013-04-01 true Lifetime Learning Credit. 1.25A-4 Section 1.25A-4... Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1) Taxable years beginning before January 1, 2003. Subject to the phaseout of the education tax credit described...

  14. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Responsibilities and functions. 352a.4 Section 352a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense...

  15. 22 CFR 3a.4 - Procedure for requesting approval.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Procedure for requesting approval. 3a.4 Section 3a.4 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.4 Procedure for requesting approval. (a) An applicant...

  16. 42 CFR 65a.4 - What are the program requirements?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What are the program requirements? 65a.4 Section 65a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.4 What are...

  17. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Responsibilities and functions. 352a.4 Section 352a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense...

  18. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Responsibilities and functions. 352a.4 Section 352a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense...

  19. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Responsibilities and functions. 352a.4 Section 352a.4 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense...

  20. 17 CFR 260.7a-4 - Calculation of time.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Calculation of time. 260.7a-4 Section 260.7a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 § 260.7a-4 Calculation...

  1. 32 CFR 809a.4 - Use of Government facilities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Use of Government facilities. 809a.4 Section 809a.4 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION... § 809a.4 Use of Government facilities. Commanders are prohibited from authorizing demonstrations...

  2. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Good faith defense. 274a.4 Section 274a.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for a fee for employment who shows good...

  3. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Good faith defense. 274a.4 Section 274a.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for...

  4. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Good faith defense. 274a.4 Section 274a.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for...

  5. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Good faith defense. 274a.4 Section 274a.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for...

  6. 8 CFR 274a.4 - Good faith defense.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Good faith defense. 274a.4 Section 274a.4 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.4 Good faith defense. An employer or a recruiter or referrer for...

  7. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  8. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  9. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  10. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  11. 42 CFR 59a.4 - How are grant applications evaluated?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false How are grant applications evaluated? 59a.4 Section 59a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.4...

  12. 75 FR 910 - Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-07

    ...-07R1, Amendment 39-15179 (72 FR 49183, August 28, 2007) and AD 2007-05-16, Amendment 39-14977 (72 FR... FR 17799). That action proposed to require: Replacing certain fan disks installed on regional jets... instructions related to operators who fly a regional jet (RJ) with the CF34-3A1 engine as a business jet...

  13. A3 Subscale Diffuser Test Article Design

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.

    2009-01-01

    This paper gives a detailed description of the design of the A3 Subscale Diffuser Test (SDT) Article Design. The subscale diffuser is a geometrically accurate scale model of the A3 altitude rocket facility. It was designed and built to support the SDT risk mitigation project located at the E3 facility at Stennis Space Center, MS (SSC) supporting the design and construction of the A3 facility at SSC. The subscale test article is outfitted with a large array of instrumentation to support the design verification of the A3 facility. The mechanical design of the subscale diffuser and test instrumentation are described here

  14. Recent developments in A2B adenosine receptor ligands.

    PubMed

    Kalla, Rao V; Zablocki, Jeff; Tabrizi, Mojgan Aghazadeh; Baraldi, Pier Giovanni

    2009-01-01

    A selective, high-affinity A(2B) adenosine receptor (AR) antagonist will be useful as a pharmacological tool to help determine the role of the A(2B)AR in inflammatory diseases and angiogenic diseases. Based on early A(2B)AR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: K(i)(hA(2B)) = 2 nM; K(i)(hA(1)) = 403 nM; K(i)(hA(2A)) = 503 NM, and K(i)(hA(3)) = 570 nM), several groups have discovered second-generation A(2B)AR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A(2B)AR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative, (CVT-6883, K(i)(hA(2B)) = 22 nM; K(i)(hA(1)) = 1,940 nM; K(i)(hA(2A)) = 3,280; and K(i)(hA(3)) = 1,070 nM). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties (T(1/2) = 4 h and F > 35% rat), and it is a functional antagonist at the A(2B)AR(K (B) = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A(2B)AR in asthma. In two Phase I clinical trails, 22 (CVT-6883) was found to be safe, well tolerated, and suitable for once-daily dosing. Baraldi et al. have independently discovered a selective, high-affinity A(2B)AR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine (K(i)(hA(2B)) = 5.5 nM; K(i)(hA(1)) = 200 nM; K(i)(hA(2A), A(3)) > 1,000, that has been selected for development in conjunction with King Pharmaceuticals. Compound 30 has been demonstrated to be a functional antagonist of the A(2B)AR, and it has been radiolabeled for use in pharmacological studies. A third compound, 58 (LAS-38096), is a 2-aminopyrimidine derivative (discovered by the Almirall group) that has high A(2B)AR affinity and selectivity (K(i)(hA(2B)) = 17 nM; K(i)(hA(1)) > 1,000 nM; K(i)(hA(2A)) > 2,500; and K(i)(hA(3)) > 1,000 nM), and 58 has been moved into preclinical safety testing. A fourth selective, high-affinity A(2B)AR antagonist, 54 (OSIP339391 K(i))(hA(2B)) = 0.5 nM; K(i))(hA(1

  15. 15 CFR 4a.3 - Classification levels.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Classification levels. 4a.3 Section 4a.3 Commerce and Foreign Trade Office of the Secretary of Commerce CLASSIFICATION, DECLASSIFICATION... E.O. 12958. The levels established by E.O. 12958 (Top Secret, Secret, and Confidential) are the...

  16. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  17. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  18. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  19. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  20. 42 CFR 2a.3 - Application; coordination.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Application; coordination. 2a.3 Section 2a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF... Institute on Drug Abuse, the Office of the Director, National Institute of Mental Health, or the Office...

  1. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Lifetime Learning Credit. 1.25A-4 Section 1.25A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Changes in Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1) Taxable years beginning before January 1,...

  2. A2E and Lipofuscin.

    PubMed

    Crouch, Rosalie K; Koutalos, Yiannis; Kono, Masahiro; Schey, Kevin; Ablonczy, Zsolt

    2015-01-01

    Lipofuscin is highly fluorescent material, formed in several tissues but best studied in the eye. The accumulation of lipofuscin in the retinal pigment epithelium (RPE) is a hallmark of aging in the eye and has been implicated in various retinal degenerations, including age-related macular degeneration. The bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), formed from retinal, has been identified as a byproduct of the visual cycle, and numerous in vitro studies have found toxicity associated with this compound. The compound is known to accumulate in the RPE with age and was the first identified compound extracted from lipofuscin. Our studies have correlated the distribution of lipofuscin and A2E across the human and mouse RPE. Lipofuscin fluorescence was imaged in the RPE from human donors of various ages and from assorted mouse models. The spatial distribution of A2E was determined using matrix-assisted laser desorption-ionization imaging mass spectrometry on both flat-mounted and transversally sectioned RPE tissue. Our data support the clinical observations in humans of strong RPE fluorescence, increasing with age, in the central area of the RPE. However, there was no correlation between the distribution of A2E and lipofuscin, as the levels of A2E were highest in the far periphery and decreased toward the central region. Interestingly, in all the mouse models, A2E distribution and lipofuscin fluorescence correlate well. These data demonstrate that the accumulation of A2E is not responsible for the increase in lipofuscin fluorescence observed in the central RPE with aging in humans. PMID:26310170

  3. α2-Chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse

    PubMed Central

    Shi, Lei; Fu, Wing-Yu; Hung, Kwok-Wang; Porchetta, Cassandra; Hall, Christine; Fu, Amy K. Y.; Ip, Nancy Y.

    2007-01-01

    EphA4-dependent growth cone collapse requires reorganization of actin cytoskeleton through coordinated activation of Rho family GTPases. Whereas various guanine exchange factors have recently been identified to be involved in EphA4-mediated regulation of Rho GTPases and growth cone collapse, the functional roles of GTPase-activating proteins in the process are largely unknown. Here we report that EphA4 interacts with α2-chimaerin through its Src homology 2 domain. Activated EphA4 induces a rapid increase of tyrosine phosphorylation of α2-chimaerin and enhances its GTPase-activating protein activity toward Rac1. More importantly, α2-chimaerin regulates the action of EphA4 in growth cone collapse through modulation of Rac1 activity. Our findings have therefore identified a new α2-chimaerin-dependent signaling mechanism through which EphA4 transduces its signals to the actin cytoskeleton and modulates growth cone morphology. PMID:17911252

  4. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  5. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... in 26 CFR part 1 edition revised as of April 1, 2011, applies to leasehold improvements placed in... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Leased property. 1.167(a)-4 Section 1.167(a)-4... property. (a) In general. Capital expenditures made by either a lessee or lessor for the erection of...

  6. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 2 2011-04-01 2011-04-01 false Leased property. 1.167(a)-4 Section 1.167(a)-4... property. Capital expenditures made by a lessee for the erection of buildings or the construction of other permanent improvements on leased property are recoverable through allowances for depreciation...

  7. 26 CFR 1.167(a)-4 - Leased property.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Leased property. 1.167(a)-4 Section 1.167(a)-4... property. Capital expenditures made by a lessee for the erection of buildings or the construction of other permanent improvements on leased property are recoverable through allowances for depreciation...

  8. 26 CFR 1.475(a)-4 - Valuation safe harbor.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Inventories § 1.475(a)-4 Valuation safe harbor. (a) Overview—(1) Purpose... the extent that portions of the payments have been recognized for tax purposes before the...

  9. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the...

  10. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the...

  11. 42 CFR 2a.4 - Contents of application; in general.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Contents of application; in general. 2a.4 Section 2a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS... valid certification submitted in accordance with 45 CFR part 46. (b) The location of the...

  12. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  13. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  14. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  15. 17 CFR 240.16a-4 - Derivative securities.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Derivative securities. 240.16a-4 Section 240.16a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the...

  16. 26 CFR 1.475(a)-4 - Valuation safe harbor.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... method—(1) Sufficient consistency. An eligible method is a mark-to-market method that is sufficiently... 26 Internal Revenue 6 2013-04-01 2013-04-01 false Valuation safe harbor. 1.475(a)-4 Section 1.475... (CONTINUED) INCOME TAXES (CONTINUED) Inventories § 1.475(a)-4 Valuation safe harbor. (a) Overview—(1)...

  17. 26 CFR 1.475(a)-4 - Valuation safe harbor.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... method—(1) Sufficient consistency. An eligible method is a mark-to-market method that is sufficiently... 26 Internal Revenue 6 2014-04-01 2014-04-01 false Valuation safe harbor. 1.475(a)-4 Section 1.475... (CONTINUED) INCOME TAXES (CONTINUED) Inventories § 1.475(a)-4 Valuation safe harbor. (a) Overview—(1)...

  18. Steel erected at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Workers erect the first fabricated steel girders to arrive at the A-3 Test Stand at Stennis Space Center. Steel work began at the construction site Oct. 29 and is scheduled to continue into next spring.

  19. Nuclear Data Sheets for A = 3

    NASA Astrophysics Data System (ADS)

    Purcell, J. E.; Sheu, C. G.

    2015-12-01

    Compilation of information about the structure of A = 3 systems. This review mainly summarizes the work presented in (2010Pu04) and has updates of mass, lifetime and nuclear moment data as noted in the text.

  20. Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

    PubMed

    Ma, Zhong-lin; Yan, Xiao-jing; Zhao, Lei; Zhou, Jiu-jiu; Pang, Wan; Kai, Zhen-peng; Wu, Fan-hong

    2016-02-01

    Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management. PMID:26711170

  1. 26 CFR 20.2056A-4 - Procedures for conforming marital trusts and nontrust marital transfers to the requirements of a...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... nontrust marital transfers to the requirements of a qualified domestic trust. 20.2056A-4 Section 20.2056A-4... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-4 Procedures for... § 20.2056A-2, and the requirements of § 20.2056A-2T(d). A reformation pursuant to the terms of...

  2. 26 CFR 20.2056A-4 - Procedures for conforming marital trusts and nontrust marital transfers to the requirements of a...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... nontrust marital transfers to the requirements of a qualified domestic trust. 20.2056A-4 Section 20.2056A-4... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-4 Procedures for... § 20.2056A-2, and the requirements of § 20.2056A-2T(d). A reformation pursuant to the terms of...

  3. Engineers conduct key water test for A-3 stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    Water cascades from the A-2 Test Stand at Stennis Space Center as engineers challenge the limits of the high-pressure water system as part of the preparation process for the A-3 Test Stand under construction. Jeff Henderson, test director for Stennis' A Complex, led a series of tests Nov. 16-20, flowing water simultaneously on the A-1 and A-2 stands, followed by the A-1 and B-1 stands, to determine if the high-pressure industrial water facility pumps and the existing pipe system can support the needs of the A-3 stand. The stand is being built to test rocket engines that will carry astronauts beyond low-Earth orbit and will need about 300,000 gallons of water per minute when operating, but the Stennis system never had been tested to that level. The recent tests were successful in showing the water facility pumps can operate at that capacity - reaching 318,000 gallons per minute in one instance. However, officials continue to analyze data to determine if the system can provide the necessary pressure at that capacity and if the delivery system piping is adequate. 'We just think if there's a problem, it's better to identify and address it now rather than when A-3 is finished and it has to be dealt with,' Henderson said.

  4. Homotropic cooperativity of monomeric cytochrome P450 3A4

    SciTech Connect

    Baas, Bradley J.; Denisov, Ilia G.; Sligar, Stephen G.

    2010-11-16

    Mechanistic studies of mammalian cytochrome P450s are often obscured by the phase heterogeneity of solubilized preparations of membrane enzymes. The various protein-protein aggregation states of microsomes, detergent solubilized cytochrome or a family of aqueous multimeric complexes can effect measured substrate binding events as well as subsequent steps in the reaction cycle. In addition, these P450 monooxygenases are normally found in a membrane environment and the bilayer composition and dynamics can also effect these catalytic steps. Here, we describe the structural and functional characterization of a homogeneous monomeric population of cytochrome P450 3A4 (CYP 3A4) in a soluble nanoscale membrane bilayer, or Nanodisc [Nano Lett. 2 (2002) 853]. Cytochrome P450 3A4:Nanodisc assemblies were formed and purified to yield a 1:1 ratio of CYP 3A4 to Nanodisc. Solution small angle X-ray scattering was used to structurally characterize this monomeric CYP 3A4 in the membrane bilayer. The purified CYP 3A4:Nanodiscs showed a heretofore undescribed high level of homotropic cooperativity in the binding of testosterone. Soluble CYP 3A4:Nanodisc retains its known function and shows prototypic hydroxylation of testosterone when driven by hydrogen peroxide. This represents the first functional characterization of a true monomeric preparation of cytochrome P450 monooxygenase in a phospholipid bilayer and elucidates new properties of the monomeric form.

  5. Functional profile of S100A4-deficient T cells.

    PubMed

    Weatherly, Kathleen; Bettonville, Marie; Torres, David; Kohler, Arnaud; Goriely, Stanislas; Braun, Michel Y

    2015-12-01

    The protein S100A4 is best known for its significant role in promoting motility and invasive capacity of cancer cells. Since S100A4 expression has been reported also in T cells, we analyzed its potential role in T cell motility and inflammation. Using S100a4(+/Gfp) mice, we show here that S100A4 is exclusively expressed by memory T cells of CD4(+) or CD8(+) subpopulations, predominantly of the effector memory T cell subtype. However, the protein was not required for in vitro memory T cell migration toward gradients of the inflammatory chemokine CXCL10. Moreover, T cell memory response was normal in S100A4-deficient mice and lack of S100a4 gene expression did not induce any defect in promoting the development of protective immunity or inflammatory reactions leading to autoimmunity. Taken together, our results demonstrate that S100A4 activity is dispensable for T cell motility/migration and inflammatory potential. PMID:26734465

  6. Role of A3 adenosine receptor in diabetic neuropathy.

    PubMed

    Yan, Heng; Zhang, Enshui; Feng, Chang; Zhao, Xin

    2016-10-01

    Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc. PMID:27319979

  7. 44 CFR Appendix A(3) to Part 61 - Appendix A(3) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(3) to Part 61 A(3) Appendix A(3) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  8. The HLA-A2-supermotif: a QSAR definition.

    PubMed

    Doytchinova, Irini; Flower, Darren

    2003-08-01

    Identification of epitopes capable of binding multiple HLA types will significantly rationalise the development of epitope-based vaccines. A quantitative method assessing the contribution of each amino acid at each position was applied to over 500 nonamer peptides binding to 5 MHC alleles--A*0201, A*0202, A*0203, A*0206 and A*6802--which together define the HLA-A2-like supertype. FXIGXI (L)IFV was identified as a supermotif for the A2-supertype based on the contributions of the common preferred amino acids at each of the nine positions. The results indicate that HLA-A*6802 is an intermediate allele standing between A2 and A3 supertypes: at anchor position 2 it is closer to A3 and at anchor position 9 it is nearer to A2. Models are available free on-line at http://www.jenner.ac.uk/MHCPred and can be used for binding affinity prediction. PMID:12948188

  9. Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

    PubMed Central

    Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz; Kolatkar, Anand; Lamberto, Ilaria; Pasquale, Elena Bianca; Kuhn, Peter

    2015-01-01

    The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins. PMID:25993310

  10. INTERIOR VIEW WITH CASTING MACHINE AND A 4" DUCTILE IRON ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    INTERIOR VIEW WITH CASTING MACHINE AND A 4" DUCTILE IRON PIPE BEING EXTRACTED FROM CASTING MACHINE - McWane Cast Iron Pipe Company, Pipe Casting Area, 1201 Vanderbilt Road, Birmingham, Jefferson County, AL

  11. INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    INTERIOR VIEW WITH CASTING MACHINE AND A 4' DUCTILE IRON PIPE BEING CENTRIFUGALLY CAST, AS OPERATOR WATCHES TO ENSURE QUALITY. - McWane Cast Iron Pipe Company, Pipe Casting Area, 1201 Vanderbilt Road, Birmingham, Jefferson County, AL

  12. Air density measurement with a falling A4 sheet

    NASA Astrophysics Data System (ADS)

    Oladyshkin, Ivan V.; Oladyshkina, Anastasia A.

    2016-09-01

    We propose a simple experiment on the air density measurement which does not require any special equipment: just an A4 sheet of paper, a stopwatch and a ruler. The discussed method uses the most basic air resistance model.

  13. CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48.

    PubMed

    Holm, Niels Bjerre; Nielsen, Line Marie; Linnet, Kristian

    2015-09-01

    Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents. PMID:26002511

  14. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 1 2013-04-01 2013-04-01 false Lifetime Learning Credit. 1.25A-4 Section 1.25A... Changes in Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1... described in § 1.25A-1(c), for taxable years beginning before 2003, the Lifetime Learning Credit amount...

  15. 26 CFR 1.25A-4 - Lifetime Learning Credit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 1 2012-04-01 2012-04-01 false Lifetime Learning Credit. 1.25A-4 Section 1.25A... Changes in Rates During A Taxable Year § 1.25A-4 Lifetime Learning Credit. (a) Amount of the credit—(1... described in § 1.25A-1(c), for taxable years beginning before 2003, the Lifetime Learning Credit amount...

  16. Increased expression of S100A4, a metastasis-associated gene, in human colorectal adenocarcinomas.

    PubMed

    Takenaga, K; Nakanishi, H; Wada, K; Suzuki, M; Matsuzaki, O; Matsuura, A; Endo, H

    1997-12-01

    The S100A4 gene (also known as pEL98/mts1/p9Ka/18A2/42A/calvasculin /FSP1/CAPL) encoding an S100-related calcium-binding protein is implied to be involved in the invasion and metastasis of murine tumor cells. In the present study, the expression of S100A4 in human colorectal adenocarcinoma cell lines (SW837, LoVo, DLD-1, HT-29, SW480, SW620, WiDr, and Colo201) and surgically resected neoplastic tissues was examined to investigate whether S100A4 plays a role in the invasion and metastasis of human tumor cells. Northern blot analysis using total RNA isolated from the adenocarcinoma cell lines revealed that five of the eight cell lines expressed substantial amounts of S100A4 mRNA. Normal colon fibroblasts (CCD-18Co) expressed little of the RNA. Using surgically resected specimens, it seemed that the amount of S100A4 mRNA in adenomas was nearly equal to that in normal colonic mucosa, whereas adenocarcinomas expressed a significantly higher amount of the RNA than did the adjacent normal colonic mucosa. Immunohistochemical analysis using formalin-fixed paraffin-embedded surgical specimens and monoclonal anti-S100A4 antibody demonstrated that none of 12 adenoma specimens were immunopositive, whereas 8 of 18 (44%) focal carcinomas in carcinoma in adenoma specimens and 50 of 53 (94%) adenocarcinoma specimens were immunopositive. Interestingly, the incidence of immunopositive cells increased according to the depth of invasion, and nearly all of the carcinoma cells in 14 metastases in the liver were positive. These results suggest that S100A4 may be involved in the progression and the metastatic process of human colorectal neoplastic cells. PMID:9815629

  17. Triple-Singlet Mixing in Si_3: the 1^3A_{1}^{''} - {a}{^3}A{^{'}_2} Transition

    NASA Astrophysics Data System (ADS)

    Zhang, Ruohan; Steimle, Timothy C.

    2013-06-01

    The electronic spectrum of the triplet states of the D_{3h} isomer of Si_3 recorded using both mass selected REMPI and LIF spectroscopy was recently reported. In that same study the dispersed laser induced fluorescence (DLIF) spectra resulting from excitation of various bands in the visible range were recorded. The DLIF spectra exhibited a progression with a 505 cm^{-1} spacing, which was assign to the breathing mode of the D_{3h}, equilateral triangle, Si_{3} molecule. In addition, and quite unexpectedly, the DLIF spectra exhibited a progression having a spacing of 173 cm^{-1}. This progression was tentatively assigned to transition involving the bending mode of the ^1A_1 state of the C_{2v} isomer. A possible explanation for the observation of transitions in the singlet manifold is that upon laser excitation in the D_{3h} triplet manifold there is rapid intersystem crossing to the singlet manifold followed by fluorescence to the ground state of C_{2v} isomer. Here we address the issue of possible intersystem crossing by recording the excitation on DLIF spectra in the present of a static magnetic field. Magnetic fields are known to enhance the singlet-triple mixing. Si_{3} was produced using a supersonic pulsed discharge source (900 V, 20 μs, 6kΩ) with a 1% SiH_{4} in argon mixture. Magnetic fields of approximately 500 and 950 Gauss were applied. We will report the interpretation of the magnetic field induced changes to the LIF and DLIF spectra and the implications for the singlet-triple mixing process. N. J. Reilly, X. Zhuang, V. Gupta, R. Nagarajan, R. C. Fortenberry, J. P. Maier, T. C. Steimle, J. F. Stanton, M. C. McCarthy; {J. Chem. Phys., {136(19)}, 194307, (2004). V. I. Makarov, I. V. Khmelinskii; {Advances in Chemical Phisics, {Volume 118}, 45-98, (2001). thanks

  18. A 3 x 2 Achievement Goal Model

    ERIC Educational Resources Information Center

    Elliot, Andrew J.; Murayama, Kou; Pekrun, Reinhard

    2011-01-01

    In the present research, a 3 x 2 model of achievement goals is proposed and tested. The model is rooted in the definition and valence components of competence, and encompasses 6 goal constructs: task-approach, task-avoidance, self-approach, self-avoidance, other-approach, and other-avoidance. The results from 2 studies provided strong support for…

  19. Steel erected at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Fabricated steel began arriving by truck Oct. 24 for construction of the A-3 Test Stand that will be used to test the engine for the nation's next generation of moon rockets. Within days workers from Lafayette Steel Erector Inc. began assembling the 16 steel stages needed on the foundation and footings poured in the previous year.

  20. A3 Subscale Rocket Hot Fire Testing

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.; Yen, J.

    2009-01-01

    This paper gives a description of the methodology and results of J2-X Subscale Simulator (JSS) hot fire testing supporting the A3 Subscale Diffuser Test (SDT) project at the E3 test facility at Stennis Space Center, MS (SSC). The A3 subscale diffuser is a geometrically accurate scale model of the A3 altitude simulating rocket test facility. This paper focuses on the methods used to operate the facility and obtain the data to support the aerodynamic verification of the A3 rocket diffuser design and experimental data quantifying the heat flux throughout the facility. The JSS was operated at both 80% and 100% power levels and at gimbal angle from 0 to 7 degrees to verify the simulated altitude produced by the rocket-rocket diffuser combination. This was done with various secondary GN purge loads to quantify the pumping performance of the rocket diffuser. Also, special tests were conducted to obtain detailed heat flux measurements in the rocket diffuser at various gimbal angles and in the facility elbow where the flow turns from vertical to horizontal upstream of the 2nd stage steam ejector.

  1. 22 CFR 9a.3 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO CERTAIN INTERNATIONAL ENERGY PROGRAMS; RELATED MATERIAL § 9a.3 Scope. These regulations apply to all information and material classified... “Classification of Certain Information and Material Obtained From Advisory Bodies Created To Implement...

  2. 22 CFR 9a.3 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DEPARTMENT OF STATE GENERAL SECURITY INFORMATION REGULATIONS APPLICABLE TO CERTAIN INTERNATIONAL ENERGY PROGRAMS; RELATED MATERIAL § 9a.3 Scope. These regulations apply to all information and material classified... “Classification of Certain Information and Material Obtained From Advisory Bodies Created To Implement...

  3. Spatiotemporal phylogenetic analysis and molecular characterization of coxsackievirus A4.

    PubMed

    Chu, Pei-Yu; Lu, Po-Liang; Tsai, Yu-Ling; Hsi, Edward; Yao, Ching-Yuan; Chen, Yu-Hsien; Hsu, Li-Ching; Wang, Sheng-Yu; Wu, Ho-Sheng; Lin, Yi-Ying; Su, Hui-Ju; Lin, Kuei-Hsiang

    2011-08-01

    Coxsackievirus A4 outbreaks occurred in Taiwan in 2004 and 2006. The spatiotemporal transmission of this error-prone RNA virus involves a continuous interaction between rapid sequence variation and natural selection. To elucidate the molecular characteristics of CV-A4 and the spatiotemporal dynamic changes in CV-A4 transmission, worldwide sequences of the 3' VP1 region (420 nt) obtained from GenBank were analyzed together with sequences isolated in Taiwan from 2002 to 2009. Sequences were characterized in terms of recombination, variability, and selection. Phylogenetic trees were constructed using neighbor-joining, maximum likelihood and Monte Carlo Markov Chain methods. Spatiotemporal dynamics of CV-A4 transmission were further estimated by a Bayesian statistical inference framework. No recombination was detected in the 420 nt region. The estimated evolution rate of CV-A4 was 8.65 × 10(-3) substitutions/site/year, and a purifying selection (d(N)/d(S)=0.032) was noted over the 3' VP1 region. All trees had similar topology: two genotypes (GI and GII), each including two subgenotypes (A and B), with the prototype and a Kenyan strain in separate branches. The results revealed that the virus first appeared in USA in 1950. Since 1998, it has evolved into the Kenya, GI-A (Asia) and GII-A (Asia and Europe) strains. Since 2004, GI-B and GII-B have evolved continuously and have remained prevalent. The co-existence of several positive selection lineages of GI-B in 2006 indicates that the subgenotype might have survived lineage extinction. This study revealed rapid lineage turnover of CV-A4 and the replacement of previously circulating strains by a new dominant variant. Therefore, continuous surveillance for further CV-A4 transmission is essential. PMID:21635970

  4. SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice

    PubMed Central

    Li, Xiangming; Sanneman, Joel D.; Harbidge, Donald G.; Zhou, Fei; Ito, Taku; Nelson, Raoul; Picard, Nicolas; Chambrey, Régine; Eladari, Dominique; Miesner, Tracy; Griffith, Andrew J.; Marcus, Daniel C.; Wangemann, Philine

    2013-01-01

    Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4 Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4. PMID:23874234

  5. Pharmacological and Therapeutic Effects of A3 Adenosine Receptor (A3AR) Agonists

    PubMed Central

    Fishman, Pnina; Bar-Yehuda, Sara; Liang, Bruce T.; Jacobson, Kenneth A.

    2011-01-01

    The Gi-coupled A3 adenosine receptor (A3AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. The present review summarizes preclinical and clinical human studies demonstrating that A3AR agonists induce specific anti-inflammatory and anticancer effects via a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. Currently, A3AR agonists are being developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis. PMID:22033198

  6. Chromomycin A2 induces autophagy in melanoma cells.

    PubMed

    Guimarães, Larissa Alves; Jimenez, Paula Christine; Sousa, Thiciana da Silva; Freitas, Hozana Patrícia S; Rocha, Danilo Damasceno; Wilke, Diego Veras; Martín, Jesús; Reyes, Fernando; Deusdênia Loiola Pessoa, Otília; Costa-Lotufo, Letícia Veras

    2014-12-01

    The present study highlights the biological effects of chromomycin A2 toward metastatic melanoma cells in culture. Besides chromomycin A2, chromomycin A3 and demethylchromomycin A2 were also identified from the extract derived from Streptomyces sp., recovered from Paracuru Beach, located in the northeast region of Brazil. The cytotoxic activity of chromomycin A2 was evaluated across a panel of human tumor cell lines, which found IC50 values in the nM-range for exposures of 48 and 72 h. MALME-3M, a metastatic melanoma cell line, showed the highest sensitivity to chromomycin A2 after 48h incubation, and was chosen as a model to investigate this potent cytotoxic effect. Treatment with chromomycin A2 at 30 nM reduced cell proliferation, but had no significant effect upon cell viability. Additionally, chromomycin A2 induced accumulation of cells in G0/G1 phase of the cell cycle, with consequent reduction of S and G2/M and unbalanced expression of cyclins. Chromomycin A2 treated cells depicted several cellular fragments resembling autophagosomes and increased expression of proteins LC3-A and LC3-B. Moreover, exposure to chromomycin A2 also induced the appearance of acidic vacuolar organelles in treated cells. These features combined are suggestive of the induction of autophagy promoted by chromomycin A2, a feature not previously described for chromomycins. PMID:25486109

  7. Interactions between CYP3A4 and Dietary Polyphenols

    PubMed Central

    Basheer, Loai; Kerem, Zohar

    2015-01-01

    The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols. PMID:26180597

  8. Interactions between CYP3A4 and Dietary Polyphenols.

    PubMed

    Basheer, Loai; Kerem, Zohar

    2015-01-01

    The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols. PMID:26180597

  9. Structure–Activity Relationships and Molecular Modeling of 3,5-Diacyl-2,4-dialkylpyridine Derivatives as Selective A3 Adenosine Receptor Antagonists

    PubMed Central

    Li, An-Hu; Moro, Stefano; Melman, Neli; Ji, Xiao-duo; Jacobson, Kenneth A.

    2012-01-01

    The structure-activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A3 adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667-4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. Ki values in the nanomolar range were observed for certain 3,5-diacyl-2,4-dialkyl-6-phenylpyridine derivatives in displacement of [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5′-N-methylcarbamoyladenosine) at recombinant human A3 adenosine receptors. Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors. Structure–activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A3 selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2-and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at A3 adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4-dihydropyridines were favorable for high affinity at human A3 adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate, 38, was highly potent at human A3 receptors, with a Ki value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A3 receptors, with Ki values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a Ki value of 7.94 nM at human A3 receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore

  10. Priapism Induced by Boceprevir-CYP3A4 Inhibition and α-Adrenergic Blockade: Case Report

    PubMed Central

    Hammond, Kyle P.; Nielsen, Craig; Linnebur, Sunny A.; Langness, Jacob A.; Ray, Graham; Maroni, Paul; Kiser, Jennifer J.

    2014-01-01

    A 44-year-old white man presented to the emergency department with a 3-day history of priapism requiring a surgically performed distal penile shunt. A drug–drug interaction is the suspected cause whereby CYP3A4 inhibition by boceprevir led to increased exposures of doxazosin, tamsulosin, and/or quetiapine, resulting in additional α-adrenergic blockade. PMID:24092799

  11. TMS delivered for A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A state-of-the-art thrust measurement system for the A-3 Test Stand under construction at NASA's John C. Stennis Space Center was delivered March 17. Once completed, the A-3 stand (seen in background) will allow simulated high-altitude testing on the next generation of rocket engines for America's space program. Work on the stand began in 2007, with activation scheduled for 2012. The stand is the first major test structure to be built at Stennis since the 1960s. The recently delivered TMS was fabricated by Thrust Measurement Systems in Illinois. It is an advanced calibration system capable of measuring vertical and horizontal thrust loads with an accuracy within 0.15 percent at 225,000 pounds.

  12. Solution structure of leptospiral LigA4 Big domain.

    PubMed

    Mei, Song; Zhang, Jiahai; Zhang, Xuecheng; Tu, Xiaoming

    2015-11-13

    Pathogenic Leptospiraspecies express immunoglobulin-like proteins which serve as adhesins to bind to the extracellular matrices of host cells. Leptospiral immunoglobulin-like protein A (LigA), a surface exposed protein containing tandem repeats of bacterial immunoglobulin-like (Big) domains, has been proved to be involved in the interaction of pathogenic Leptospira with mammalian host. In this study, the solution structure of the fourth Big domain of LigA (LigA4 Big domain) from Leptospira interrogans was solved by nuclear magnetic resonance (NMR). The structure of LigA4 Big domain displays a similar bacterial immunoglobulin-like fold compared with other Big domains, implying some common structural aspects of Big domain family. On the other hand, it displays some structural characteristics significantly different from classic Ig-like domain. Furthermore, Stains-all assay and NMR chemical shift perturbation revealed the Ca(2+) binding property of LigA4 Big domain. PMID:26449456

  13. A Binding Site Model and Structure-Activity Relationships for the Rat A3 Adenosine Receptor

    PubMed Central

    VAN GALEN, PHILIP J. M.; VAN BERGEN, ANDREW H.; GALLO-RODRIGUEZ, CAROLA; MELMAN, NELI; OLAH, MARK E.; IJZERMAN, AD P.; STILES, GARY L.; JACOBSON, KENNETH A.

    2012-01-01

    SUMMARY A novel adenosine receptor, the A3 receptor, has recently been cloned. We have systematically investigated the hitherto largely unexplored structure-activity relationships (SARs) for binding at A3 receptors, using 125I-N6-2-(4-aminophenyl)ethyladenosine as a radioligand and membranes from Chinese hamster ovary cells stably transfected with the rat A3-cDNA. As is the case for A1 and A2a, receptors, substitutions at the N6 and 5′ positions of adenosine, the prototypic agonist ligand, may yield fairly potent compounds. However, the highest affinity and A3 selectivity is found for N6,5′-disubstituted compounds, in contrast to A1 and A2a receptors. Thus, N6-benzyladenosine-5′-N-ethylcarboxamide is highly potent (Ki, 6.8 nM) and moderately selective (13- and 14-fold versus A1 and A2a). The N6 region of the A3 receptor also appears to tolerate hydrophilic substitutions, in sharp contrast to the other subtypes. Potencies of N6,5′-disubstituted compounds in inhibition of adenylate cyclase via A3 receptors parallel their high affinity in the binding assay. None of the typical xanthine or nonxanthine (A1/A2) antagonists tested show any appreciable affinity for rat A3 receptors. 1,3-Dialkylxanthines did not antagonize the A3 agonist-induced inhibition of adenylate cyclase. A His residue in helix 6 that is absent in A3 receptors but present in A1/A2 receptors may be causal in this respect. In a molecular model for the rat A3 receptor, this mutation, together with an increased bulkiness of residues surrounding the ligand, make antagonist binding unfavorable when compared with a previously developed A1 receptor model. Second, this A3 receptor model predicted similarities with A1 and A2 receptors in the binding requirements for the ribose moiety and that xanthine-7-ribosides would bind to rat A3 receptors. This hypothesis was supported experimentally by the moderate affinity (Ki 6 μM) of 7-riboside of 1,3-dibutylxanthine, which appears to be a partial agonist at

  14. Storing a 3d City Model, its Levels of Detail and the Correspondences Between Objects as a 4d Combinatorial Map

    NASA Astrophysics Data System (ADS)

    Arroyo Ohori, K.; Ledoux, H.; Stoter, J.

    2015-10-01

    3D city models of the same region at multiple LODs are encumbered by the lack of links between corresponding objects across LODs. In practice, this causes inconsistency during updates and maintenance problems. A radical solution to this problem is to model the LOD of a model as a dimension in the geometric sense, such that a set of connected polyhedra at a series of LODs is modelled as a single polychoron—the 4D analogue of a polyhedron. This approach is generally used only conceptually and then discarded at the implementation stage, losing many of its potential advantages in the process. This paper therefore shows that this approach can be instead directly realised using 4D combinatorial maps, making it possible to store all topological relationships between objects.

  15. Identification of A3 adenosine receptor agonists as novel non-narcotic analgesics.

    PubMed

    Janes, K; Symons-Liguori, A M; Jacobson, K A; Salvemini, D

    2016-04-01

    Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new therapeutics. Adenosine and its four cognate receptors (A1 , A2A , A2B and A3 ) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A1 and A2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A3 receptor is only in its infancy, but exciting preclinical observations of A3 receptor antinociception, which have been bolstered by clinical trials of A3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A3 receptor-mediated antinociception. We will highlight recent findings regarding the impact of the A3 receptor on pain pathways and examine the current state of selective A3 receptor agonists used for these studies. The adenosine-to-A3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain. PMID:26804983

  16. 26 CFR 48.4161(a)-4 - Use considered sale.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Use considered sale. 48.4161(a)-4 Section 48... sale. For provisions relating to the tax on use of taxable articles by the manufacturer, producer, or importer thereof, see section 4218 relating to use by a manufacturer being considered a sale, and...

  17. 49 CFR 178.33a-4 - Duties of inspector.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Specifications for Inside Containers, and Linings § 178.33a-4 Duties of inspector. (a) To inspect material and completed containers and witness tests, and to reject defective materials or containers. (b) ... Transportation Other Regulations Relating to Transportation PIPELINE AND HAZARDOUS MATERIALS...

  18. 32 CFR 352a.4 - Responsibilities and functions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.4 Responsibilities and functions. (a) The Director, Defense Finance and Accounting Service (DFAS), is the principal DoD executive for... shall: 1 Copies may be obtained, at cost, from the National Technical Information Service, 5285...

  19. Framing Retention for Institutional Improvement: A 4 Ps Framework

    ERIC Educational Resources Information Center

    Kalsbeek, David H.

    2013-01-01

    A 4 Ps framework for student retention strategy is a construct for reframing the retention discussion in a way that enables institutional improvement by challenging some conventional wisdom and prevailing perspectives that have characterized retention strategy for years. It opens new possibilities for action and improvement by suggesting that…

  20. Inhibition of Osteoclast Bone Resorption by Disrupting Vacuolar H+-ATPase a3-B2 Subunit Interaction*

    PubMed Central

    Kartner, Norbert; Yao, Yeqi; Li, Keying; Crasto, Gazelle J.; Datti, Alessandro; Manolson, Morris F.

    2010-01-01

    Vacuolar H+-ATPases (V-ATPases) are highly expressed in ruffled borders of bone-resorbing osteoclasts, where they play a crucial role in skeletal remodeling. To discover protein-protein interactions with the a subunit in mammalian V-ATPases, a GAL4 activation domain fusion library was constructed from an in vitro osteoclast model, receptor activator of NF-κB ligand-differentiated RAW 264.7 cells. This library was screened with a bait construct consisting of a GAL4 binding domain fused to the N-terminal domain of V-ATPase a3 subunit (NTa3), the a subunit isoform that is highly expressed in osteoclasts (a1 and a2 are also expressed, to a lesser degree, whereas a4 is kidney-specific). One of the prey proteins identified was the V-ATPase B2 subunit, which is also highly expressed in osteoclasts (B1 is not expressed). Further characterization, using pulldown and solid-phase binding assays, revealed an interaction between NTa3 and the C-terminal domains of both B1 and B2 subunits. Dual B binding domains of equal affinity were observed in NTa, suggesting a possible model for interaction between these subunits in the V-ATPase complex. Furthermore, the a3-B2 interaction appeared to be moderately favored over a1, a2, and a4 interactions with B2, suggesting a mechanism for the specific subunit assembly of plasma membrane V-ATPase in osteoclasts. Solid-phase binding assays were subsequently used to screen a chemical library for inhibitors of the a3-B2 interaction. A small molecule benzohydrazide derivative was found to inhibit osteoclast resorption with an IC50 of ∼1.2 μm on both synthetic hydroxyapatite surfaces and dentin slices, without significantly affecting RAW 264.7 cell viability or receptor activator of NF-κB ligand-mediated osteoclast differentiation. Further understanding of these interactions and inhibitors may contribute to the design of novel therapeutics for bone loss disorders, such as osteoporosis and rheumatoid arthritis. PMID:20837476

  1. Structural and functional analysis of human HtrA3 protease and its subdomains

    SciTech Connect

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; van Raaij, Mark J.

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

  2. Structural and functional analysis of human HtrA3 protease and its subdomains

    DOE PAGESBeta

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; et al

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that themore » protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.« less

  3. A-3 Test Stand construction update

    NASA Technical Reports Server (NTRS)

    2007-01-01

    The concrete foundation placed Dec. 18 (foreground) for Stennis Space Center's future A-3 Test Stand has almost completely cured by early January, according to Bo Clarke, NASA's contracting officer technical representative for the foundation contract. By late December, construction on foundations for many of the test stand's support structures - diffuser, liquid oxygen, isopropyl alcohol and water tanks and gaseous nitrogen bottle battery - had begun with the installation of (background) `mud slabs.' The slabs provide a working surface for the reinforcing steel and foundation forms.

  4. A 3-d modular gripper design tool

    SciTech Connect

    Brown, R.G.; Brost, R.C.

    1997-02-01

    Modular fixturing kits are sets of components used for flexible, rapid construction of fixtures. A modular vise is a parallel-jaw vise, each jaw of which is a modular fixture plate with a regular grid of precisely positioned holes. To fixture a part, one places pins in some of the holes so that when the vise is closed, the part is reliably located and completely constrained. The modular vise concept can be adapted easily to the design of modular parallel-jaw grippers for robots. By attaching a grid-plate to each jaw of a parallel-jaw gripper, one gains the ability to easily construct high-quality grasps for a wide variety of parts from a standard set of hardware. Wallack and Canny developed an algorithm for planning planar grasp configurations for the modular vise. In this paper, the authors expand this work to produce a 3-d fixture/gripper design tool. They describe several analyses they have added to the planar algorithm, including a 3-d grasp quality metric based on force information, 3-d geometric loading analysis, and inter-gripper interference analysis. Finally, the authors describe two applications of their code. One of these is an internal application at Sandia, while the other shows a potential use of the code for designing part of an agile assembly line.

  5. Ephrin-as cooperate with EphA4 to promote trunk neural crest migration.

    PubMed

    McLennan, R; Krull, C E

    2002-01-01

    Trunk neural crest cells delaminate from the dorsal neural tube and migrate on two distinct pathways: a dorsolateral route, between the ectoderm and somites,and a ventromedial route, through the somitic mesoderm. Neural crest cells that migrate ventromedially travel in a segmental manner through rostral half-somites, avoiding caudal halves. Recent studies demonstrate that various molecular cues guide the migration of neural crest cells, primarily by serving as inhibitors to premature pathway entry orby preventing neural crest from entering inappropriate territories. Trajectories of migrating trunk neural crest are well organized and generally linear in nature, suggesting that positive, migration-promoting factors may be responsible for this organized cell behavior. However, the identity of these factors and their function are not well understood. Here we examine the expression of members of the EphA subclass of receptor tyrosine kinases and ephrins using RT-PCR and immunocytochemistry. Neural crest cells express ephrins and EphA4 at distinct stages during their migration. In functional analyses, addition of ephrin-A2-, ephrin-A5-, and EphA4-Fc disrupted the segmental organization of trunk neural crest migration in explants: neural crest cells entered rostral and caudal halves of somites. Finally, to test the specific effects of these factors on cell behavior, neural crest cells were exposed in vitro to substrate-bound EphA and ephrin-As. Surprisingly, neural crest cells avoided ephrin-A2 or ephrin-A5 substrates; this avoidance was abolished by the addition of EphA4. Together, these data suggest that ephrin-As and EphA4 cooperate to positively promote the migration of neural crest cells through rostral half somites in vivo. PMID:12450221

  6. [Significance and progress of DIAN/A4/API].

    PubMed

    Shimada, Hiroyuki

    2016-03-01

    The DIAN observational study compared the pathophysiological markers between mutation carriers and non-carriers for autosomal dominant Alzheimer's disease. It has revealed the biomarker changes in the mutation carrier's brain started as early as 20, even 25 years prior to symptoms. The researchers of DIAN started the prevention trial(DIAN-TU) with two monoclonal antibodies. The API study is the clinical trial of the anti-amyloid monoclonal antibody therapy to the kindred of early onset familial AD (EOAD) who carry the PSEN1 E280A mutation. This study has also shown the same biomarker changes that were reported in the DIAN study. Anti-Amyloid Treatment in Asymptomatic AD (A4) is a prevention trial aimed at treating cognitive normal older individuals at risk of developing Alzheimer's disease dementia on the basis of having biomarker evidence of amyloid (pre-clinical AD). Solanezumab was selected for the anti-amyloid treatment for A4. PMID:27025079

  7. Preparation and structure of the alkali-metal fulleride A4C60

    NASA Astrophysics Data System (ADS)

    Fleming, R. M.; Rosseinsky, M. J.; Ramirez, A. P.; Murphy, D. W.; Tully, J. C.; Haddon, R. C.; Siegrist, T.; Tycko, R.; Glarum, S. H.; Marsh, P.; Dabbagh, G.; Zahurak, S. M.; Makhija, A. V.; Hampton, C.

    1991-08-01

    SUPERCONDUCTING K3C60 (ref. 1) has been shown2 to have an intercalated face-centred cubic (f.c.c.) structure, and other A3C60 compounds (where A is K, Rb or mixtures of K, Rb and/or Cs) form an isostructural series with superconducting transition temperatures up to 31.3 K (ref. 3). Recently we reported4 13C NMR studies of K x C60 for x<3, and concluded that the system contained two phases (x = 0 and x = 3) for 0A3C60 (refs 2, 3) and body-centred cubic A6C60 (ref. 5), A4C60 (where A is K, Rb, Cs) has a body-centred tetragonal structure. We show that all of the experimentally observed phases of A x C60 can be predicted solely on the basis of electrostatic considerations. We have found no evidence for superconductivity in A4C60.

  8. Retroperitoneal necrotizing fasciitis in a 4-year-old girl.

    PubMed

    Paya, K; Hayek, B F; Rebhandl, W; Pollak, A; Horcher, E

    1998-05-01

    Necrotizing fasciitis is a rare but serious condition with a poor prognosis both in adults and in children. Retroperitoneal localization is mostly associated with fatal outcome. Early diagnosis, extensive and repeated surgical debridement, and use of antibiotics are necessary. Herein the authors report on a 4-year-old girl in whom retroperitoneal necrotizing fasciitis developed after she suffered from pyelonephritis. In this case, the outcome was favorable because of early surgical intervention, confirming the diagnosis. PMID:9607500

  9. Obsessive Compulsive Disorder in a 4-Year-Old Child

    PubMed Central

    Kulkarni, Harish; Sudarshan, C. Y.

    2015-01-01

    Obsessive-compulsive disorder (OCD) is a very distressing disorder for both patient and caregiver. Usual onset of the disorder is in late second or early third decade of life. It is diagnosed in children but rarely before 5 years. A case of OCD in a 4-year-old girl is reported here. Diagnostic and therapeutic dilemmas in such a situation are discussed. PMID:25969614

  10. A 3-terminal single molecule nanoscale amperometer

    NASA Astrophysics Data System (ADS)

    Hliwa, M.; Ami, S.; Joachim, C.

    2006-07-01

    A 3-terminal single molecule transducer is presented which is able to measure tunnel current intensities. The conformation of a pyrene-phenyl molecule is changed under an intramolecular inelastic current effect. This conformation change is detected by a third lateral electrode interacting also with the molecule. The full multi-channel electronic scattering matrix of the device is calculated taking into account the chemisorption of the molecule at one end and the details mechanics of the conformation change of this molecule. A semi-classical model is used to describe the intramolecular transduction effect between the electrons transferred through the molecule and its conformation change. It results a linear transduction curve between the input and the detection currents of the device for a range of tunnel current of interest for mono-molecular electronics.

  11. Towards a complete A4 × SU(5) SUSY GUT

    NASA Astrophysics Data System (ADS)

    Björkeroth, Fredrik; de Anda, Francisco J.; de Medeiros Varzielas, Ivo; King, Stephen F.

    2015-06-01

    We propose a renormalisable model based on A 4 family symmetry with an SU(5) grand unified theory (GUT) which leads to the minimal supersymmetric standard model (MSSM) with a ℤ9 × ℤ6 symmetry provides the fermion mass hierarchy in both the quark and lepton sectors, while ℤ {4/ R } symmetry is broken to ℤ {2/ R }, identified as usual R-parity. Proton decay is highly sup-pressed by these symmetries. The strong CP problem is solved in a similar way to the Nelson-Barr mechanism. We discuss both the A 4 and SU(5) symmetry breaking sectors, including doublet-triplet splitting, Higgs mixing and the origin of the μ term. The model provides an excellent fit (better than one sigma) to all quark and lepton (including neu-trino) masses and mixing with spontaneous CP violation. With the A 4 vacuum alignments, (0, 1, 1) and (1, 3, 1), the model predicts the entire PMNS mixing matrix with no free pa-rameters, up to a relative phase, selected to be 2π/3 from a choice of the nine complex roots of unity, which is identified as the leptogenesis phase. The model predicts a normal neutrino mass hierarchy with leptonic angles θ{13/ ι } ≈ 8.7∘, θ{12/ ι } ≈ 34∘, θ{23/ ι } ≈ 46∘ and an oscillation phase δ ι ≈ - 87∘.

  12. 26 CFR 1.6038A-4 - Monetary penalty.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... to meet the non-U.S. record maintenance requirements within the applicable time prescribed in § 1... maintain or cause another to maintain records, or for a failure to comply with the non-U.S. maintenance... another to maintain records as required by § 1.6038A-3, and not complying with the non-U.S....

  13. Study Liver Cytochrome P450 3A4 Inhibition and Hepatotoxicity Using DMSO-Differentiated HuH-7 Cells.

    PubMed

    Liu, Yitong

    2016-01-01

    Metabolically competent, inexpensive, and robust in vitro cell models are needed for studying liver drug-metabolizing enzymes and hepatotoxicity. Human hepatoma HuH-7 cells develop into a differentiated in vitro model resembling primary human hepatocytes after a 2-week dimethyl sulfoxide (DMSO) treatment. DMSO-treated HuH-7 cells express elevated cytochrome P450 3A4 (CYP3A4) enzyme gene expression and activity compared to untreated HuH-7 cells. This cell model could be used to study CYP3A4 inhibition by reversible and time-dependent inhibitors, including drugs, food-related substances, and environmental chemicals. The DMSO-treated HuH-7 model is also a suitable tool for investigating hepatotoxicity. This chapter describes a detailed methodology for developing DMSO-treated HuH-7 cells, which are subsequently used for CYP3A4 inhibition and hepatotoxicity studies. PMID:27518624

  14. Short-term effects of amelogenin gene splice products A+4 and A-4 implanted in the exposed rat molar pulp

    PubMed Central

    Jegat, Nadège; Septier, Dominique; Veis, Arthur; Poliard, Anne; Goldberg, Michel

    2007-01-01

    In order to study the short-time effects of two bioactive low-molecular amelogenins A+4 and A-4, half-moon cavities were prepared in the mesial aspect of the first maxillary molars, and after pulp exposure, agarose beads alone (controls) or beads soaked in A+4 or A-4 (experimental) were implanted into the pulp. After 1, 3 or 7 days, the rats were killed and the teeth studied by immunohistochemistry. Cell proliferation was studied by PCNA labeling, positive at 3 days, but decreasing at day 7 for A+4, whilst constantly high between 3 and 7 days for A-4. The differentiation toward the osteo/odontoblast lineage shown by RP59 labeling was more apparent for A-4 compared with A+4. Osteopontin-positive cells were alike at days 3 and 7 for A-4. In contrast, for A+4, the weak labeling detected at day 3 became stronger at day 7. Dentin sialoprotein (DSP), an in vivo odontoblast marker, was not detectable until day 7 where a few cells became DSP positive after A-4 stimulation, but not for A+4. These results suggest that A +/- 4 promote the proliferation of some pulp cells. Some of them further differentiate into osteoblast-like progenitors, the effects being more precocious for A-4 (day 3) compared with A+4 (day 7). The present data suggest that A +/- 4 promote early recruitment of osteogenic progenitors, and evidence functional differences between A+4 and A-4. PMID:18154672

  15. MHDust: A 3-fluid dusty plasma code

    NASA Astrophysics Data System (ADS)

    Lazerson, Samuel

    MHDust is a next generation 3-fluid magnetized dusty plasma code, treating the inertial dynamics of both the dust and ion components. Coded in ANSI C, the numerical method employs Leap-Frog and Dufort-Frankel integration schemes. Features include: nonlinear collisional terms, quasi-neutrality or continuity based electron densities, and dynamical dust charge number. Tests of wave-mode propagation (Acoustic and Electromagnetic) allow a comparison to linear wave mode theory. Additional nonlinear phenomena are presented including magnetic reconnection and shear-flow instabilities. Relevant parameters for the space environment are considered, allowing a comparison to be made with previous dusty plasma codes (DENISIS). The utility of the code is expanded through the possibility of small dust mass. This allows MH- Dust to be used as a 2-ion plasma code. MHDust considerably expands the range of numerical investigations into nonlinear phenomena in the field of astrophysical dusty plasmas.

  16. Bifrost: A 4th Generation Launch Architecture Concept

    NASA Astrophysics Data System (ADS)

    Rohrschneider, R. R.; Young, D.; St.Germain, B.; Brown, N.; Crowley, J.; Maatsch, J.; Olds, J. R.

    2002-01-01

    A 4th generation launch architecture is studied for the purpose of drastically reducing launch costs and hence enabling new large mass missions such as space solar power and human exploration of other planets. The architecture consists of a magnetic levitation launch tube placed on the equator with the exit end elevated to approximately 20 km. Several modules exist for sending manned and unmanned payloads into Earth orbit. Analysis of the launch tube operations, launch trajectories, module aerodynamics, propulsion modules, and system costs are presented. Using the hybrid logistics module, it is possible to place payloads into low Earth orbit for just over 100 per lb.

  17. A 3-d modular gripper design tool

    SciTech Connect

    Brown, R.G.; Brost, R.C.

    1997-01-01

    Modular fixturing kits are precisely machined sets of components used for flexible, short-turnaround construction of fixtures for a variety of manufacturing purposes. A modular vise is a parallel-jaw vise, where each jaw is a modular fixture plate with a regular grid of precisely positioned holes. A modular vise can be used to locate and hold parts for machining, assembly, and inspection tasks. To fixture a part, one places pins in some of the holes so that when the vise is closed, the part is reliably located and completely constrained. The modular vise concept can be adapted easily to the design of modular parallel-jaw grippers for robots. By attaching a grid plate to each jaw of a parallel-jaw gripper, the authors gain the ability to easily construct high-quality grasps for a wide variety of parts from a standard set of hardware. Wallack and Canny developed a previous algorithm for planning planar grasp configurations for the modular vise. In this paper, the authors expand this work to produce a 3-d fixture/gripper design tool. They describe several analyses added to the planar algorithm to improve its utility, including a three-dimensional grasp quality metric based on geometric and force information, three-dimensional geometric loading analysis, and inter-gripper interference analysis to determine the compatibility of multiple grasps for handing the part from one gripper to another. Finally, the authors describe two applications which combine the utility of modular vise-style grasping with inter-gripper interference: The first is the design of a flexible part-handling subsystem for a part cleaning workcell under development at Sandia National Laboratories; the second is the automatic design of grippers that support the assembly of multiple products on a single assembly line.

  18. Recent Results and Future Plans from the A4 Experiment

    NASA Astrophysics Data System (ADS)

    Deconinck, Wouter; A4 Collaboration

    2011-04-01

    In the A4 experiment at the MAMI facility in Mainz, Germany, we use the parity-violating asymmetry present in the scattering of longitudinally polarized electrons from unpolarized protons or deuterons to measure the strangeness contribution to the electromagnetic form factors of the nucleon. The A4 experiment uses a PbF2 calorimeter that can be positioned in the forward or backward direction to measure the electrons scattered in a liquid hydrogen or deuterium target. Recent results for the proton at a momentum transfer Q2 = 0 . 23 GeV2 /c2 and the ongoing analysis of the data at Q2 = 0 . 61 GeV2 /c2 will be discussed. Future plans include the measurement of the strangeness form factor at Q2 = 0 . 1 GeV2 /c2 with the current detector to a twice higher precision than the currently available data, and a high precision measurement at an even lower Q2 with an upgraded polarimeter and detector.

  19. Spontaneous CP violation in A4 flavor symmetry and leptogenesis

    NASA Astrophysics Data System (ADS)

    Ahn, Y. H.; Kang, Sin Kyu; Kim, C. S.

    2013-06-01

    We propose a simple renormalizable model for the spontaneous CP violation based on SU(2)L×U(1)Y×A4 symmetry in a radiative seesaw mechanism, which can be guaranteed by an extra Z2 symmetry. In our model CP is spontaneously broken at high energies, after the breaking of flavor symmetry, by a complex vacuum expectation value of the A4 triplet and gauge-singlet scalar field. We show that the spontaneously generated CP phase could become a natural source of leptogenesis, and also investigate CP violation at low energies in the lepton sector and show how the CP phases in the Pontecorvo-Maki-Nakagawa-Sakata formalism could arise through a spontaneous symmetry-breaking mechanism. As a numerical study, interestingly, we show that the normal mass hierarchy favors relatively large values of θ13, large deviations from maximality of θ23<π/4, and the Dirac-CP phase 0°≤δCP≤50° and 300°≤δCP≤360°. For the inverted hierarchy case, the experimentally measured values of θ13 favors θ23>π/4 and discrete values of δCP around 100°, 135°, 255°, and 300°. Finally, with a successful leptogenesis our numerical results give more predictive values on the Dirac CP phase: for the normal mass hierarchy 1°≲δCP≲10° and for inverted one δCP˜100°, 135°, 300°.

  20. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

    Hosseinbor, A. Pasha; Chung, Moo K.; Wu, Yu-Chien; Bendlin, Barbara B.; Alexander, Andrew L.

    2015-01-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we derive several well-established q-space indices and numerically estimate the diffusion orientation distribution function (dODF). We also derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. Most importantly, we will demonstrate that for hybrid diffusion imaging (HYDI) acquisitions low order linear expansion of the HSH basis is sufficient to characterize diffusion in neural tissue. In fact, the HSH basis achieves comparable signal and better dODF reconstructions than other well-established methods, such as Bessel Fourier orientation reconstruction (BFOR), using fewer fitting parameters. All in all, this work provides a new way of looking at q-space. PMID:25624043

  1. Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia.

    PubMed

    Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda; Chen, Miao; Keimig, David; Bielitz, Robert C; Xie, Hehuang; He, Jia-Qiang; Huckle, William R; Theus, Michelle H

    2016-01-01

    Leptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID:27467069

  2. Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia

    PubMed Central

    Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda; Chen, Miao; Keimig, David; Bielitz, Robert C.; Xie, Hehuang; He, Jia-Qiang; Huckle, William R.; Theus, Michelle H.

    2016-01-01

    Leptomeningeal anastomoses play a critical role in regulating vascular re-perfusion following obstruction, however, the mechanisms regulating their development remains under investingation. Our current findings indicate that EphA4 receptor is a novel negative regulator of collaterogenesis. We demonstrate that EphA4 is highly expressed on pial arteriole collaterals at post-natal day (P) 1 and 7, then significantly reduced by P21. Endothelial cell (EC)-specific loss of EphA4, EphA4f/f/Tie2::Cre (KO), resulted in an increase in the density but not diameter of pial collaterals compared to WT mice. ECs isolated from KO mice displayed a 3-fold increase in proliferation, enhanced migration, tube formation and elevated levels of phospho(p)-Akt compared to WT ECs. Attenuating p-Akt, using LY294002, reduced the proliferative and migration effects in the KO ECs. RNAseq analysis also revealed altered expression patterns for genes that regulate cell proliferation, vascular development, extracellular matrix and immune-mediate responses, namely MCP-1, MMP2 and angiopoietin-1. Lastly, we show that induction of hindlimb ischemia resulted in accelerated re-perfusion, collateral remodeling and reduced tissue necrosis in the absence of EC-specific EphA4 compared to WT mice. These findings demonstrate a novel role for EphA4 in the early development of the pial collateral network and suggests a role in regulating vascular remodeling after obstruction. PMID:27467069

  3. A 3-D shape model of Interamnia

    NASA Astrophysics Data System (ADS)

    Sato, Isao

    2015-08-01

    A 3-D shape model of the sixth largest of the main belt asteroids, (704) Interamnia, is presented. The model is reproduced from its two stellar occultation observations and six lightcurves between 1969 and 2011. The first stellar occultation was the occultation of TYC 234500183 on 1996 December 17 observed from 13 sites in the USA. An elliptical cross section of (344.6±9.6km)×(306.2±9.1km), for position angle P=73.4±12.5 was fitted. The lightcurve around the occultation shows that the peak-to-peak amplitude was 0.04 mag. and the occultation phase was just before the minimum. The second stellar occultation was the occultation of HIP 036189 on 2003 March 23 observed from 39 sites in Japan and Hawaii. An elliptical cross section of (349.8±0.9km)×(303.7±1.7km), for position angle P=86.0±1.1 was fitted. A companion of 8.5 mag. of the occulted star was discovered whose separation is 12±2 mas (milli-arcseconds), P=148±11 . A combined analysis of rotational lightcurves and occultation chords can return more information than can be obtained with either technique alone. From follow-up photometric observations of the asteroid between 2003 and 2011, its rotation period is determined to be 8.728967167±0.00000007 hours, which is accurate enough to fix the rotation phases at other occultation events. The derived north pole is λ2000=259±8, β2000=-50±5 (retrograde rotation); the lengths of the three principal axes are 2a=361.8±2.8km, 2b=324.4±5.0km, 2c=297.3±3.5km, and the mean diameter is D=326.8±3.0km. Supposing the mass of Interamnia as (3.5±0.9)×10-11 solar masses, the density is then ρ=3.8±1.0 g cm-3.

  4. Encoding degree testing in a 4f architecture

    NASA Astrophysics Data System (ADS)

    Amaya, Dafne; Tebaldi, Myrian; Torroba, Roberto; Bolognini, Néstor

    2011-08-01

    The distribution of the encrypted information at the output of an encoding system is of major concern. When the encrypted information is conveyed to the final user, the finite size of the recording medium affects the quality of the encoded information. In this case, we face possible information degradation when recovering. In the present contribution we focus our attention on the finite size of the recorder medium in an actual experimental situation. In order to improve the quality of the decrypted data, we study the role that both the scattering element size of the masks and the input object size play in the encrypting system. Therefore, we analyze the optimal spatial distribution of the encoded information at the output of a 4f encrypting system. We present examples that support our proposal.

  5. The role of annexin A4 in cancer.

    PubMed

    Yao, Houshan; Sun, Chang; Hu, Zhiqian; Wang, Weijun

    2016-01-01

    Annexin A4 (ANXA4) is a member of the annexin family that binds to both calcium ions and phospholipids. Studies indicate that ANXA4 modulates membrane permeability and membrane trafficking, participates in cellular growth and apoptosis, enhances tumor invasion and promotes anti-tumor drug resistance. The overexpression of ANXA4 has been identified in various clinical epithelial tumors including: lung, gastric, colorectal, pancreatic, gallbladder, breast, renal, ovarian, laryngeal, and prostate cancers. In addition, upregulation and nuclear translocation of ANXA4 have been observed in the progression of colorectal cancer and ovarian serous carcinoma. Knockdown of ANXA4 attenuated migration in ovarian cancer and breast cancer cells. In contrast, knockdown of ANXA4 increased susceptibility to platinum in ovarian cancer and malignant mesothelioma cells. It is conceivable that ANXA4 is an indicator for tumor development, invasion, chemo-resistance, poor outcomes of cancer patients, and may be a potential target for therapeutic intervention. PMID:27100483

  6. Rectal bleeding in a 4-month-old boy

    SciTech Connect

    Dutro, J.A.; Santanello, S.A.; Unger, F.; Goodwin, C.D.

    1986-10-24

    A case of bleeding Meckel's diverticulum is described in an infant. A 4-month-old boy was seen initially with a 24-hour history of painless hematochezia. His parents had noted two episodes of maroon-colored stool that did not appear to be associated with any abdominal distress. His medical history was unremarkable, with normal growth and development. Physical examination revealed a well-nourished, well-hydrated infant in no apparent distress. Vital signs were normal. Rectal examination revealed no masses, but bright-red blood was noted on the examining finger. Findings from the remainder of the examination were normal. An upright roentgenogram of the abdomen was obtained and demonstrated no abnormalities. The abdominal technetium scan was abnormal. An exploratory laparotomy was performed later on the day of admission.

  7. Organising evidence for environmental management decisions: a '4S' hierarchy.

    PubMed

    Dicks, Lynn V; Walsh, Jessica C; Sutherland, William J

    2014-11-01

    Making decisions informed by the best-available science is an objective for many organisations managing the environment or natural resources. Yet, available science is still not widely used in environmental policy and practice. We describe a '4S' hierarchy for organising relevant science to inform decisions. This hierarchy has already revolutionised clinical practice. It is beginning to emerge for environmental management, although all four levels need substantial development before environmental decision-makers can reliably and efficiently find the evidence they need. We expose common bypass routes that currently lead to poor or biased representation of scientific knowledge. We argue that the least developed level of the hierarchy is that closest to decision-makers, placing synthesised scientific knowledge into environmental decision support systems. PMID:25280588

  8. Inhibitory effect of salvianolate on human cytochrome P450 3A4 in vitro involving a noncompetitive manner

    PubMed Central

    Qin, Chong-Zhen; Ren, Xian; Zhou, Hong-Hao; Mao, Xiao-Yuan; Liu, Zhao-Qian

    2015-01-01

    Salvianolic acid B (Sal B), which is purified from Danshen, is a popular herb extract. Sal B has anti-oxidative, anti-inflammatory, anti-hypoxic, anti-arteriosclerotic and anti-apoptotic properties. This substance can also ameliorate brain injury or neurodegenerative diseases. The listed drug Salvianolate, which contains a substantial amount of Sal B, has been used for the treatment of coronary heart disease. Our present work aimed to evaluate the inhibitory effect of salvianolate on seven cytochrome P450 isoforms (CYP450), namely, CYP1A2, CYP2A6, CYP2E1, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, in human liver microsomes (HLMs) and recombinant enzymes through high-performance liquid chromatography (HPLC) assay. Salvianolate have a potent inhibitory effect on CYP3A4 activity with IC50 values of 1.438 (HLMs) and 3.582 (recombinant cDNA-expressed CYP3A4) mg/L, respectively. Salvianolate strongly dose, but not time-dependently decreased CYP3A4 activity in HLMs. The typical Lineweaver-Burk plots showed that Salvianolate inhibited CYP3A4 activity noncompetitively, with a Ki value of 2.27 mg/L in HLMs. Other CYP450 isoforms are not markedly affected by Salvianolate. These findings indicate that salvianolate may be involved in potential drug interactions when co-administrated with CYP3A4 substrates. PMID:26629047

  9. A 3T Sodium and Proton Composite Array Breast Coil

    PubMed Central

    Kaggie, Joshua D.; Hadley, J. Rock; Badal, James; Campbell, John R.; Park, Daniel J.; Parker, Dennis L.; Morrell, Glen; Newbould, Rexford D.; Wood, Ali F.; Bangerter, Neal K.

    2013-01-01

    Purpose The objective of this study was to determine whether a sodium phased array would improve sodium breast MRI at 3T. The secondary objective was to create acceptable proton images with the sodium phased array in place. Methods A novel composite array for combined proton/sodium 3T breast MRI is compared to a coil with a single proton and sodium channel. The composite array consists of a 7-channel sodium receive array, a larger sodium transmit coil, and a 4-channel proton transceive array. The new composite array design utilizes smaller sodium receive loops than typically used in sodium imaging, uses novel decoupling methods between the receive loops and transmit loops, and uses a novel multi-channel proton transceive coil. The proton transceive coil reduces coupling between proton and sodium elements by intersecting the constituent loops to reduce their mutual inductance. The coil used for comparison consists of a concentric sodium and proton loop with passive decoupling traps. Results The composite array coil demonstrates a 2–5x improvement in SNR for sodium imaging and similar SNR for proton imaging when compared to a simple single-loop dual resonant design. Conclusion The improved SNR of the composite array gives breast sodium images of unprecedented quality in reasonable scan times. PMID:24105740

  10. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  11. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  12. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  13. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  14. 42 CFR 5a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Applicability. 5a.2 Section 5a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL PHYSICIAN... Public Health Service Act....

  15. 2-Triazole-Substituted Adenosines: A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

    PubMed Central

    Cosyn, Liesbet; Palaniappan, Krishnan K.; Kim, Soo-Kyung; Duong, Heng T.; Gao, Zhan-Guo; Jacobson, Kenneth A.; Van Calenbergh, Serge

    2016-01-01

    “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1–14). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A3AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists, partial agonists, and agonists. PMID:17149867

  16. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  17. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  18. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  19. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  20. 42 CFR 63a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 63a.2 Section 63a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.2 Definitions. As used in this part: Act means...

  1. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  2. 18 CFR 3a.2 - Authority.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Authority. 3a.2 Section 3a.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.2 Authority. Official information...

  3. 32 CFR 352a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 352a.2 Section 352a.2 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.2 Applicability. This part applies to the Office of the Secretary of Defense...

  4. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 51a.2 Section 51a.2 Public Health... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  5. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  6. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  7. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 2a.2 Section 2a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS PROTECTION OF IDENTITY-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services...

  8. 14 CFR 374a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Applicability. 374a.2 Section 374a.2 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.2 Applicability....

  9. 32 CFR 383a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Applicability. 383a.2 Section 383a.2 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE COMMISSARY AGENCY (DeCA) § 383a.2 Applicability. This part applies to the Office of...

  10. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 1 2010-07-01 2010-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  11. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 1 2014-07-01 2014-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  12. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 1 2012-07-01 2012-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  13. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 1 2013-07-01 2013-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  14. 32 CFR 168a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 1 2011-07-01 2011-07-01 false Applicability. 168a.2 Section 168a.2 National Defense Department of Defense OFFICE OF THE SECRETARY OF DEFENSE DEFENSE CONTRACTING NATIONAL DEFENSE SCIENCE AND ENGINEERING GRADUATE FELLOWSHIPS § 168a.2 Applicability. This part applies to the Office...

  15. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.2 Definitions. Undefined...

  16. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.2 Definitions. Undefined...

  17. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.2 Definitions. Undefined...

  18. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.2 Definitions. Undefined...

  19. 42 CFR 59a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definitions. 59a.2 Section 59a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL LIBRARY OF MEDICINE GRANTS Grants for Establishing, Expanding, and Improving Basic Resources § 59a.2 Definitions. Undefined...

  20. 14 CFR 374a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Applicability. 374a.2 Section 374a.2 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.2 Applicability....

  1. 7 CFR 15a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false Definitions. 15a.2 Section 15a.2 Agriculture Office of the Secretary of Agriculture EDUCATION PROGRAMS OR ACTIVITIES RECEIVING OR BENEFITTING FROM FEDERAL FINANCIAL ASSISTANCE Introduction § 15a.2 Definitions. As used in this part, the term: (a) Title IX means title IX of the Education Amendments...

  2. Theoretical Studies of Observable Transitions to Recoupled Pair Bonded States of Sulfur Halide Compounds: SF/SCl (X^2{Π}{→}A^2{Σ}^-), SF_2/SCl_2 (X^1A_1{→}1^1B_1, X^1A_1{→}1^1A_2), and SFCl (X^1A'{→}A^1A{'{'}})

    NASA Astrophysics Data System (ADS)

    Leiding, Jeff; Woon, David E.; Dunning, Thom H.; , Jr.

    2011-06-01

    In previous studies regarding the nature of hypervalent behavior, we identified low-lying excited states of SF(a^4{Σ}^-), SCl(a^4{Σ}^-), SF_2(a^3B_1,b^3A_2), SFCl(a^3A{'{'}}) and SCl_2(a^3B_1) that involve recoupled pair bonding (rpb), where the electrons of the S 3p^2 pair are made available to form bonds. While the transitions from the ground states to the quartet states of SF/SCl and the triplet states of SF_2/SFCl/SCl_2 are spin-forbidden, each of these excited states have analogs with formally spin- and dipole-allowed transitions (except ^1A_2). We performed high level MRCI+Q/aug-cc-pV(Q+d)Z calculations in order to characterize the electronic spectra, spectroscopic constants, and bonding of these species, and made comparisons to available experimental data. We found that excitation into the experimentally known and dipole-forbidden singlet rpb state, SCl_2(B^1A_2), can explain the well-known photodissociation behavior of SCl_2 used to produce SCl(X^2{Π}) radicals in the laboratory. Finally, we have also found a possible system of bond-stretch isomers on the SFCl(A^1A{'{'}}) potential energy surface that is analogous to the behavior on the triplet surface reported in our previous study. Howe, J. D.; Ashfold, M. N. R.; Morgan, R. A.;Western, C. M.; Buma, W. J.; Milan, J. B. and de Lang, C. A. J. Chem. Soc. Faraday Trans. 1995, 91, 773. Leiding, J.; Woon, D. E., and Dunning, T. H., Jr. J. Phys. Chem. A 2011, 115, 329.

  3. Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models.

    PubMed

    Gleeson, M Paul; Davis, Andrew M; Chohan, Kamaldeep K; Paine, Stuart W; Boyer, Scott; Gavaghan, Claire L; Arnby, Catrin Hasselgren; Kankkonen, Cecilia; Albertson, Nan

    2007-01-01

    In-silico models were generated to predict the extent of inhibition of cytochrome P450 isoenzymes using a set of relatively interpretable descriptors in conjunction with partial least squares (PLS) and regression trees (RT). The former was chosen due to the conservative nature of the resultant models built and the latter to more effectively account for any non-linearity between dependent and independent variables. All models are statistically significant and agree with the known SAR and they could be used as a guide to P450 liability through a classification based on the continuous pIC50 prediction given by the model. A compound is classified as having either a high or low P450 liability if the predicted pIC(50) is at least one root mean square error (RMSE) from the high/low pIC(50) cut-off of 5. If predicted within an RMSE of the cut-off we cannot be confident a compound will be experimentally low or high so an indeterminate classification is given. Hybrid models using bulk descriptors and fragmental descriptors do significantly better in modeling CYP450 inhibition, than bulk property QSAR descriptors alone. PMID:18034311

  4. Combretastatin A4 disodium phosphate-induced myocardial injury

    PubMed Central

    Tochinai, Ryota; Nagata, Yuriko; Ando, Minoru; Hata, Chie; Suzuki, Tomo; Asakawa, Naoyuki; Yoshizawa, Kazuhiko; Uchida, Kazumi; Kado, Shoichi; Kobayashi, Toshihide; Kaneko, Kimiyuki; Kuwahara, Masayoshi

    2016-01-01

    Histopathological and electrocardiographic features of myocardial lesions induced by combretastatin A4 disodium phosphate (CA4DP) were evaluated, and the relation between myocardial lesions and vascular changes and the direct toxic effect of CA4DP on cardiomyocytes were discussed. We induced myocardial lesions by administration of CA4DP to rats and evaluated myocardial damage by histopathologic examination and electrocardiography. We evaluated blood pressure (BP) of CA4DP-treated rats and effects of CA4DP on cellular impedance-based contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). The results revealed multifocal myocardial necrosis with a predilection for the interventricular septum and subendocardial regions of the apex of the left ventricular wall, injury of capillaries, morphological change of the ST junction, and QT interval prolongation. The histopathological profile of myocardial lesions suggested that CA4DP induced a lack of myocardial blood flow. CA4DP increased the diastolic BP and showed direct effects on hiPS-CMs. These results suggest that CA4DP induces dysfunction of small arteries and capillaries and has direct toxicity in cardiomyocytes. Therefore, it is thought that CA4DP induced capillary and myocardial injury due to collapse of the microcirculation in the myocardium. Moreover, the direct toxic effect of CA4DP on cardiomyocytes induced myocardial lesions in a coordinated manner.

  5. Aerodynamic analysis of Audi A4 Sedan using CFD

    NASA Astrophysics Data System (ADS)

    Birwa, S. K.; Rathi, N.; Gupta, R.

    2013-04-01

    This paper presents the aerodynamic influence of velocity and ground clearance for Audi A4 Sedan. The topology of the test vehicle was modeled using CATIA P3 V5 R17. ANSYS FLUENT 12 was the CFD solver employed in this study. The distribution of pressure and velocity was obtained. The velocities were 30, 40, 50 and 60 m/s and ground clearances were 76.2 mm,101.6 mm,127 mm and 152.4 mm. The simulation results were compared with the available resources. It was found that the drag coefficient decreases with the velocity increasing from 30 to 60 m/s and increases with the ground clearance from 101.6 mm to 152.4 mm. Further decrease in ground clearance showed no effect on the value of coefficient of drag. The lift coefficient was found to decrease firstly with ground clearance from 152.4 mm to 101.6 mm, and then increase from 101.6 mm to 76.2 mm. Both the lift coefficient and drag coefficient was found to be minimum for the ground clearance of 101.6 mm as designed by the company.

  6. Rotordynamic and leakage characteristics of a 4-stage brush seal

    NASA Astrophysics Data System (ADS)

    Conner, K. J.; Childs, D. W.

    1992-12-01

    Experimental results are presented for the direct and cross-coupled stiffness and damping coefficients as well as the leakage performance for a 4-stage brush seal. Variable test parameters include the inlet pressure, pressure ratio, shaft speed, fluid prerotation, and seal spacing. Direct damping is shown to increase with running speed; otherwise, the rotordynamic coefficients are relatively insensitive to changes in the test parameters. Cross-coupled stiffness is generally unchanged by increasing the inlet tangential velocity to the seals, suggesting that the brush seal is not affected by inlet swirl. Direct stiffness is shown to increase with frequency; however, the magnitudes of direct stiffness are always positive. Cross-coupled stiffness increases slightly with frequency; yet not as drastically as direct stiffness. Comparisons of test results for the 4-stage brush seal with an 8-cavity labyrinth showed superior rotordynamics performance for the brush seal; viz., large values for direct stiffness and lower values for the (destabilizing) cross-coupled stiffness coefficient. The damping for brush seals is smaller, but comparable to labyrinth seals. The whirl-frequency ratio is always smaller for the brush seal.

  7. Curved optical tubes in a 4Pi focusing system.

    PubMed

    Yan, Shaohui; Yu, Xianghua; Li, Manman; Yao, Baoli

    2015-08-24

    We demonstrate the possibility of creating curved optical tubes in a 4Pi focusing system. The focal fields of such optical tubes have interesting properties: the energy is concentered in the neighborhood of a prescribed three-dimensional (3D) curve while the cross section is of hollow shape. The creation of these optical tubes is based on the annular focal spot of a vortex beam, which is employed as a building block. An optical tube is thus obtained by covering the central-axis curve of the tube by various such building blocks. Each building block has a certain orientation and position, realized by a rotation plus a certain translation. The spatial spectrum (the input field as well) of the optical tube is obtained by linearly superposing the spectrum of each transformed building block. The curve is rather arbitrary. Three examples of optical tubes: a torus, a solenoid and a trefoil knot are given, showing a good agreement with the expected results. PMID:26368256

  8. Combretastatin A4 disodium phosphate-induced myocardial injury.

    PubMed

    Tochinai, Ryota; Nagata, Yuriko; Ando, Minoru; Hata, Chie; Suzuki, Tomo; Asakawa, Naoyuki; Yoshizawa, Kazuhiko; Uchida, Kazumi; Kado, Shoichi; Kobayashi, Toshihide; Kaneko, Kimiyuki; Kuwahara, Masayoshi

    2016-07-01

    Histopathological and electrocardiographic features of myocardial lesions induced by combretastatin A4 disodium phosphate (CA4DP) were evaluated, and the relation between myocardial lesions and vascular changes and the direct toxic effect of CA4DP on cardiomyocytes were discussed. We induced myocardial lesions by administration of CA4DP to rats and evaluated myocardial damage by histopathologic examination and electrocardiography. We evaluated blood pressure (BP) of CA4DP-treated rats and effects of CA4DP on cellular impedance-based contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). The results revealed multifocal myocardial necrosis with a predilection for the interventricular septum and subendocardial regions of the apex of the left ventricular wall, injury of capillaries, morphological change of the ST junction, and QT interval prolongation. The histopathological profile of myocardial lesions suggested that CA4DP induced a lack of myocardial blood flow. CA4DP increased the diastolic BP and showed direct effects on hiPS-CMs. These results suggest that CA4DP induces dysfunction of small arteries and capillaries and has direct toxicity in cardiomyocytes. Therefore, it is thought that CA4DP induced capillary and myocardial injury due to collapse of the microcirculation in the myocardium. Moreover, the direct toxic effect of CA4DP on cardiomyocytes induced myocardial lesions in a coordinated manner. PMID:27559241

  9. A 4-node Bilinear Isoparametric Element in Rockwell NASTRAN

    NASA Technical Reports Server (NTRS)

    Liao, C.; Allison, R. E.

    1985-01-01

    The development and evaluation of the Rockwell NASTRAN four node quadrilateral (QUAD4) element is presented. The element derivation utilizes bilinear isoparametric techniques both for membrane and bending characteristics. The QUAD4 element coordinate system, membrane properties, lumped mass matrix, and treatment of warping are based upon the COSMIC/NASTRAN QDMEMI element while the bending characteristics are based on a paper by T. J. R. Hughes. The effects of warping on the bending stiffness, consistent mass, and geometric stiffness are based upon a paper by R. H. MacNeal. Numerical integration is accomplished by Gaussian quadrature on a 2 x 2 grid. Practical user support features include variable element thickness, thermal analysis and layered composite material definitions.

  10. A 4 GHz digital receiver using the Uniboard platform

    NASA Astrophysics Data System (ADS)

    Comoretto, Giovanni; Russo, Antonietta; Quertier, Benjamin; Cais, Philippe; Camino, Pascal

    2012-09-01

    The Uniboard is a general purpose board, developed as a part of the Radionet FP7 program, that hosts 8 Altera StratixIV FPGAs interconnected by high speed links. It can be used standalone or as a part of a more complex system. The Digital receiver application uses a single Uniboard to implement a flexible packetization of a wideband signal in the frequency domain. It accepts a 4 GHz (8 GS/s) input bandwidth and provides up to 64 output bands. The bandwidth and position of each output band can be independently adjusted. The input signal is first analyzed by a polyphase filterbank, that splits the input band into 32 sub-bands with a bandwidth of 190 MHz and a spacing of 128 MHz. The overlap among adjacent bands allows the positioning of the output bands without dead regions. This filterbank is followed by an array of digitally defined downconverters, each one composed of a mixer/LO and a variable decimation filter. The filter band can be adjusted in binary steps from 1 to 128 MHz. Using tap recirculation, the filter shape remains constant over this whole range, with about 60 dB of stopband rejection and 90% usable passband. The output bands are packetized according to the VDIF VLBI standard, over eight 10G Ethernet links. Further processing can be done either on board, or in a cluster of conventional PCs. In addition, high speed ADC are in-house developed (ASIC 65nm CMOS STmicroelectronics) to feed the Uniboard card with 8GS/s, 4GHz BW, 3bits samples.

  11. Successive Translocation of the Rings in a [3]Rotaxane.

    PubMed

    Jagesar, Dhiredj C; Wiering, Piet G; Kay, Euan R; Leigh, David A; Brouwer, Albert M

    2016-06-17

    A [2]rotaxane, a [3]rotaxane and the corresponding thread containing two succinamide (succ) binding stations and a central redox-active pyromellitimide (pmi) station were studied. Infrared spectroelectrochemical experiments revealed the translocation of the macrocycle between the succinamide station and the electrochemically reduced pmi station (radical anion and dianion). Remarkably, in the [3]rotaxane, the rings can be selectively translocated. One-electron reduction leads to the translocation of one of the two macrocycles from the succinamide to the pyromellitimide station, whereas activation of the shuttle through two-electron reduction results in the translocation of both macrocycles: the dianion, due to its higher electron density and hence greater hydrogen-bond accepting affinity, is hydrogen bonded to both macrocycles. Systems with such an on-command contraction are known as molecular muscles. The relative strengths of the binding between the macrocycle and the imide anions could be estimated from the hydrogen-bond-induced shifts in the C=O stretching frequencies of hydrogen-bond accepting amide groups of the macrocycle. PMID:26918870

  12. Use of Projectional Phase Space Data to Infer a 4D Particle Distribution

    SciTech Connect

    Friedman, A; Grote, D P; Celata, C M; Staples, J W

    2002-05-15

    We consider beams which are described by a 4D transverse distribution f(x, y, x', y'), where x' {triple_bond} p{sub x}/p{sub z} and z is the axial coordinate. A two-slit scanner is commonly employed to measure, over a sequence of shots, a 2D projection of such a beam's phase space, e.g., f(x, x'). Another scanner might yield f(y, y') or, using crossed slits, f(x, y). A small set of such 2D scans does not uniquely specify f(x, y, x', y'). We have developed ''tomographic'' techniques to synthesize a ''reasonable'' set of particles in a 4D phase space having 2D densities consistent with the experimental data. These techniques are described in a separate document [A. Friedman, et. al., submitted to Phys. Rev. ST-AB, 2002]. Here we briefly summarize one method and describe progress in validating it, using simulations of the High Current Experiment at Lawrence Berkeley National Laboratory.

  13. Crystal structure of metastasis-associated protein S100A4 in the active, calcium-bound form

    PubMed Central

    Pathuri, Puja; Vogeley, Lutz; Luecke, Hartmut

    2008-01-01

    Summary S100A4 (metastasin) is a member of the S100 family of calcium-binding proteins that is directly involved in tumorgenesis. Until recently, the only structural information available was the solution NMR structure of the inactive, calcium-free form of the protein. Here we report the crystal structure of human S100A4 in the active, calcium-bound state at 2.03 Å resolution that was solved by molecular replacement in the space group P65 with two molecules in the asymmetric unit from perfectly merohedrally twinned crystals. The Ca2+-bound S100A4 structure reveals a large conformational change in the three-dimensional structure of the dimeric S100A4 protein upon calcium binding. This calcium-dependent conformational change opens up a hydrophobic binding pocket that is capable of binding to target proteins such as annexin A2, the p53 tumor suppressor protein, and myosin IIA. The structure of the active form of S100A4 provides insight into its interactions with its binding partners and a better understanding on its role in metastasis. PMID:18783790

  14. A useful model capable of predicting the clearance of cytochrome 3A4 (CYP3A4) substrates in humans: validity of CYP3A4 transgenic mice lacking their own Cyp3a enzymes.

    PubMed

    Mitsui, Tetsuya; Nemoto, Takayuki; Miyake, Taiji; Nagao, Shunsuke; Ogawa, Kotaro; Kato, Motohiro; Ishigai, Masaki; Yamada, Hideyuki

    2014-09-01

    The accurate prediction for the body clearance of a novel drug candidate by humans during the preclinical stage contributes to its successful development. To improve the predictability of human hepatic clearance, we focused on CYP3A4, which is involved in the metabolism of more than 50% of all currently marketed drugs. In this study, we investigated the validity of the in vivo model using transgenic mice carrying the human CYP3A4 gene and lacking their own Cyp3a genes (CYP3A4-Tg mice). The CYP3A4 activity toward its substrates in liver microsomes was similar in CYP3A4-Tg mice and humans. As for the clearance, six CYP3A4 substrates (alprazolam, felodipine, midazolam, nifedipine, nitrendipine, and quinidine) were given intravenously to CYP3A4-Tg mice, and their hepatic intrinsic clearance (CLint,h) was evaluated. A regression analysis of the data obtained indicated that the CLint,h values of six substrates in CYP3A4-Tg mice were highly correlated with those in humans (R(2) = 0.95). This correlation could be improved by correcting the CLint,h values by the relative contribution of artificially expressed CYP3A4 to the overall metabolism in the mice. From these findings, it is reasonable to expect that the CLint,h of a particular drug in humans is predictable by applying the CLint,h obtained in CYP3A4-Tg mice to a regression line prepared in advance. The variance of the CLint,h prediction by this method was evaluated and found to be within a range of 2-fold of the regression value. These results suggest that the CYP3A4-Tg mouse model has the potential to accurately predict the human hepatic clearance of CYP3A4 substrates. PMID:25005602

  15. 12 CFR 261a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 3 2011-01-01 2011-01-01 false Definitions. 261a.2 Section 261a.2 Banks and... citizen of the United States or an alien lawfully admitted for permanent residence. (d) Maintain includes... print, or photograph. (f) Routine use means, with respect to disclosure of a record, the use of...

  16. 42 CFR 85a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definitions. 85a.2 Section 85a.2 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES OCCUPATIONAL SAFETY AND HEALTH RESEARCH... Health of the Centers for Disease Control and Prevention, Department of Health and Human Services....

  17. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... military requirement. (3) Properties subject to special legislation directing a particular action. (4... subject to section 202(a)(2) of the Federal Property and Administrative Service Act of 1949, as amended... HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  18. 45 CFR 12a.2 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... military requirement. (3) Properties subject to special legislation directing a particular action. (4... subject to section 202(a)(2) of the Federal Property and Administrative Service Act of 1949, as amended... HOMELESS § 12a.2 Applicability. (a) This part applies to Federal real property which has been designated...

  19. Structural and Biochemical Characterization of the Oxidoreductase NmDsbA3 from Neisseria meningitidis

    SciTech Connect

    Vivian, Julian P.; Scoullar, Jessica; Robertson, Amy L.; Bottomley, Stephen P.; Horne, James; Chin, Yanni; Wielens, Jerome; Thompson, Philip E.; Velkov, Tony; Piek, Susannah; Byres, Emma; Beddoe, Travis; Wilce, Matthew C.J.; Kahler, Charlene M.; Rossjohn, Jamie; Scanlon, Martin J.

    2009-09-02

    DsbA is an enzyme found in the periplasm of Gram-negative bacteria that catalyzes the formation of disulfide bonds in a diverse array of protein substrates, many of which are involved in bacterial pathogenesis. Although most bacteria possess only a single essential DsbA, Neisseria meningitidis is unusual in that it possesses three DsbAs, although the reason for this additional redundancy is unclear. Two of these N. meningitidis enzymes (NmDsbA1 and NmDsbA2) play an important role in meningococcal attachment to human epithelial cells, whereas NmDsbA3 is considered to have a narrow substrate repertoire. To begin to address the role of DsbAs in the pathogenesis of N. meningitidis, we have determined the structure of NmDsbA3 to 2.3-{angstrom} resolution. Although the sequence identity between NmDsbA3 and other DsbAs is low, the NmDsbA3 structure adopted a DsbA-like fold. Consistent with this finding, we demonstrated that NmDsbA3 acts as a thiol-disulfide oxidoreductase in vitro and is reoxidized by Escherichia coli DsbB (EcDsbB). However, pronounced differences in the structures between DsbA3 and EcDsbA, which are clustered around the active site of the enzyme, suggested a structural basis for the unusual substrate specificity that is observed for NmDsbA3.

  20. Structural and biochemical characterization of the oxidoreductase NmDsbA3 from Neisseria meningitidis.

    PubMed

    Vivian, Julian P; Scoullar, Jessica; Robertson, Amy L; Bottomley, Stephen P; Horne, James; Chin, Yanni; Wielens, Jerome; Thompson, Philip E; Velkov, Tony; Piek, Susannah; Byres, Emma; Beddoe, Travis; Wilce, Matthew C J; Kahler, Charlene M; Rossjohn, Jamie; Scanlon, Martin J

    2008-11-21

    DsbA is an enzyme found in the periplasm of Gram-negative bacteria that catalyzes the formation of disulfide bonds in a diverse array of protein substrates, many of which are involved in bacterial pathogenesis. Although most bacteria possess only a single essential DsbA, Neisseria meningitidis is unusual in that it possesses three DsbAs, although the reason for this additional redundancy is unclear. Two of these N. meningitidis enzymes (NmDsbA1 and NmDsbA2) play an important role in meningococcal attachment to human epithelial cells, whereas NmDsbA3 is considered to have a narrow substrate repertoire. To begin to address the role of DsbAs in the pathogenesis of N. meningitidis, we have determined the structure of NmDsbA3 to 2.3-A resolution. Although the sequence identity between NmDsbA3 and other DsbAs is low, the NmDsbA3 structure adopted a DsbA-like fold. Consistent with this finding, we demonstrated that NmDsbA3 acts as a thiol-disulfide oxidoreductase in vitro and is reoxidized by Escherichia coli DsbB (EcDsbB). However, pronounced differences in the structures between DsbA3 and EcDsbA, which are clustered around the active site of the enzyme, suggested a structural basis for the unusual substrate specificity that is observed for NmDsbA3. PMID:18715864

  1. Diallelic microsatellites developed for Agrostis stolonifera L. population analyses provide evidence for A. transcaspica Litv. as the source of the bentgrass A3 sub-genome

    EPA Science Inventory

    Little is known about the genetic connectivity between creeping bentgrass (Agrostis stolonifera L.) populations. A fundamental challenge to DNA fragment-based population structure analyses of allopolyploid species like creeping bentgrass (2n=4x=28, A2A2A3A3) is scoring individual...

  2. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  3. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 2 2012-07-01 2012-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  4. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  5. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  6. 32 CFR 352a.3 - Organization and management.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Organization and management. 352a.3 Section 352a.3 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS DEFENSE FINANCE AND ACCOUNTING SERVICE (DFAS) § 352a.3 Organization and management....

  7. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  8. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  9. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 8 Aliens and Nationality 1 2013-01-01 2013-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  10. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 8 Aliens and Nationality 1 2012-01-01 2012-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  11. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true QDOT election. 20.2056A-3 Section 20.2056A-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT...

  12. 26 CFR 1.167(a)-3 - Intangibles.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Intangibles. 1.167(a)-3 Section 1.167(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Itemized Deductions for Individuals and Corporations § 1.167(a)-3 Intangibles. (a) In general. If an intangible asset...

  13. 26 CFR 1.409A-3 - Permissible payments.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Permissible payments. 1.409A-3 Section 1.409A-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.409A-3 Permissible payments. (a) In general. The requirements...

  14. 8 CFR 274a.3 - Continuing employment of unauthorized aliens.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 8 Aliens and Nationality 1 2014-01-01 2014-01-01 false Continuing employment of unauthorized aliens. 274a.3 Section 274a.3 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.3 Continuing employment...

  15. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  16. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  17. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  18. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  19. 42 CFR 52a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible to apply? 52a.3 Section 52a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS NATIONAL INSTITUTES OF HEALTH CENTER GRANTS § 52a.3 Who is eligible to apply? (a) Any public or private nonprofit...

  20. 26 CFR 1.512(a)-3 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true 1.512(a)-3 Section 1.512(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.512(a)-3...

  1. Vavilosides A1/A2-B1/B2, new furostane glycosides from the bulbs of Allium vavilovii with cytotoxic activity.

    PubMed

    Zolfaghari, Behzad; Sadeghi, Masoud; Troiano, Raffaele; Lanzotti, Virginia

    2013-04-01

    A phytochemical analysis of the bulbs of Allium vavilovii M. Pop. & Vved. was attained for the first time extensively, affording to the isolation of four new furostanol saponins, named vavilosides A1/A2-B1/B2 (1a/b-2a/2b), as two couple of isomers in equilibrium, together with ascalonicoside A1/A2 (3a/3b) and 22-O-methyl ascalonicoside A1/A2 (4a/4b), previously isolated from shallot, Allium ascalonicum. High concentrations of kaempferol, kaempferide, and kaempferol 4(I)-glucoside were also isolated. The chemical structures of the new compounds, established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses, were identified as (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-galactopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside A1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-galactopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside A2), (25R)-furost-5(6)-en-1β,3β,22α,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-D-xylopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside B1), (25R)-furost-5(6)-en-1β,3β,22β,26-tetraol 1-O-α-L-rhamnopyranosyl-(1→2)-O-β-d-xylopyranosyl 26-O-α-L-rhamnopyranoside (vaviloside B2). The isolated saponins showed cytotoxic activity on J-774, murine monocyte/macrophage, and WEHI-164, murine fibrosarcoma, cell lines with the following rank: vaviloside B1/B2>ascalonicoside A1/A2>vaviloside A1/A2. PMID:23415085

  2. Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles

    SciTech Connect

    Rodriguez-Antona, Cristina . E-mail: cristina.rodriguez-antona@cnio.es; Sayi, Jane G.; Gustafsson, Lars L.; Bertilsson, Leif; Ingelman-Sundberg, Magnus

    2005-12-09

    The human cytochrome P450 3A (CYP3A) enzymes, which metabolize 50% of currently used therapeutic drugs, exhibit great interindividual differences in activity that have a major impact on drug treatment outcome, but hitherto no genetic background importantly contributing to this variation has been identified. In this study we show that CYP3A4 mRNA and hnRNA contents with a few exceptions vary in parallel in human liver, suggesting that mechanisms affecting CYP3A4 transcription, such as promoter polymorphisms, are relevant for interindividual differences in CYP3A4 expression. Tanzanian (n = 143) healthy volunteers were phenotyped using quinine as a CYP3A probe and the results were used for association studies with CYP3A4 genotypes. Carriers of CYP3A4*1B had a significantly lower activity than those with CYP3A4*1 whereas no differences were seen for five other SNPs investigated. Nuclear proteins from the B16A2 hepatoma cells were found to bind with less affinity to the CYP3A4*1B element around -392 bp as compared to CYP3A4*1. The data indicate the existence of a genetic CYP3A4 polymorphism with functional importance for interindividual differences in enzyme expression.

  3. Aggregation Limits Surface Expression of Homomeric GluA3 Receptors.

    PubMed

    Coleman, Sarah K; Hou, Ying; Willibald, Marina; Semenov, Artur; Möykkynen, Tommi; Keinänen, Kari

    2016-04-15

    AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Tyr-454 and Arg-461, in its ligand binding domain (LBD). Surface expression of GluA3 was improved by co-assembly with GluA2 but not with stargazin, a trafficking chaperone and modulator of AMPA receptors. The secretion efficiency of GluA2 and GluA3 LBDs paralleled the transport difference between the respective full-length receptors and was similarly dependent on Tyr-454/Arg-461 but not on LBD stability. In comparison to GluA2, GluA3 homomeric receptors showed a strong and Tyr-454/Arg-461-dependent tendency to aggregate both in the macroscopic scale measured as lower solubility in nonionic detergent and in the microscopic scale evident as the preponderance of hydrodynamically large structures in density gradient centrifugation and native gel electrophoresis. We conclude that the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Tyr-454 and Arg-461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3 receptors to the secretory pathway. PMID:26912664

  4. The mouse lp(A3)/Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern.

    PubMed

    Contos, J J; Chun, J

    2001-04-18

    The extracellular signaling molecule, lysophosphatidic acid (LPA), mediates proliferative and morphological effects on cells and has been proposed to be involved in several biological processes including neuronal development, wound healing, and cancer progression. Three mammalian G protein-coupled receptors, encoded by genes designated lp (lysophospholipid) receptor or edg (endothelial differentiation gene), mediate the effects of LPA, activating similar (e.g. Ca(2+) release) as well as distinct (neurite retraction) responses. To understand the evolution and function of LPA receptor genes, we characterized lp(A3)/Edg7 in mouse and human and compared the expression pattern with the other two known LPA receptor genes (lp(A1)/Edg2 and lp(A2)/Edg4non-mutant). We found mouse and human lp(A3) to have nearly identical three-exon genomic structures, with introns upstream of the coding region for transmembrane domain (TMD) I and within the coding region for TMD VI. This structure is similar to lp(A1) and lp(A2), indicating a common ancestral gene with two introns. We localized mouse lp(A3) to distal Chromosome 3 near the varitint waddler (Va) gene, in a region syntenic with the human lp(A3) chromosomal location (1p22.3-31.1). We found highest expression levels of each of the three LPA receptor genes in adult mouse testes, relatively high expression levels of lp(A2) and lp(A3) in kidney, and moderate expression of lp(A2) and lp(A3) in lung. All lp(A) transcripts were expressed during brain development, with lp(A1) and lp(A2) transcripts expressed during the embryonic neurogenic period, and lp(A3) transcript during the early postnatal period. Our results indicate both overlapping as well as distinct functions of lp(A1), lp(A2), and lp(A3). PMID:11313151

  5. COL4A4 gene study of a European population: description of new mutations causing autosomal dominant Alport syndrome

    PubMed Central

    Rosado, Consolación; Bueno, Elena; Felipe, Carmen; González-Sarmiento, Rogelio

    2014-01-01

    Background: Autosomal forms of Alport syndrome represent 20% of all patients (15% recessive and 5% dominant). They are caused by mutations in the COL4A3 and COL4A4 genes, which encode a-3 and a-4 collagen IV chains of the glomerular basement membrane, cochlea and eye. Thin basement membrane nephropathy may affect up to 1% of the population. The pattern of inheritance in the 40% of cases is the same as autosomal dominant Alport syndrome: heterozygous mutations in these genes. The aim of this study is to detect new pathogenic mutations in the COL4A4 gene in the patients previously diagnosed with autosomal Alport syndrome and thin basement membrane nephropathy in our hospital. Methods: We conducted a clinical and genetic study in eleven patients belonging to six unrelated families with aforementioned clinical symptoms and a negative study of COL4A3 gene. The molecular study was made by conformation of sensitive gel electrophoresis (CSGE) and direct sequencing of the fragments that show an altered electrophoretic migration pattern. Results: We found two pathogenic mutations, not yet described: IVS3 + 1G > C is a replacement of Guanine to Cytosine in position +1 of intron 3, in the splicing region, which leads to a pathogenic mutation. c.4267C > T; p.P1423S is a missense mutation, also considered pathogenic. We also found seven new polymorphisms. Conclusions: We describe two new pathogenic mutations, responsible for autosomal dominant Alport syndrome. The other families of the study were undiagnosed owing to problems in the method employed and the possibility of mutations in other genes, giving rise to other diseases with similar symptoms. PMID:25755845

  6. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  7. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  8. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  9. 42 CFR 51a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CHILD HEALTH § 51a.2 Definitions. Act means the Social Security Act, as amended. Genetic diseases means.... Hemophilia means a genetically transmitted bleeding disorder resulting from a deficiency of a plasma...

  10. Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin.

    PubMed

    Huwyler, Jörg; Wright, Matthew B; Gutmann, Heike; Drewe, Juergen

    2006-02-01

    Clinical findings indicate that co-administration of the isoxazolyl-penicillin flucloxacillin with cyclosporine may reduce the plasma concentrations of cyclosporine. We have explored in the present study if induction of cytochrome P450 3A4 or P-glycoprotein may offer a mechanistic explanation of the observed effects. Flucloxacillin is neither an inhibitor nor a substrate of drug metabolizing cytochrome P450 isoenzymes (CYP3A4, 1A2, 2C9, 2C19 and 2D6) or P-glycoprotein as shown by an in vitro assay for CYP inhibition, a fluorescent indicator assay for P-glycoprotein inhibition and a functional P-glycoprotein ATPase assay. However, incubation of human LS 180 colorectal adenocarcinoma cells with flucloxacillin led to a dose-dependent induction of MDR1 as well as of CYP3A4 mRNA, which was also confirmed in primary human hepatocytes. At high concentrations, flucloxacillin activated the human Pregnane-X-Receptor, PXR, a ligand-dependent transcription factor that is the target of many drugs that induce CYP3A4, with consequences for the metabolism of other drugs. Liver microsomes from control rats or rats, which received for 3 consecutive days 100 mg/kg of oral flucloxacillin, were used to study the metabolism and metabolite pattern of midazolam, a model substrate of CYP 3A4. There was a trend towards a higher intrinsic microsomal clearance of midazolam using microsomes from flucloxacillin treated rats. In addition, there was a significant increase in the formation of the principal midazolam metabolites 1-hydroxy midazolam, 4-hydroxy midazolam and 1,4-dihydroxy midazolam as compared to controls. These findings indicate that flucloxacillin has the potential to induce expression of both CYP3A4 as well as P-glycoprotein, most likely through activation of the nuclear hormone receptor PXR. This would offer an explanation for the observed clinical drug-drug interactions between the antibiotic and cyclosporine. PMID:16472102

  11. Serine protease inhibitor A3 in atherosclerosis and aneurysm disease.

    PubMed

    Wågsäter, Dick; Johansson, Daniel; Fontaine, Vincent; Vorkapic, Emina; Bäcklund, Alexandra; Razuvaev, Anton; Mäyränpää, Mikko I; Hjerpe, Charlotta; Caidahl, Kenneth; Hamsten, Anders; Franco-Cereceda, Anders; Wilbertz, Johannes; Swedenborg, Jesper; Zhou, Xinghua; Eriksson, Per

    2012-08-01

    Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe-/- mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl2-induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta. PMID:22580763

  12. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  13. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  14. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  15. 26 CFR 20.2056A-3 - QDOT election.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true QDOT election. 20.2056A-3 Section 20.2056A-3... ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Taxable Estate § 20.2056A-3 QDOT election. (a) General rule. Subject to the time period prescribed in section 2056A(d), the election to treat...

  16. An Overview of the A-3 Subscale Diffuser Test Project

    NASA Technical Reports Server (NTRS)

    Ryan, James E.; Mulkey, Christopher; Raines, Nickey; Saunders, Grady P.

    2008-01-01

    The Subscale Diffuser Test (SDT) Project comprised a series of tests of a subscale model of SSC s A-3 Test Stand diffuser. SDT was conducted at NASA s Stennis Space Center (SSC) Apr 2007 - Jan 2008. Purpose of SDT was to mitigate design risk for the A-3 diffuser. Initial scope of the SDT project successfully completed in Jan 2008. Follow-on A-3 risk mitigation testing being planned/considered. This presentation presents an overview of the SDT project.

  17. METSAT: Advanced Microwave Sounding Unit-A2 (AMSU-A2) structural mathematical model

    NASA Technical Reports Server (NTRS)

    Ely, Wayne

    1995-01-01

    This plan describes the Structural Mathematical Model of the METSAT AMSU-A2 instrument. The model is used to verify the structural adequacy of the AMSU-A2 instrument for the specified loading environments.

  18. Safety of Herbal Medicinal Products: Echinacea and Selected Alkylamides Do Not Induce CYP3A4 mRNA Expression.

    PubMed

    Modarai, Maryam; Silva, Elisabete; Suter, Andy; Heinrich, Michael; Kortenkamp, Andreas

    2011-01-01

    A major safety concern with the use of herbal medicinal products (HMP) is their interactions with conventional medicines, which are often mediated via the cytochrome P450 (CYP) system. Echinacea is a widely used over-the-counter HMP, with proven immunomodulatory properties. Its increasing use makes research into its safety an urgent concern. Previously, we showed that Echinacea extracts and its alkylamides (thought to be important for Echinacea's immunomodulatory activity) mildly inhibit the enzymatic activity of the main drug metabolising CYP isoforms, but to this date, there is insufficient work on its ability to alter CYP expression levels. We now report for the first time the effect of a commercial Echinacea extract (Echinaforce) and four Echinacea alkylamides on the transcription of the major drug metabolizing enzyme CYP3A4. HepG2 cells were exposed for 96 h to clinically relevant concentrations of Echinaforce (22, 11.6 and 1.16 μg mL(-1)) or the alkylamides (1.62 and 44 nM). CYP3A4 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). Neither Echinaforce nor the alkylamides produced any significant changes in the steady-state CYP3A4 mRNA levels, under these conditions. In contrast, treatment with 50 μM rifampicin resulted in a 3.8-fold up-regulation over the vehicle control. We conclude that Echinaforce is unlikely to affect CYP3A4 transcriptional levels, even at concentrations which can inhibit the enzymatic activity of CYP3A4. Overall, our data provides further evidence for the lack of interactions between Echinacea and conventional drugs. PMID:19906827

  19. 44 CFR Appendix A(2) to Part 61 - Appendix A(2) to Part 61

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Appendix A(2) to Part 61 A(2) Appendix A(2) to Part 61 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY INSURANCE AND HAZARD MITIGATION National Flood Insurance Program INSURANCE COVERAGE AND RATES Pt. 61, App....

  20. Investigating the role of CheA-3 in Dusulfovibrio Vulgaris Hildenborough

    SciTech Connect

    Ray, Jayashee; Keller, Kimberley; Krierim, Bernhard; Auer, Manfred; Keasling, Jay; Wall, Judy; Mukhopadhyay, Aindrila

    2010-05-22

    Multiple sets of chemotaxis genes including three cheA homologs were identified in the genome sequence of the anaerobic bacterium Desulfovibrio vulgaris Hildenborough. Each CheA is a histidine kinase (HK) and part of a two component signal transduction system. Knock out mutants in the three cheA genes were created using single cross-over homologous recombination insertion. We studied the phenotypes of the cheA mutants in detail and discovered that ?cheA-3 has a non swarming/swimming phenotype both in the soft agar plates and Palleroni chamber assays. CheA-3 shows similarity to the Shewanella oneidensis CheA-3 and the Vibrio cholerae CheA-2 that are responsible for chemotaxis in the respective organisms. We did not find any morphological or structural differences between the three Delta cheA mutants and the wild type cells in electron microscopy. Our results from these studies are presented.

  1. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Definition of Underserved Rural Community. 5a.3... PROVISIONS RURAL PHYSICIAN TRAINING GRANT PROGRAM § 5a.3 Definition of Underserved Rural Community. Underserved Rural Community means a community: (a) Located in: (1) A non-Metropolitan County or...

  2. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Definition of Underserved Rural Community. 5a.3... PROVISIONS RURAL PHYSICIAN TRAINING GRANT PROGRAM § 5a.3 Definition of Underserved Rural Community. Underserved Rural Community means a community: (a) Located in: (1) A non-Metropolitan County or...

  3. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  4. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  5. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... any amount paid by reason of the application of this acceleration rule). (3) The payment described...

  6. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2)...

  7. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2)...

  8. 42 CFR 5a.3 - Definition of Underserved Rural Community.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Definition of Underserved Rural Community. 5a.3 Section 5a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Professions Shortage Area, (under section 332(a)(1)(A) of the Public Health Service Act) or (2)...

  9. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... amount of $100,000 in 10 installments of $10,000. The first installment is due on April 1, 1960....

  10. 26 CFR 20.6166A-3 - Acceleration of payment.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Acceleration of payment. 20.6166A-3 Section 20... § 20.6166A-3 Acceleration of payment. (a) In general. Under the circumstances described in this section... amount of $100,000 in 10 installments of $10,000. The first installment is due on April 1, 1960....

  11. Using Toyota's A3 Thinking for Analyzing MBA Business Cases

    ERIC Educational Resources Information Center

    Anderson, Joe S.; Morgan, James N.; Williams, Susan K.

    2011-01-01

    A3 Thinking is fundamental to Toyota's benchmark management philosophy and to their lean production system. It is used to solve problems, gain agreement, mentor team members, and lead organizational improvements. A structured problem-solving approach, A3 Thinking builds improvement opportunities through experience. We used "The Toyota…

  12. 26 CFR 48.4061(a)-3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Definitions. 48.4061(a)-3 Section 48.4061(a)-3 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Motor Vehicles, Tires, Tubes, Tread Rubber, and...

  13. A 3-approximation for the minimum tree spanning k vertices

    SciTech Connect

    Garg, N.

    1996-12-31

    In this paper we give a 3-approximation algorithm for the problem of finding a minimum tree spanning any k-vertices in a graph. Our algorithm extends to a 3-approximation algorithm for the minimum tour that visits any k-vertices.

  14. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS...

  15. 42 CFR 68a.3 - Who is eligible to apply?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible to apply? 68a.3 Section 68a.3 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH (NIH) CLINICAL RESEARCH LOAN REPAYMENT PROGRAM FOR INDIVIDUALS...

  16. 26 CFR 1.401(a)(4)-13 - Effective dates and fresh-start rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...)(i) (nonelective plans), §§ 1.401(a)(4)-1 through 1.401(a)(4)-13 apply to plan years beginning on or...), including plans subject to section 403(b)(12)(A)(i) (nonelective plans), §§ 1.401(a)(4)-1 through 1.401(a)(4... satisfied. (3) Definition of frozen—(i) General rule. An employee's accrued benefit under a plan is...

  17. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and... subdivision or agency, business trust, partnership, association, or other legal entity. (c) Research means... includes, but is not limited to, behavioral science studies, surveys, evaluations, and...

  18. 42 CFR 2a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...-RESEARCH SUBJECTS § 2a.2 Definitions. (a) Secretary means the Secretary of Health and Human Services and... subdivision or agency, business trust, partnership, association, or other legal entity. (c) Research means... includes, but is not limited to, behavioral science studies, surveys, evaluations, and...

  19. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is a... labor, two members will represent the occupational health professions, two members will represent...

  20. 29 CFR 1912a.2 - Membership.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.2 Membership. The Committee is a... labor, two members will represent the occupational health professions, two members will represent...

  1. 29 CFR 4041A.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... plan year, available resources as described in section 4245(b)(3) of ERISA. Benefits subject to... Relating to Labor (Continued) PENSION BENEFIT GUARANTY CORPORATION PLAN TERMINATIONS TERMINATION OF MULTIEMPLOYER PLANS General Provisions § 4041A.2 Definitions. The following terms are defined in § 4001.1...

  2. 29 CFR 4041A.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... plan year, available resources as described in section 4245(b)(3) of ERISA. Benefits subject to... Relating to Labor (Continued) PENSION BENEFIT GUARANTY CORPORATION PLAN TERMINATIONS TERMINATION OF MULTIEMPLOYER PLANS General Provisions § 4041A.2 Definitions. The following terms are defined in § 4001.1...

  3. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  4. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  5. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  6. 42 CFR 65a.2 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES HAZARDOUS SUBSTANCES BASIC RESEARCH AND TRAINING GRANTS § 65a.2 Definitions. As used in this part: Act means the Comprehensive Environmental Response... of the National Institute of Environmental Health Sciences, or the Director's delegate. HHS means...

  7. The A2 Experiment Program at MAMI

    NASA Astrophysics Data System (ADS)

    Briscoe, William; A2 Collaboration

    2014-09-01

    The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. The Mainz Microtron MAMI is an accelerator for electron beams run by the Institut für Kernphysik of the Johannes Gutenberg-Universität Mainz used for hadron physics experiments. Of it's three active experimental halls, the A2 facility, which features the presence of the SLAC Crystal Ball detector, has produced a plethora of experimental results, which has contributed to the understanding of the structure of the nucleon. An overview and update of the current A2 program will be presented. Funded in part by SFB 1044. US collaborators funded by USDOE and USNSF.

  8. Effect of Laminin-A4 inhibition on cluster formation of human osteoarthritic chondrocytes.

    PubMed

    Moazedi-Fuerst, Florentine C; Gruber, Gerald; Stradner, Martin H; Guidolin, Diego; Jones, Jonathan C; Bodo, Koppany; Wagner, Karin; Peischler, Daniela; Krischan, Verena; Weber, Jennifer; Sadoghi, Patrick; Glehr, Mathias; Leithner, Andreas; Graninger, Winfried B

    2016-03-01

    Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is also observed in cell culture. Active locomotion of chondrocytes is controlled by integrins in vitro. Integrins bind to Laminin-A4 (LAMA4), a protein that is highly expressed in vivo in clusters of hypertrophic chondrocytes. We tested if LAMA4 is relevant for cluster formation. Human chondrocytes were cultured in a 2D matrigel model and treated with different concentrations of a monoclonal inhibitory anti-LAMA4-antibody. Migration and cluster formation was analysed using live cell imaging technique. Full genome gene expression analysis was performed to assess the effect of LAMA4 inhibition. The data set were screened for genes relevant to cell motility. F-actin staining was performed to document cytoskeletal changes. Anti-LAMA4 treatment significantly reduced the rate of cluster formation in human chondrocytes. Cells changed their surface morphology and exhibited fewer protrusions. Expression of genes associated with cellular motility and migration was affected by anti-LAMA4 treatment. LAMA4-integrin signalling affects chondrocyte morphology and gene expression in vitro, thereby contributing to cluster formation in human osteoarthritic chondrocytes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:419-426, 2016. PMID:26295200

  9. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  10. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  11. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  12. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  13. 42 CFR 63a.4 - Who is eligible for a training grant?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Who is eligible for a training grant? 63a.4 Section 63a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES FELLOWSHIPS, INTERNSHIPS, TRAINING NATIONAL INSTITUTES OF HEALTH TRAINING GRANTS § 63a.4 Who is eligible for a...

  14. 26 CFR 1.475(a)-4T - Valuation safe harbor (temporary).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 6 2012-04-01 2012-04-01 false Valuation safe harbor (temporary). 1.475(a)-4T Section 1.475(a)-4T Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Inventories § 1.475(a)-4T Valuation safe harbor (temporary). (a) through (d)(4) introductory text...

  15. S100A4 promotes endometrial cancer progress through epithelial-mesenchymal transition regulation.

    PubMed

    Hua, Teng; Liu, Shuangge; Xin, Xiaoyan; Cai, Liqiong; Shi, Rui; Chi, Shuqi; Feng, Dilu; Wang, Hongbo

    2016-06-01

    Epithelial-mesenchymal transition (EMT) is a major cause of endometrial cancer (EC) to initiate invasion and metastasis. S100A4, a calcium-binding protein, is implicated in multistage of tumorigenesis and tumor progression. The correlation between S100A4 and EMT in EC is still unclear. This study was aimed to clarify the role of S100A4 in EC and the relationship between S100A4 expression and EMT markers. S100A4, E-cadherin, and vimentin were detected in tissues of EC patients (n=50) by immunohistochemistry. The impact of S100A4 on EC cell proliferation, migration and invasion was investigated via RNA interference, and the correlation between S100A4 and EMT markers were also explored. The results showed that S100A4 was significantly increased in epithelial cells of EC compared with the normal endometrium (P<0.05), also S100A4 level was positively related to age (P=0.021), histological grade (P<0.001), and lymph node metastasis (P<0.001). Additionally, silencing of S100A4 remarkably attenuated EC cell migration and invasion. Significant morphological change accompanied with the downregulation of EMT markers, E-cadherin and vimentin were also observed. Aberrant S100A4 expression may predict EC progression and play an important role in regulating EC cell invasion through EMT regulation. Hence, S100A4 is a promising therapeutic target. PMID:27109209

  16. 17 CFR 260.10a-4 - Consent of trustee to service of process.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... of process. 260.10a-4 Section 260.10a-4 Commodity and Securities Exchanges SECURITIES AND EXCHANGE... § 260.10a-4 Consent of trustee to service of process. At the time of filing an application pursuant to... business under the laws of a foreign government shall furnish to the Commission on Form F-X (§ 249.250...

  17. 26 CFR 1.263(a)-4 - Amounts paid to acquire or create intangibles.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 3 2011-04-01 2011-04-01 false Amounts paid to acquire or create intangibles. 1.263(a)-4 Section 1.263(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Items Not Deductible § 1.263(a)-4 Amounts paid to acquire or create intangibles....

  18. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  19. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  20. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  1. 26 CFR 1.512(a)-4 - Special rules applicable to war veterans organizations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Special rules applicable to war veterans organizations. 1.512(a)-4 Section 1.512(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Exempt Organizations § 1.512(a)-4 Special rules applicable to war veterans organizations. (a) In...

  2. 26 CFR 1.263(a)-4 - Amounts paid to acquire or create intangibles.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Amounts paid to acquire or create intangibles. 1.263(a)-4 Section 1.263(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Items Not Deductible § 1.263(a)-4 Amounts paid to acquire or create intangibles. (a) Overview....

  3. Design of a 3-stage ADR for the soft x-ray spectrometer instrument on the ASTRO-H mission

    NASA Astrophysics Data System (ADS)

    Shirron, Peter J.; Kimball, Mark O.; Wegel, Donald C.; Canavan, Edgar R.; Dipirro, Michael J.

    2010-07-01

    The Japanese Astro-H mission will include the Soft X-ray Spectrometer (SXS) instrument, whose 36-pixel detector array of ultra-sensitive x-ray microcalorimeters requires cooling to 50 mK. This will be accomplished using a 3-stage adiabatic demagnetization refrigerator (ADR). The design is dictated by the need to operate with full redundancy with both a superfluid helium dewar at 1.3 K or below, and with a 4.5 K Joule-Thomson (JT) cooler. The ADR is configured as a 2-stage unit that is located in a well in the helium tank, and a third stage that is mounted to the top of the helium tank. The third stage is directly connected through two heat switches to the JT cooler and the helium tank, and manages heat flow between the two. When liquid helium is present, the 2-stage ADR operates in a single-shot manner using the superfluid helium as a heat sink. The third stage may be used independently to reduce the time-average heat load on the liquid to extend its lifetime. When the liquid is depleted, the 2nd and 3rd stages operate as a continuous ADR to maintain the helium tank at as low a temperature as possible - expected to be 1.2 K - and the 1st stage cools from that temperature as a single-stage, single-shot ADR. The ADR's design and operating modes are discussed, along with test results of the prototype 3-stage ADR.

  4. Design of a 3-Stage ADR for the Soft X-Ray Spectrometer Instrument on the Astro-H Mission

    NASA Technical Reports Server (NTRS)

    Shirron, Peter J.; Kimball, Mark O.; Wegel, Donald C.; Canavan, Edgar R.; DiPirro, Michael J.

    2011-01-01

    The Japanese Astro-H mission will include the Soft X-ray Spectrometer (SXS) instrument, whose 36-pixel detector array of ultra-sensitive x-ray microcalorimeters requires cooling to 50 mK. This will be accomplished using a 3-stage adiabatic demagnetization refrigerator (ADR). The design is dictated by the need to operate with full redundancy with both a superfluid helium dewar at 1.3 K or below, and with a 4.5 K Joule-Thomson (JT) cooler. The ADR is configured as a 2-stage unit that is located in a well in the helium tank, and a third stage that is mounted to the top of the helium tank. The third stage is directly connected through two heat switches to the JT cooler and the helium tank, and manages heat flow between the two. When liquid helium is present, the 2-stage ADR operates in a single-shot manner using the superfluid helium as a heat sink. The third stage may be used independently to reduce the time-average heat load on the liquid to extend its lifetime. When the liquid is depleted, the 2nd and 3rd stages operate as a continuous ADR to maintain the helium tank at as low a temperature as possible - expected to be 1.2 K - and the 1st stage cools from that temperature as a single-stage, single-shot ADR. The ADR s design and operating modes are discussed, along with test results of the prototype 3-stage ADR.

  5. Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV.

    PubMed

    Jeovanio-Silva, André L; Monteiro, Thaís P; El-Jaick, Kênia B; do Brasil, Pedro E A A; Rolla, Valéria C; de Castro, Liane

    2012-01-01

    CYP3A4 is involved in tuberculosis (TB) and human immunodeficiency virus (HIV) drug metabolism. Transcriptional activation by rifampicin involves the CYP3A4 gene 5'-upstream region. Consequently, variation may interfere with transcription and enzymatic activity and even drug response. However, genetic polymorphisms and distribution of CYP3A4 allelic frequencies in individuals from Rio de Janeiro remain unknown. The aim of this study was to conduct research into sequencing the CYP3A4 5'-upstream region in Brazilian patients with and without HIV. This follow-up study involved 106 individuals undergoing treatment for TB and/or HIV. The CYP3A4 5'-upstream region was analyzed using PCR, sequencing and clinical data. Male patients revealed a higher HIV frequency (p=0.021). The TB forms observed were pulmonary (48.1%), extrapulmonary (22.64%) and disseminated (27.36%). Lymph node form was the most frequent (70.83%) extrapulmonary form of TB. The only single nucleotide polymorphism detected in the population was c.-392A>G. Genotypes observed were CYP3A4*1A/CYP3A4*1A (45.3%), CYP3A4*1A/CYP3A4*1B (40.6%) and CYP3A4*1B/CYP3A4*1B (14.2%), revealing a different distribution with extrapulmonary TB cases (17.6% CYP3A4*1A/CYP3A4*1B and 23.5% CYP3A4*1B/CYP3A4*1B). The CYP3A4*1A allele was found to be associated with tobacco use. The CYP3A4*1B mutant allele occurred in 34% of patients. This study revealed that the CYP3A4 5'-upstream regulatory region was highly conserved with the exception of the -392 position. Genotype association with tobacco suggests that CYP3A4 may participate in tobacco metabolism. Genotype distribution inversion in extrapulmonary TB cases suggests that CYP3A4 may be involved in TB prognosis. PMID:21964586

  6. A2B adenosine receptor dampens hypoxia-induced vascular leak

    PubMed Central

    Eckle, Tobias; Faigle, Marion; Grenz, Almut; Laucher, Stefanie; Thompson, Linda F.

    2008-01-01

    Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (ARs: A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR−/−-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 ± 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR−/−-, A2AAR−/−-, or A3AR−/−-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 [2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)-. phenyl]pyridin-2-ylsulfanyl]acetamide]) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 ± 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak. PMID:18056839

  7. Distinct neurological disorders with ATP1A3 mutations

    PubMed Central

    Heinzen, Erin L.; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J.; Gurrieri, Fiorella; Goldstein, David B.; Jóhannesson, Sigurður H.; Mikati, Mohamad A.; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J.; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J.; van den Maagdenberg, Arn; Vilsen, Bente

    2014-01-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na+/K+-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in vitro and animal model systems, and the role of Na+/K+-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  8. Distinct neurological disorders with ATP1A3 mutations.

    PubMed

    Heinzen, Erin L; Arzimanoglou, Alexis; Brashear, Allison; Clapcote, Steven J; Gurrieri, Fiorella; Goldstein, David B; Jóhannesson, Sigurður H; Mikati, Mohamad A; Neville, Brian; Nicole, Sophie; Ozelius, Laurie J; Poulsen, Hanne; Schyns, Tsveta; Sweadner, Kathleen J; van den Maagdenberg, Arn; Vilsen, Bente

    2014-05-01

    Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases. PMID:24739246

  9. Neutron structure function and A=3 mirror nuclei

    SciTech Connect

    Afnan, I.R.; Bissey, F.; Gomez, J.; Katramatou, A.T.; Melnitchouk, W.; Petratos, G.G.; Thomas, A.W.

    2000-06-01

    The authors demonstrate that the free neutron structure function can be extracted in deep-inelastic scattering from A=3 mirror nuclei, with nuclear effects canceling to within 2% for x {approx_lt} 0.85.

  10. Laser Anemometer Measurements of the Flow Field in a 4:1 Pressure Ratio Centrifugal Impeller

    NASA Technical Reports Server (NTRS)

    Skoch, G. J.; Prahst, P. S.; Wernet, M. P.; Wood, J. R.; Strazisar, A. J.

    1997-01-01

    A laser-doppler anemometer was used to obtain flow-field velocity measurements in a 4:1 pressure ratio, 4.54 kg/s (10 lbm/s), centrifugal impeller, with splitter blades and backsweep, which was configured with a vaneless diffuser. Measured through-flow velocities are reported for ten quasi-orthogonal survey planes at locations ranging from 1% to 99% of main blade chord. Measured through-flow velocities are compared to those predicted by a 3-D viscous steady flow analysis (Dawes) code. The measurements show the development and progression through the impeller and vaneless diffuser of a through-flow velocity deficit which results from the tip clearance flow and accumulation of low momentum fluid centrifuged from the blade and hub surfaces. Flow traces from the CFD analysis show the origin of this deficit which begins to grow in the inlet region of the impeller where it is first detected near the suction surface side of the passage. It then moves toward the pressure side of the channel, due to the movement of tip clearance flow across the impeller passage, where it is cut by the splitter blade leading edge. As blade loading increases toward the rear of the channel the deficit region is driven back toward the suction surface by the cross-passage pressure gradient. There is no evidence of a large wake region that might result from flow separation and the impeller efficiency is relatively high. The flow field in this impeller is quite similar to that documented previously by NASA Lewis in a large low-speed backswept impeller.

  11. Evaluation of a 4D cone-beam CT reconstruction approach using a simulation framework.

    PubMed

    Hartl, Alexander; Yaniv, Ziv

    2009-01-01

    Current image-guided navigation systems for thoracic abdominal interventions utilize three dimensional (3D) images acquired at breath-hold. As a result they can only provide guidance at a specific point in the respiratory cycle. The intervention is thus performed in a gated manner, with the physician advancing only when the patient is at the same respiratory cycle in which the 3D image was acquired. To enable a more continuous workflow we propose to use 4D image data. We describe an approach to constructing a set of 4D images from a diagnostic CT acquired at breath-hold and a set of intraoperative cone-beam CT (CBCT) projection images acquired while the patient is freely breathing. Our approach is based on an initial reconstruction of a gated 4D CBCT data set. The 3D CBCT images for each respiratory phase are then non-rigidly registered to the diagnostic CT data. Finally the diagnostic CT is deformed based on the registration results, providing a 4D data set with sufficient quality for navigation purposes. In this work we evaluate the proposed reconstruction approach using a simulation framework. A 3D CBCT dataset of an anthropomorphic phantom is deformed using internal motion data acquired from an animal model to create a ground truth 4D CBCT image. Simulated projection images are then created from the 4D image and the known CBCT scan parameters. Finally, the original 3D CBCT and the simulated X-ray images are used as input to our reconstruction method. The resulting 4D data set is then compared to the known ground truth by normalized cross correlation(NCC). We show that the deformed diagnostic CTs are of better quality than the gated reconstructions with a mean NCC value of 0.94 versus a mean 0.81 for the reconstructions. PMID:19964143

  12. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling

    PubMed Central

    North, Hilary A.; Zhao, Xiumei; Kolk, Sharon M.; Clifford, Meredith A.; Ziskind, Daniela M.; Donoghue, Maria J.

    2009-01-01

    Summary Eph receptors are widely expressed during cerebral cortical development, yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division. PMID:19542359

  13. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect. PMID:25374256

  14. 4-Coumaroyl coenzyme A 3-hydroxylase activity from cell cultures of Lithospermum erythrorhizon and its relationship to polyphenol oxidase.

    PubMed

    Wang, Z X; Li, S M; Löscher, R; Heide, L

    1997-11-15

    A 4-coumaroyl-CoA 3-hydroxylase activity was purified 4600-fold from cell cultures of Lithospermum erythrorhizon. The enzyme showed a molecular mass of 42,400 +/- 1700 Da in gel chromatography and required ascorbate, NADH, or NADPH as cofactors. 4-Coumaroyl-CoA, 4-coumarate, p-cresol, and several other phenolic substances, but not tyrosine, were accepted as substrates for the hydroxylation. Besides hydroxylase activity, the enzyme showed diphenol oxidase activity. Both activities were inhibited by diethyldithiocarbamate or beta-mercaptoethanol, although at different concentrations. The enzyme showed striking similarity to a 4-coumaroyl-glucose 3-hydroxylase from sweet potato (Ipomoe batatas) roots, which has reportedly been purified to homogeneity and identified as a specific enzyme of chlorogenic acid biosynthesis. Close examination and comparison to a commercially available polyphenol oxidase, however, suggest that the enzyme activities purified from both Lithospermum and sweet potato are polyphenol oxidases rather than specific enzymes of secondary metabolism. PMID:9367532

  15. Phenothiazines inhibit S100A4 function by inducing protein oligomerization

    SciTech Connect

    Malashkevich, Vladimir N.; Dulyaninova, Natalya G.; Ramagopal, Udupi A.; Liriano, Melissa A.; Varney, Kristen M.; Knight, David; Brenowitz, Michael; Weber, David J.; Almo, Steven C.; Bresnick, Anne R.

    2010-06-22

    S100A4, a member of the S100 family of Ca{sup 2+}-binding proteins, regulates carcinoma cell motility via interactions with myosin-IIA. Numerous studies indicate that S100A4 is not simply a marker for metastatic disease, but rather has a direct role in metastatic progression. These observations suggest that S100A4 is an excellent target for therapeutic intervention. Using a unique biosensor-based assay, trifluoperazine (TFP) was identified as an inhibitor that disrupts the S100A4/myosin-IIA interaction. To examine the interaction of S100A4 with TFP, we determined the 2.3 {angstrom} crystal structure of human Ca{sup 2+}-S100A4 bound to TFP. Two TFP molecules bind within the hydrophobic target binding pocket of Ca{sup 2+}-S100A4 with no significant conformational changes observed in the protein upon complex formation. NMR chemical shift perturbations are consistent with the crystal structure and demonstrate that TFP binds to the target binding cleft of S100A4 in solution. Remarkably, TFP binding results in the assembly of five Ca{sup 2+}-S100A4/TFP dimers into a tightly packed pentameric ring. Within each pentamer most of the contacts between S100A4 dimers occurs through the TFP moieties. The Ca{sup 2+}-S100A4/prochlorperazine (PCP) complex exhibits a similar pentameric assembly. Equilibrium sedimentation and cross-linking studies demonstrate the cooperative formation of a similarly sized S100A4/TFP oligomer in solution. Assays examining the ability of TFP to block S100A4-mediated disassembly of myosin-IIA filaments demonstrate that significant inhibition of S100A4 function occurs only at TFP concentrations that promote S100A4 oligomerization. Together these studies support a unique mode of inhibition in which phenothiazines disrupt the S100A4/myosin-IIA interaction by sequestering S100A4 via small molecule-induced oligomerization.

  16. 17 CFR Appendix A to Part 3 - Interpretative Statement With Respect to Section 8a(2)(C) and (E) and Section 8a(3)(J) and (M) of...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... exchange imposed a relatively minor sanction. 2 Commission rules referred to herein are found at 17 CFR Ch...”), including settled disciplinary actions. 5 Commission rules referred to in this letter are found at 17 CFR Ch... in which NFA appears to have had the most uncertainty is with regard to previous...

  17. 17 CFR Appendix A to Part 3 - Interpretative Statement With Respect to Section 8a(2)(C) and (E) and Section 8a(3)(J) and (M) of...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... exchange imposed a relatively minor sanction. 2 Commission rules referred to herein are found at 17 CFR Ch...”), including settled disciplinary actions. 5 Commission rules referred to in this letter are found at 17 CFR Ch... in which NFA appears to have had the most uncertainty is with regard to previous...

  18. 17 CFR Appendix A to Part 3 - Interpretative Statement With Respect to Section 8a(2)(C) and (E) and Section 8a(3)(J) and (M) of...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... exchange imposed a relatively minor sanction. 2 Commission rules referred to herein are found at 17 CFR Ch...”), including settled disciplinary actions. 5 Commission rules referred to in this letter are found at 17 CFR Ch... in which NFA appears to have had the most uncertainty is with regard to previous...

  19. 17 CFR Appendix A to Part 3 - Interpretative Statement With Respect to Section 8a(2)(C) and (E) and Section 8a(3)(J) and (M) of...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... exchange imposed a relatively minor sanction. 2 Commission rules referred to herein are found at 17 CFR Ch...”), including settled disciplinary actions. 5 Commission rules referred to in this letter are found at 17 CFR Ch... continuing any activity involving any transaction in or advice concerning contracts of sale of a...

  20. 17 CFR Appendix A to Part 3 - Interpretative Statement With Respect to Section 8a(2)(C) and (E) and Section 8a(3)(J) and (M) of...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... exchange imposed a relatively minor sanction. 2 Commission rules referred to herein are found at 17 CFR Ch...”), including settled disciplinary actions. 5 Commission rules referred to in this letter are found at 17 CFR Ch... governmental body is a party, from (i) acting as a futures commission merchant, introducing broker,...

  1. Generalization of rectangular element stiffness matrix and thermal load vector associated with a(0) + a(1)x + a(2)y + a(3)xy type interpolation rule

    NASA Technical Reports Server (NTRS)

    Ray, Sujit K.; Utku, Senol; Wada, Ben K.

    1986-01-01

    The stiffness-matrix formulation for the rectangular finite element described by Melosh (1963) and Weaver and Johnston (1984) is generalized to orthotropic materials with material axes not necessarily coincident with the x and y axes; i.e., the condition d(13) = d(23) = 0 is removed. Also included are explicit expressions for the element load vector associated with nonuniform temperature increase in the element. Applications to the analysis of thermal stresses in thin Si-crystal ribbons subjected to temperature changes with highly nonuniform lengthwise and transverse gradients (Utku et al., 1986) and to the simulation of the thermoviscoelastic behavior of growing Si ribbons (Utku and Ray, 1986) are indicated.

  2. 17 CFR 240.14a-2 - Solicitations to which § 240.14a-3 to § 240.14a-15 apply.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., recapitalization, reorganization, sale of assets or other extraordinary transaction recommended or approved by the... is the subject of a proposed roll-up transaction engages in preliminary communications with other... suspended. To the extent specified below, certain of these sections also apply to roll-up transactions...

  3. Inhibitory Effects of Vegetable Juices on CYP3A4 Activity in Recombinant CYP3A4 and LS180 Cells.

    PubMed

    Tsujimoto, Masayuki; Uchida, Tomoe; Kozakai, Hiroyuki; Yamamoto, Saori; Minegaki, Tetsuya; Nishiguchi, Kohshi

    2016-01-01

    It is thought that eating habits induces individual variation in intestinal absorption and metabolism of drugs. The objective of this research was to clarify the influence of vegetables juices on CYP3A4 activity, which is an important enzyme in intestine. Five vegetables juices (VJ-o, Kagome Original(®); VJ-g, Kagome 30 kinds of vegetables and fruits(®); VJ-p, Kagome Purple vegetables(®); VJ-r, Kagome Sweet Tomato(®); and VJ-y, Kagome Fruity Salada(®); KAGOME Co., Ltd., Aichi, Japan) were centrifuged (1630×g, 10 min) and filtered using filter paper and 0.45-µm membrane filters. In this study, recombinant CYP3A4 and LS180 cells were used for the evaluation of CYP3A4 activity. The metabolisms to 6β-hydroxytestosterone by recombinant CYP3A4 were significantly inhibited by VJ-o, VJ-g, and VJ-y in a preincubation time-dependent manner, and CYP3A4 activity in LS180 cells were significantly inhibited by VJ-o and VJ-y. These results show that the difference in ingestion volume of vegetable juices and vegetables might partially induce individual difference in intestinal drug metabolism. PMID:27582329

  4. Recent improvements in the development of A2B adenosine receptor agonists

    PubMed Central

    Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Preti, Delia

    2009-01-01

    Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary

  5. Recent improvements in the development of A2B adenosine receptor agonists

    PubMed Central

    Tabrizi, Mojgan Aghazadeh; Fruttarolo, Francesca; Romagnoli, Romeo; Preti, Delia

    2008-01-01

    Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N′-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-β-D-ribofuranuronamide (19, hA1Ki = 1050 nM, hA2AKi = 1550 nM, hA2B EC50 = 82 nM, hA3Ki > 5 μM) and its 2-chloro analogue 23 (hA1Ki = 3500 nM, hA2AKi = 4950 nM, hA2B EC50 = 210 nM, hA3Ki > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60–6583, hA1, hA2A, hA3 EC50 > 10 μM; hA2B EC50 = 3 nM) is currently under preclinical-phase investigation for treating coronary

  6. In vitro inhibition of cytochrome P450 3A4 by Aronia melanocarpa constituents.

    PubMed

    Bräunlich, Marie; Christensen, Hege; Johannesen, Siri; Slimestad, Rune; Wangensteen, Helle; Malterud, Karl E; Barsett, Hilde

    2013-01-01

    Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin. PMID:23250807

  7. Precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons

    SciTech Connect

    Lemaire, H.G.; Kang, J.; Mueller-Hill, B. ); Salbaum, J.M.; Multhaup, G.; Beyreuther, K. ); Bayney, R.M.; Unterbeck, A. )

    1989-01-25

    Alzheimer's disease (AD) is characterized by the cerebral deposition of fibrillar aggregates of the amyloid A4 protein. Complementary DNA's coding for the precursor of the amyloid A4 protein have been described. In order to identify the structure of the precursor gene relevant clones from several human genomic libraries were isolated. Sequence analysis of the various clones revealed 16 exons to encode the 695 residue precursor protein (PreA4{sub 695}) of Alzheimer's disease amyloid A4 protein. The DNA sequence coding for the amyloid A4 protein is interrupted by an intron. This finding supports the idea that amyloid A4 protein arises by incomplete proteolysis of a larger precursor, and not by aberrant splicing.

  8. Isotridecanyl side chain of plusbacin-A3 is essential for the transglycosylase inhibition of peptidoglycan biosynthesis§

    PubMed Central

    Kim, Sung Joon; Singh, Manmilan; Wohlrab, Aaron; Yu, Tsyr-Yan; Patti, Gary J.; O’Connor, Robert D.; VanNieuwenhze, Michael; Schaefer, Jacob

    2013-01-01

    Plusbacin-A3 (pb-A3) is a cyclic lipodepsipeptide which exhibits antibacterial activity against multidrug-resistant Gram-positive pathogens. Plusbacin-A3 is thought not to enter the cell cytoplasm and its lipophilic isotridecanyl side chain is presumed to insert into the membrane bilayer thereby facilitating either lipid II binding or some form of membrane disruption. Analogues of pb-A3, [2H]pb-A3 and deslipo-pb-A3, were synthesized to test membrane insertion as key to the mode of action. [2H]pb-A3 has a 2H-isotopically labeled isopropyl subunit of the lipid side chain, and deslipo-pb-A3 is missing the isotridecanyl side chain. Both analogues have the pb-A3 core structure. The loss of antimicrobial activity in deslipo-pb-A3 showed that the isotridecanyl side chain is crucial for the drug mode of action. However, rotational-echo double resonance NMR characterization of [2H]pb-A3 bound to [1-13C]glycine labeled whole-cells of Staphylococcus aureus showed that the isotridecanyl side chain does not insert into the lipid membrane, but instead is found in the staphylococcal cell wall, positioned near the pentaglycyl cross-bridge of the cell-wall peptidoglycan. Addition of [2H]pb-A3 during S. aureus growth resulted in an accumulation of Park’s nucleotide, consistent with the inhibition of the transglycosylation step of peptidoglycan biosynthesis. PMID:23421534

  9. Exploring the role of CheA3 in Desulfovibrio vulgaris Hildenborough motility

    PubMed Central

    Ray, Jayashree; Keller, Kimberly L.; Catena, Michela; Juba, Thomas R.; Zemla, Marcin; Rajeev, Lara; Knierim, Bernhard; Zane, Grant M.; Robertson, Jarrod J.; Auer, Manfred; Wall, Judy D.; Mukhopadhyay, Aindrila

    2014-01-01

    Sulfate-reducing bacteria such as Desulfovibrio vulgaris Hildenborough are often found in environments with limiting growth nutrients. Using lactate as the electron donor and carbon source, and sulfate as the electron acceptor, wild type D. vulgaris shows motility on soft agar plates. We evaluated this phenotype with mutants resulting from insertional inactivation of genes potentially related to motility. Our study revealed that the cheA3 (DVU2072) kinase mutant was impaired in the ability to form motility halos. Insertions in two other cheA loci did not exhibit a loss in this phenotype. The cheA3 mutant was also non-motile in capillary assays. Complementation with a plasmid-borne copy of cheA3 restores wild type phenotypes. The cheA3 mutant displayed a flagellum as observed by electron microscopy, grew normally in liquid medium, and was motile in wet mounts. In the growth conditions used, the D. vulgaris ΔfliA mutant (DVU3229) for FliA, predicted to regulate flagella-related genes including cheA3, was defective both in flagellum formation and in forming the motility halos. In contrast, a deletion of the flp gene (DVU2116) encoding a pilin-related protein was similar to wild type. We conclude that wild type D. vulgaris forms motility halos on solid media that are mediated by flagella-related mechanisms via the CheA3 kinase. The conditions under which the CheA1 (DVU1594) and CheA2 (DVU1960) kinase function remain to be explored. PMID:24639670

  10. Modulation of CYP3A4 activity alters the cytotoxicity of lipophilic phycotoxins in human hepatic HepaRG cells.

    PubMed

    Ferron, P J; Hogeveen, K; De Sousa, G; Rahmani, R; Dubreil, E; Fessard, V; Le Hegarat, L

    2016-06-01

    The aim of this study was to investigate (i) the cytotoxic effects of lipophilic phycotoxins, including okadaic acid (OA) and dinophysistoxin-1 and -2 (DTX-1 and DTX-2), pectenotoxin-2 (PTX-2), yessotoxin (YTX), spirolide (SPX), and azaspiracids-1, -2 and -3 (AZA-1, AZA-2 and AZA-3), in human HepaRG cells using a multiparametric high content analysis approach, (ii) the ability of nine lipophilic phycotoxins to act as PXR agonists in a HepG2-PXR cell line, (iii) their potential to induce CYP450 activity, and (iv) the role of CYP3A4 in cytotoxicity induced by lipophilic phycotoxins. Our results indicate that while OA, DTX-1 and DTX-2 activated PXR-dependent transcriptional activity in HepG2 cells, no increase of CYP450 (1A2, 3A4, 2C9, 2C19) activities were observed in HepaRG cell following a 72h treatment with these toxins. Multiparametric analysis showed that OA, DTX-1, DTX-2, and PTX-2 were highly cytotoxic in HepaRG cells; inducing cell loss, activation of caspase-3 and γ-H2AX formation. However, no toxicity was observed for YTX, SPX, and AZAs. Moreover, we found that inhibition of CYP3A4 activity by ketoconazole enhances the toxic effects of OA, DTX-1, DTX-2, and PTX-2 in HepaRG cells. Taken together, these results suggest that CYP3A4-mediated metabolism of some lipophilic phycotoxins decreases their in vitro toxicity. PMID:26956883

  11. Characterization of dihydro-A2PE: an Intermediate in the A2E Biosynthetic Pathway†

    PubMed Central

    Kim, So R.; He, Jiangtao; Yanase, Emiko; Jang, Young P.; Berova, Nina; Nakanishi, Koji; Sparrow, Janet R.

    2008-01-01

    Bisretinoid lipofuscin pigments that accumulate in retinal pigment epithelial cells are implicated in the etiology of several forms of macular degeneration including juvenile onset Stargardt disease, Best vitelliform macular degeneration and age-related macular degeneration. One of these compounds, A2E, is generated by phosphate hydrolysis of a phosphatidylpyridinium bisretinoid (A2PE) that forms within photoreceptor outer segments. Here we demonstrate that the formation of the aromatic pyridinium ring of A2PE follows from the oxidation of a dihydropyridinium intermediate. Time-dependent density functional theory calculation, based on the structure of dihydro-A2E, produced a simulated UV-visible absorbance spectrum characterized by maxima of 494 and 344 nm. Subsequently, a compound exhibiting similar UV-visible absorbance maxima (λmax 490 and 330 nm) was identified in the A2E biomimetic reaction mixture. By liquid chromatography-mass spectrometry (LC-MS) this bischromophore had the expected mass of the dihydro-pyridinium bisretinoid. The compound also exhibited the behavior of a biosynthetic intermediate, since it formed in advance of the final product A2E and was consumed as A2E accumulated. Moreover, under deoxygenated conditions, conversion to the aromatic pyridinium bisretinoid was inhibited. Taken together, these findings indicate that A2E biosynthesis involves the oxidation of a dihydropyridinium intermediate dihydro-A2PE. An understanding of the biosynthetic pathways of retinal pigment epithelial lipofuscin pigments is critical to the development of therapies for macular degeneration that are based on limiting the formation of these damaging compounds. PMID:17685561

  12. 26 CFR 1.401(a)(4)-11 - Additional rules.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Additional rules. 1.401(a)(4)-11 Section 1.401(a)(4)-11 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-11 Additional rules. (a) Introduction. This section...

  13. 26 CFR 1.401(a)(4)-6 - Contributory defined benefit plans.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Contributory defined benefit plans. 1.401(a)(4)-6 Section 1.401(a)(4)-6 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-6 Contributory defined...

  14. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 8 2012-07-01 2012-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  15. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 8 2014-07-01 2014-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  16. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 7 2010-07-01 2010-07-01 true Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  17. 26 CFR 1.401(a)(4)-0 - Table of contents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Table of contents. 1.401(a)(4)-0 Section 1.401(a)(4)-0 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-0 Table of contents. This section contains...

  18. 40 CFR Appendix A-4 to Part 60 - Test Methods 6 through 10B

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 7 2011-07-01 2011-07-01 false Test Methods 6 through 10B A Appendix A-4 to Part 60 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES (CONTINUED) Pt. 60, App. A-4 Appendix A-4 to Part 60—Test Methods 6 through 10B Method...

  19. 26 CFR 1.1402(a)-4 - Rentals from real estate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Rentals from real estate. 1.1402(a)-4 Section 1.1402(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(a)-4 Rentals from real estate. (a) In general. Rentals from...

  20. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.

    PubMed

    Engdal, Silje; Nilsen, Odd Georg

    2009-07-01

    The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6-beta-OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC(50): 73 microg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 microg/mL, respectively). All IC(50) values were high compared with those determined for crude extracts of other herbal remedies. The IC(50)/IC(25) ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. PMID:19170155

  1. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir

    PubMed Central

    Sevrioukova, Irina F.; Poulos, Thomas L.

    2010-01-01

    Ritonavir is a HIV protease inhibitor routinely prescribed to HIV patients that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. By inhibiting CYP3A4, ritonavir increases plasma concentrations of other anti-HIV drugs oxidized by CYP3A4 thereby improving clinical efficacy. Despite the importance and wide use of ritonavir in anti-HIV therapy, the precise mechanism of CYP3A4 inhibition remains unclear. The available data are inconsistent and suggest that ritonavir acts as a mechanism-based, competitive or mixed competitive-noncompetitive CYP3A4 inactivator. To resolve this controversy and gain functional and structural insights into the mechanism of CYP3A4 inhibition, we investigated the ritonavir binding reaction by kinetic and equilibrium analysis, elucidated how the drug affects redox properties of the hemoprotein, and determined the 2.0 Å X-ray structure of the CYP3A4-ritonavir complex. Our results show that ritonavir is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase. PMID:20937904

  2. Isopropyl alcohol tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    An isopropyl alcohol (IPA) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen IPA, water and liquid oxygen (LOX) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  3. Liquid oxygen tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A liquid oxygen (LOX) tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen LOX, isopropyl alcohol (IPA) and water tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  4. Water tank installed at A-3 Test Stand

    NASA Technical Reports Server (NTRS)

    2009-01-01

    A water tank is lifted into place at the A-3 Test Stand being built at NASA's John C. Stennis Space Center. Fourteen water, liquid oxygen (LOX) and isopropyl alcohol (IPA) tanks are being installed to support the chemical steam generators to be used on the A-3 Test Stand. The IPA and LOX tanks will provide fuel for the generators. The water will allow the generators to produce steam that will be used to reduce pressure inside the stand's test cell diffuser, enabling operators to simulate altitudes up to 100,000 feet. In that way, operators can perform the tests needed on rocket engines being built to carry humans back to the moon and possibly beyond. The A-3 Test Stand is set for completion and activation in 2011.

  5. Mechanism of Inhibition of the GluA2 AMPA Receptor Channel Opening by Talampanel and Its Enantiomer: The Stereochemistry of the 4-Methyl Group on the Diazepine Ring of 2,3-Benzodiazepine Derivatives

    PubMed Central

    2013-01-01

    Stereoselectivity of 2,3-benzodiazepine compounds provides a unique way for the design of stereoisomers as more selective and more potent inhibitors as drug candidates for treatment of the neurological diseases involving excessive activity of AMPA receptors. Here we investigate a pair of enantiomers known as Talampanel and its (+) counterpart about their mechanism of inhibition and selectivity toward four AMPA receptor subunits or GluA1–4. We show that Talampanel is the eutomer with the endismic ratio being 14 for the closed-channel and 10 for the open-channel state of GluA2. Kinetic evidence supports that Talampanel is a noncompetitive inhibitor and it binds to the same site for those 2,3-benzodiazepine compounds with the C-4 methyl group on the diazepine ring. This site, which we term as the “M” site, recognizes preferentially those 2,3-benzodiazepine compounds with the C-4 methyl group being in the R configuration, as in the chemical structure of Talampanel. Given that Talampanel inhibits GluA1 and GluA2, but is virtually ineffective on the GluA3 and GluA4 AMPA receptor subunits, we hypothesize that the “M” site(s) on GluA1 and GluA2 to which Talampanel binds is different from that on GluA3 and GluA4. If the molecular properties of the AMPA receptors and Talampanel are used for selecting an inhibitor as a single drug candidate for controlling the activity of all AMPA receptors in vivo, Talampanel is not ideal. Our results further suggest that addition of longer acyl groups to the N-3 position should produce more potent 2,3-benzodiazepine inhibitors for the “M” site. PMID:23402301

  6. Description and Operation of the A3 Subscale Facility

    NASA Technical Reports Server (NTRS)

    Saunders, G. P.; Varner, D. G.; Grover, J. B.

    2010-01-01

    The purpose of this paper is to give an overview of the general design and operation of the A3 Subscale test facility. The goal is to provide the reader with a general understanding of what the major facility systems are, where they are located, and how they are used to meet the objectives supporting the design of the A3 altitude rocket test facility. This paper also provides the reader with the background information prior to reading the subsequent papers detailing the design and test results of the various systems described herein.

  7. A 2 X 2 achievement goal framework.

    PubMed

    Elliot, A J; McGregor, H A

    2001-03-01

    A 2 x 2 achievement goal framework comprising mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance goals was proposed and tested in 3 studies. Factor analytic results supported the independence of the 4 achievement goal constructs. The goals were examined with respect to several important antecedents (e.g., motive dispositions, implicit theories, socialization histories) and consequences (e.g., anticipatory test anxiety, exam performance, health center visits), with particular attention allocated to the new mastery-avoidance goal construct. The results revealed distinct empirical profiles for each of the achievement goals; the pattern for mastery-avoidance goals was, as anticipated, more negative than that for mastery-approach goals and more positive than that for performance-avoidance goals. Implications of the present work for future theoretical development in the achievement goal literature are discussed. PMID:11300582

  8. La cometa 2001 A2 (LINEAR)

    NASA Astrophysics Data System (ADS)

    Milani, Giannantonio; Ligustri, Rolando; Facchini, Mauro; Tirelli, Diego

    2002-05-01

    The Comet C/2001 A2 (LINEAR) was expected as a relatively faint object for early summer 2001, but in March an outburst increased its brightness by more than 5 magnitudes with the development both of a diffuse coma and of a plasma tail. A dust tail was really evident only after perihelion. The comet was observed actively by the northern hemisphere before and after the perihelion passage, while in the southern hemisphere it was an easy naked eye object around the epoch of the perihelion passage. The behaviour of the light curve is dominated by the presence of several outbursts that are also related to the partial fragmentation of the nucleus. This had a strong influence in the development end extension of the coma and the tail. A relevant jet activity, documented by several observers,was detected within the coma in July.

  9. Holotoxin Activity of Botulinum Neurotoxin Subtype A4 Originating from a Nontoxigenic Clostridium botulinum Expression System

    PubMed Central

    Bradshaw, Marite; Tepp, William H.; Whitemarsh, Regina C. M.; Pellett, Sabine

    2014-01-01

    Clostridium botulinum subtype A4 neurotoxin (BoNT/A4) is naturally expressed in the dual-toxin-producing C. botulinum strain 657Ba at 100× lower titers than BoNT/B. In this study, we describe purification of recombinant BoNT/A4 (rBoNT/A4) expressed in a nonsporulating and nontoxigenic C. botulinum expression host strain. The rBoNT/A4 copurified with nontoxic toxin complex components provided in trans by the expression host and was proteolytically cleaved to the active dichain form. Activity of the recombinant BoNT/A4 in mice and in human neuronal cells was about 1,000-fold lower than that of BoNT/A1, and the recombinant BoNT/A4 was effectively neutralized by botulism heptavalent antitoxin. A previous report using recombinant truncated BoNT/A4 light chain (LC) expressed in Escherichia coli has indicated reduced stability and activity of BoNT/A4 LC compared to BoNT/A1 LC, which was surmounted by introduction of a single-amino-acid substitution, I264R. In order to determine whether this mutation would also affect the holotoxin activity of BoNT/A4, a recombinant full-length BoNT/A4 carrying this mutation as well as a second mutation predicted to increase solubility (L260F) was produced in the clostridial expression system. Comparative analyses of the in vitro, cellular, and in vivo activities of rBoNT/A4 and rBoNT/A4-L260F I264R showed 1,000-fold-lower activity than BoNT/A1 in both the mutated and nonmutated BoNT/A4. This indicates that these mutations do not alter the activity of BoNT/A4 holotoxin. In summary, a recombinant BoNT from a dual-toxin-producing strain was expressed and purified in an endogenous clostridial expression system, allowing analysis of this toxin. PMID:25239905

  10. The A3 adenosine receptor (A3AR): therapeutic target and predictive biological marker in rheumatoid arthritis.

    PubMed

    Fishman, Pnina; Cohen, Shira

    2016-09-01

    The Gi protein-associated A3 adenosine receptor (A3AR) is over-expressed in inflammatory cells, and this high expression is also reflected in the peripheral blood mononuclear cells of patients with autoimmune inflammatory diseases such as rheumatoid arthritis, psoriasis, and Crohn's disease. CF101, a selective agonist with high affinity to the A3AR, is known to induce robust anti-inflammatory effect in experimental animal models of adjuvant-, collagen-, and tropomyosin-induced arthritis. The effect is mediated via a definitive molecular mechanism entailing deregulation of the nuclear factor-κB (NF-κB) and the Wnt signal transduction pathways resulting in apoptosis of inflammatory cells. CF101 was found to be safe and well tolerated in all preclinical, phase I, and phase II human clinical studies. In two phase II clinical studies where CF101 was administered to rheumatoid arthritis (RA) patients as a stand-alone drug, a significant anti-rheumatic effect and a direct significant correlation were found between receptor expression at baseline and patients' response to the drug, suggesting that A3AR may be utilized as a predictive biomarker. The A3AR is a promising therapeutic target in rheumatoid arthritis and can be used also as a biological marker to predict patients' response to CF101. This is a unique type of a personalized medicine approach which may pave the way for a safe and efficacious treatment for this patient population. PMID:26886128

  11. Sperry versus Hebb: Topographic mapping in Isl2/EphA3 mutant mice

    PubMed Central

    2010-01-01

    Background In wild-type mice, axons of retinal ganglion cells establish topographically precise projection to the superior colliculus of the midbrain. This means that axons of neighboring retinal ganglion cells project to the proximal locations in the target. The precision of topographic projection is a result of combined effects of molecular labels, such as Eph receptors and ephrins, and correlated neural activity. In the Isl2/EphA3 mutant mice the expression levels of molecular labels are changed. As a result the topographic projection is rewired so that the neighborhood relationships between retinal cell axons are disrupted. Results Here we study the computational model for retinocollicular connectivity formation that combines the effects of molecular labels and correlated neural activity. We argue that the effects of correlated activity presenting themselves in the form of Hebbian learning rules can facilitate the restoration of the topographic connectivity even when the molecular labels carry conflicting instructions. This occurs because the correlations in electric activity carry information about retinal cells' origin that is independent on molecular labels. We argue therefore that partial restoration of the topographic property of the retinocollicular projection observed in Isl2/EphA3 heterozygous knockin mice may be explained by the effects of correlated neural activity. We address the maps observed in Isl2/EphA3 knockin/EphA4 knockout mice in which the levels of retinal labels are uniformly reduced. These maps can be explained by either the saturation of EphA receptor mapping leading to the relative signaling model or by the reverse signaling conveyed by ephrin-As expressed by retinal axons. Conclusion According to our model, experiments in Isl2/EphA3 knock-in mice test the interactions between effects of molecular labels and correlated activity during the development of neural connectivity. Correlated activity can partially restore topographic order even

  12. A 2.5m astronomical telescope project

    NASA Astrophysics Data System (ADS)

    Phaichith, Oudomsanith

    2008-07-01

    The paper reports a recently started project for a 2,5 meter diameter robotic telescope dedicated to astronomy and education for the University of Moscow's Sternberg Institute. As a prime contractor Sagem Defense Securite's REOSC department will take on the program design as well as the production of the optical components. The project includes the Alt-Az mount, the dome and its cooling and air stabilization system, the weather station, the high-resolution camera and realization, transport and installation on-site at the Kislovodsk solar station located in the Caucasus mountains as well as the initial training for the operators. The telescope will provide a wide field of view of 40 arcmin at the Cassegrain F/8 focus. An escapable and rotating tertiary mirror will allow to direct the light to the two Nasmyth foci and two student ports located at 90° from the Nasmyth foci. A 4k x 4k CCD camera cryogenically cooled to 140 K will be provided as a first light camera. All will be delivered by end 2009. Remotely controlled via the internet, the telescope will allow Russia to train doctors in astronomy, participate in international research projects and draw up the future specifications of a larger and more advanced telescope.

  13. Congenital aganglionosis in a 3-day-old Holstein calf

    PubMed Central

    2005-01-01

    Abstract Necropsy of a 3-day-old Holstein heifer revealed proximal megacolon and distal colorectal hypoplasia. Histologically, the hypoplastic distal colon and rectum lacked submucosal and myenteric ganglia. Clinical history, physical examination, and pathologic findings were consistent with intestinal aganglionosis, a congenital anomaly well documented in humans and foals but not previously reported in cattle. PMID:15943121

  14. Interferometer using a 3 × 3 coupler and Faraday mirrors

    NASA Astrophysics Data System (ADS)

    Breguet, J.; Gisin, N.

    1995-06-01

    A new interferometric setup using a 3 \\times 3 coupler and two Faraday mirrors is presented. It has the advantages of being built only with passive components, of freedom from the polarization fading problem, and of operation with a LED. It is well suited for sensing time-dependent signals and does not depend on reciprocal or nonreciprocal constant perturbations.

  15. The Coulomb problem on a 3-sphere and Heun polynomials

    NASA Astrophysics Data System (ADS)

    Bellucci, Stefano; Yeghikyan, Vahagn

    2013-08-01

    The paper studies the quantum mechanical Coulomb problem on a 3-sphere. We present a special parametrization of the ellipto-spheroidal coordinate system suitable for the separation of variables. After quantization we get the explicit form of the spectrum and present an algebraic equation for the eigenvalues of the Runge-Lentz vector. We also present the wave functions expressed via Heun polynomials.

  16. The Coulomb problem on a 3-sphere and Heun polynomials

    SciTech Connect

    Bellucci, Stefano; Yeghikyan, Vahagn

    2013-08-15

    The paper studies the quantum mechanical Coulomb problem on a 3-sphere. We present a special parametrization of the ellipto-spheroidal coordinate system suitable for the separation of variables. After quantization we get the explicit form of the spectrum and present an algebraic equation for the eigenvalues of the Runge-Lentz vector. We also present the wave functions expressed via Heun polynomials.

  17. Interferometer using a 3 x 3 coupler and Faraday mirrors.

    PubMed

    Breguet, J; Gisin, N

    1995-06-15

    A new interferometric setup using a 3 x 3 coupler and two Faraday mirrors is presented. It has the advantages of being built only with passive components, of freedom from the polarization fading problem, and of operation with a LED. It is well suited for sensing time-dependent signals and does not depend on reciprocal or nonreciprocal constant perturbations. PMID:19862044

  18. 45 CFR 12a.3 - Collecting the information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., and 41 CFR part 101-47.800. Each canvass will collect information on properties not previously... PROPERTY TO ASSIST THE HOMELESS § 12a.3 Collecting the information. (a) Canvass of landholding agencies. On... described below, of the suitability of a property for use as a facility to assist the homeless. (2) HUD...

  19. Controlled teleportation of a 3-dimensional bipartite quantum state

    NASA Astrophysics Data System (ADS)

    Cao, Hai-Jing; Chen, Zhong-Hua; Song, He-Shan

    2008-07-01

    A controlled teleportation scheme of an unknown 3-dimensional (3D) two-particle quantum state is proposed, where a 3D Bell state and 3D GHZ state function as the quantum channel. This teleportation scheme can be directly generalized to teleport an unknown d-dimensional bipartite quantum state.

  20. A 3D Serious City Building Game on Waste Disposal

    ERIC Educational Resources Information Center

    Cuccurullo, Stefania; Francese, Rita; Passero, Ignazio; Tortora, Genoveffa

    2013-01-01

    The environmental priority requires structural interventions that will be effective in the long period only if they are accompanied by modifications of behaviors, orientations and beliefs, specially investing in the new generations. This paper presents a 3D Virtual World serious game named Pappi World, designed according to pedagogical theories…

  1. Development of a 3D digitizer for breast surgery procedures

    NASA Astrophysics Data System (ADS)

    Rodriguez-Larena, Jorge; Canal Bienzobas, Fernando

    1999-03-01

    The planning of a breast reconstruction surgical operation has to resolve the problem of measuring directly on the patient meaningful anthropometric points from which distances, areas and volumes have to be calculated. In this paper, we propose using a 3D optical digitizer to perform this task.

  2. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for...

  3. 29 CFR 1912a.3 - Terms of membership.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.3 Terms of membership... occupational safety and health professions, and of the public. Appointment of a member to the Committee for...

  4. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Calculation of income inclusion. 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... Calculation of income inclusion....

  5. 26 CFR 1.401(a)(4)-5 - Plan amendments and plan terminations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Plan amendments and plan terminations. 1.401(a)(4... (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(a)(4)-5 Plan amendments and plan terminations. (a) Introduction—(1) Overview. This...

  6. 26 CFR 31.6011(a)-4 - Returns of income tax withheld.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Returns of income tax withheld. 31.6011(a)-4 Section 31.6011(a)-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Administrative Provisions of...

  7. Constraining a type I seesaw model with A4 flavor symmetry from neutrino data and leptogenesis

    NASA Astrophysics Data System (ADS)

    Kalita, Rupam; Borah, Debasish

    2015-09-01

    We study a type I seesaw model of neutrino masses within the framework of A4 flavor symmetry. Incorporating the presence of both singlet and triplet flavons under A4 symmetry, we construct the leptonic mass matrices involved in the type I seesaw mechanism. We then construct the light neutrino mass matrix using the 3 σ values of neutrino oscillation parameters keeping the presently undetermined parameters, namely, the lightest neutrino mass mlightest , one Dirac CP phase δ , and two Majorana phases α ,β , as free parameters. Comparing the mass matrices derived using A4 parameters as well as light neutrino parameters, we then evaluate all the A4 parameters in terms of light neutrino parameters. Assuming some specific vacuum alignments of the A4 triplet flavon field, we then numerically evaluate all the free parameters in the light neutrino sector, using them to find out the remaining A4 parameters. We then use the numerical values of these parameters to calculate baryon asymmetry through the mechanism of leptogenesis. We constrain not only the A4 vacuum alignments from the requirement of successful leptogenesis, but also the free parameters in the light neutrino sector (mlightest,δ ,α ,β ) to a certain range of values. These values can be tested in ongoing and future neutrino experiments, providing a way to discriminate between different possible A4 vacuum alignments discussed in this work.

  8. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross...

  9. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross...

  10. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross Estate §...

  11. 26 CFR 20.2032A-4 - Method of valuing farm real property.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Method of valuing farm real property. 20.2032A-4 Section 20.2032A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) ESTATE AND GIFT TAXES ESTATE TAX; ESTATES OF DECEDENTS DYING AFTER AUGUST 16, 1954 Gross Estate §...

  12. Should Community College Students Earn an Associate Degree before Transferring to a 4-Year Institution?

    ERIC Educational Resources Information Center

    Kopko, Elizabeth M.; Crosta, Peter M.

    2016-01-01

    Using data on over 41,000 students in one state who entered community college before transferring to a 4-year institution, this study examines the following question: Are community college students who earn an associate degree before transferring to a 4-year college more likely to earn a bachelor's degree? Due to the causal nature surrounding this…

  13. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS... governed by 45 CFR 74.40 through 74.47 and 45 CFR 92.25); (j) The proposed budget for the center and...

  14. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS... governed by 45 CFR 74.40 through 74.47 and 45 CFR 92.25); (j) The proposed budget for the center and...

  15. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS... governed by 45 CFR 74.40 through 74.47 and 45 CFR 92.25); (j) The proposed budget for the center and...

  16. 42 CFR 52a.4 - What information must each application contain?

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false What information must each application contain? 52a.4 Section 52a.4 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GRANTS... governed by 45 CFR 74.40 through 74.47 and 45 CFR 92.25); (j) The proposed budget for the center and...

  17. 14 CFR 374a.4 - Conditions governing extension of unsecured credit.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Conditions governing extension of unsecured credit. 374a.4 Section 374a.4 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL...

  18. 26 CFR 1.409A-4 - Calculation of income inclusion. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Calculation of income inclusion. 1.409A-4 Section 1.409A-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME... of income inclusion....

  19. Adenosine A2A receptor dynamics studied with the novel fluorescent agonist Alexa488-APEC

    PubMed Central

    Brand, Frank; Klutz, Athena; Jacobson, Kenneth A.; Fredholm, Bertil B.; Schulte, Gunnar

    2009-01-01

    G protein-coupled receptors, such as the adenosine A2A receptor, are dynamic proteins, which undergo agonist-dependent redistribution from the cell surface to intracellular membranous compartments, such as endosomes. In order to study the kinetics of adenosine A2A receptor redistribution in living cells, we synthesized a novel fluorescent agonist, Alexa488-APEC. Alexa488-APEC binds to adenosine A2A (Ki = 149 ± 27 nM) as well as A3 receptors (Ki= 240 ± 160 nM) but not to adenosine A1 receptors. Further, we characterized the dose-dependent increase in Alexa488-APEC-induced cAMP production as well as cAMP response element binding (CREB) protein phosphorylation, verifying the ligand’s functionality at adenosine A2A but not A2B receptors. In live cell imaging studies, Alexa488-APEC induced adenosine A2A receptor internalization, which was blocked by the competitive reversible antagonist ZM 241385 and hyperosmolaric sucrose. Further, internalized adenosine A2A receptors co-localized with clathrin and Rab5, indicating that agonist stimulation promotes adenosine A2A receptor uptake through a clathrin-dependent mechanism to Rab5-positive endosomes. The basic characterization of Alexa488-APEC provided here showed that it provides a usefultool for tracing adenosine A2A receptors in vitro. PMID:18603240

  20. Pyran Template Approach to the Design of Novel A3 Adenosine Receptor Antagonists

    PubMed Central

    Li, An-Hu; Ji, Xiao-duo; Kim, Hak Sung; Melman, Neli; Jacobson, Kenneth A.

    2016-01-01

    2A receptors, and at recombinant human A2B receptors displayed Ki values of 17.3 and 23.2 μM, respectively. The selectivity, but not affinity, of the pyran derivatives in binding to the A3 receptor subtype was generally enhanced vs. the corresponding DHP derivatives. PMID:27182099