Sample records for a1 b1 c1

  1. Alcohol binding in the C1 (C1A + C1B) domain of protein kinase C epsilon

    PubMed Central

    Pany, Satyabrata; Das, Joydip

    2015-01-01

    Background Alcohol regulates the expression and function of protein kinase C epsilon (PKCε). In a previous study we identified an alcohol binding site in the C1B, one of the twin C1 subdomains of PKCε. Methods In this study, we investigated alcohol binding in the entire C1 domain (combined C1A and C1B) of PKCε. Fluorescent phorbol ester, SAPD and fluorescent diacylglycerol (DAG) analog, dansyl-DAG were used to study the effect of ethanol, butanol, and octanol on the ligand binding using fluorescence resonance energy transfer (FRET). To identify alcohol binding site(s), PKCεC1 was photolabeled with 3-azibutanol and 3-azioctanol, and analyzed by mass spectrometry. The effects of alcohols and the azialcohols on PKCε were studied in NG108-15 cells. Results In the presence of alcohol, SAPD and dansyl-DAG showed different extent of FRET, indicating differential effects of alcohol on the C1A and C1B subdomains. Effects of alcohols and azialcohols on PKCε in NG108-15 cells were comparable. Azialcohols labeled Tyr-176 of C1A and Tyr-250 of C1B. Inspection of the model structure of PKCεC1 reveals that these residues are 40 Å apart from each other indicating that these residues form two different alcohol binding sites. Conclusions The present results provide evidence for the presence of multiple alcohol-binding sites on PKCε and underscore the importance of targeting this PKC isoform in developing alcohol antagonists. PMID:26210390

  2. 76 FR 39254 - Airworthiness Directives; Schweizer Aircraft Corporation (Schweizer) Model 269A, A-1, B, C, C-1...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-06

    ... Airworthiness Directives; Schweizer Aircraft Corporation (Schweizer) Model 269A, A-1, B, C, C-1, and TH-55... reviewed Schweizer Service Bulletins No. B-295 for Model 269A, A-1, B, and C helicopters, and No. C1B-032... citation for Part 39 continues to read as follows: Authority: 49 U.S.C. 106(g), 40113, 44701. Sec. 39.13...

  3. Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

    DOE PAGES

    Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.; ...

    2015-03-16

    Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex.more » We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A 1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A 1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.« less

  4. Biophysical Analysis of Anopheles gambiae Leucine-Rich Repeat Proteins APL1A1, APL1B and APL1C and Their Interaction with LRIM1

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

    Williams, Marni; Summers, Brady J.; Baxter, Richard H. G.

    Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A—C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex.more » We report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A 1 and APL1B form a stable complex with LRIM1. Our results support a model in which APL1A 1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.« less

  5. Quantum dynamics of the C(1D)+HD and C(1D)+n-D2 reactions on the ã 1A' and b 1A" surfaces.

    PubMed

    Defazio, Paolo; Gamallo, Pablo; González, Miguel; Akpinar, Sinan; Bussery-Honvault, Béatrice; Honvault, Pascal; Petrongolo, Carlo

    2010-03-14

    We present the Born-Oppenheimer, quantum dynamics of the reactions C((1)D)+HD and C((1)D)+n-D(2) on the uncoupled potential energy surfaces ã (1)A' and b (1)A", considering the Coriolis interactions and the nuclear-spin statistics. Using the real wavepacket method, we obtain initial-state-resolved probabilities, cross sections, isotopic branching ratios, and rate constants. Similarly to the C+n-H(2) reaction, the probabilities present many ã (1)A' or few b (1)A" sharp resonances, and the cross sections are very large at small collision energies and decrease at higher energies. At any initial condition, the C+HD reaction gives preferentially the CD+H products. Thermal cross sections, isotopic branching ratios, and rate constant k vary slightly with temperature and agree very well with the experimental values. At 300 K, we obtain for the various products k(CH+H)=(2.45+/-0.08) x 10(-10), k(CD+H)=(1.19+/-0.04) x 10(-10), k(CH+D)=(0.71+/-0.02) x 10(-10), k(CD+D)=(1.59+/-0.05) x 10(-10) cm(3) s(-1), and k(CD+H)/k(CH+D)=1.68+/-0.01. The b (1)A" contribution to cross sections and rate constants is always large, up to a maximum value of 62% for a rotationally resolved C+D(2) rate constant. The upper b (1)A" state is thus quite important in the C((1)D) collision with H(2) and its deuterated isotopes, as the agreement between theory and experiment shows.

  6. Mapping the Complement Factor H-Related Protein 1 (CFHR1):C3b/C3d Interactions

    PubMed Central

    Laskowski, Jennifer; Thurman, Joshua M.; Hageman, Gregory S.; Holers, V. Michael

    2016-01-01

    Complement factor H-related protein 1 (CFHR1) is a complement regulator which has been reported to regulate complement by blocking C5 convertase activity and interfering with C5b surface association. CFHR1 also competes with complement factor H (CFH) for binding to C3b, and may act as an antagonist of CFH-directed regulation on cell surfaces. We have employed site-directed mutagenesis in conjunction with ELISA-based and functional assays to isolate the binding interaction that CFHR1 undertakes with complement components C3b and C3d to a single shared interface. The C3b/C3d:CFHR1 interface is identical to that which occurs between the two C-terminal domains (SCR19-20) of CFH and C3b. Moreover, we have been able to corroborate that dimerization of CFHR1 is necessary for this molecule to bind effectively to C3b and C3d, or compete with CFH. Finally, we have established that CFHR1 competes with complement factor H-like protein 1 (CFHL-1) for binding to C3b. CFHL-1 is a CFH gene splice variant, which is almost identical to the N-terminal 7 domains of CFH (SCR1-7). CFHR1, therefore, not only competes with the C-terminus of CFH for binding to C3b, but also sterically blocks the interaction that the N-terminus of CFH undertakes with C3b, and which is required for CFH-regulation. PMID:27814381

  7. A Novel Role for C5a in B-1 Cell Homeostasis

    PubMed Central

    Bröker, Katharina; Figge, Julia; Magnusen, Albert F.; Manz, Rudolf A.; Köhl, Jörg; Karsten, Christian M.

    2018-01-01

    B-1 cells constitute a unique subpopulation of lymphocytes residing mainly in body cavities like the peritoneal cavity (PerC) but are also found in spleen and bone marrow (BM). As innate-like B cells, they mediate first line immune defense through low-affinity natural IgM (nIgM) antibodies. PerC B-1 cells can egress to the spleen and differentiate into nIgM antibody-secreting plasma cells that recognize conserved exogenous and endogenous cellular structures. Homing to and homeostasis within the PerC are regulated by the chemokine CXCL13 released by PerC macrophages and stroma cells. However, the exact mechanisms underlying the regulation of CXCL13 and B-1 homeostasis are not fully explored. B-1 cells play important roles in the inflammatory response to infection, autoimmunity, ischemia/reperfusion injury, obesity, and atherosclerosis. Remarkably, this list of inflammatory entities has a strong overlap with diseases that are regulated by complement suggesting a link between B-1 cells and the complement system. Interestingly, up to now, no data exist regarding the role of complement in B-1 cell biology. Here, we demonstrate for the first time that C5a regulates B-1 cell steady-state dynamics within the peritoneum, the spleen, and the BM. We found decreased B-1a cell numbers in the peritoneum and the spleen of C5aR1−/− mice associated with increased B1-a and B1-b numbers in the spleen and high serum titers of nIgM antibodies directed against phosphorylcholine and several pneumococcal polysaccharides. Similarly, peritoneal B-1a cells were decreased in the peritoneum and splenic B-1a and B-1b cells were increased in C5aR2−/− mice. The decrease in peritoneal B-1 cell numbers was associated with decreased peritoneal CXCL13 levels in C5aR1−/− and C5aR2−/− mice. In search for mechanisms, we found that combined TLR2 and IL-10 receptor activation in PerC macrophages induced strong CXCL13 production, which was significantly reduced in cells from C5aR1- and C5a

  8. Study of Infrared Emission Spectroscopy for the B1Δg-A1Πu and B'1Σg+-A1Πu Systems of C2

    NASA Astrophysics Data System (ADS)

    Tang, Jian; Chen, Wang; Kawaguchi, Kentarou; Bernath, Peter F.

    2016-06-01

    Recently, we carried out the perturbation analysis of C_2 spectra and identified forbidden singlet-triplet intersystem transitions, which aroused further interest in other C_2 spectra for the many low-lying electronic states of this fundamental molecule. In 1988, the B1Δg-A1Πu and B'1Σg+-A1Πu band systems were discovered by Douay et al., who observed eight bands of the B1Δg-A1Πu system with v up to 5 for the B1Δg state and six bands of the B'1Σg+-A1Πu system with v up to 3 for the B'1Σg+ state in the Fourier transform infrared emission spectra of hydrocarbon discharges. In the work presented here, we identified twenty-four bands of the two systems, among which the B'1Σg+ v = 4 and the B1Δg v = 6, 7 and 8 vibrational levels involved in nine bands were studied for the first time. A direct global analysis with Dunham parameters was carried out satisfactorily for the B1Δg-A1Πu system except for a small perturbation in the B1Δg v = 6 level. The calculated rovibrational term energies up to B1Δg v = 12 showed that the level crossing between the B1Δg and d3Πg states is responsible for many of the prominent perturbations in the Swan system observed previously. Nineteen lines of the B1Δg-a3Πu forbidden transitions were identified and the off-diagonal spin-orbit interaction constant AdB between d3Πg and B1Δg was derived as 8.3(1) wn. For the B'1Σg+-A1Πu system, only individual band analyses for each vibrational level in the B'1Σg+ state could be done satisfactorily and Dunham parameters obtained from these effective parameters showed that the anharmonic vibrational constant ω_e x_e is anomalously small (nearly zero). Inspection of the RKR potential curves for the B'1Σg+ and X1Σg+ states revealed that an avoided crossing may occur around 30000 wn, which is responsible for the anomalous molecular constants in these two states. W. Chen, K. Kawaguchi, P. F. Bernath, and J. Tang, J. Chem. Phys., 141, 064317 (2015) M. Douay, R. Nietmann and P. F. Bernath

  9. HLA-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in the Serbian population.

    PubMed

    Andric, Zorana; Popadic, Dusan; Jovanovic, Barbara; Jaglicic, Ivana; Bojic, Svetlana; Simonovic, Ruzica

    2014-03-01

    This study provides the first published detailed analysis of five loci polymorphisms as well as reports of two, three and five loci haplotype frequencies in the Serbian population in a sample of 1992 volunteer bone marrow donors recruited from different part of the country. Typing was performed by PCR SSO method combined with PCR SSP techniques to resolve ambiguities. In total, 16 HLA-A, 28 HLA-B, 14 HLA-C, 13 HLA-DRB1 and 5 HLA-DQB1 allelic groups were identified. The most frequent in allele groups are HLA-A(∗)02 (29.5%), HLA-A(∗)01 (14.2%), HLA-B(∗)35 (13.1%), HLA-B(∗)51 (12.8%), HLA-C(∗)07 (24.8%), HLA-DRB1(∗)11 (16.9%), HLA-DRB1(∗)13 (13.2%), HLA-DQB1(∗)03 (33.3%) and DQB1(∗)05 (33.0%). The most frequent three- and five-loci haplotypes were A(∗)01-B(∗)08-DRB1(∗)03 (5.9%) and A(∗)02-B(∗)18-DRB1(∗)11 (1.9%), A(∗)01-B(∗)08-C(∗)07-DRB1(∗)03-DQB1(∗)02 (6.6%) followed by A(∗)02-B(∗)18-C(∗)07-DRB1(∗)11-DQB1(∗)03 (2.5%), then A(∗)33-B(∗)14-C(∗)08-DRB1(∗)01-DQB1(∗)05 and A(∗)02-B(∗)35-C(∗)04-DRB1(∗)16-DQB1(∗)05 (2.2% both), respectively. The results of cluster analysis showed that the Serbian population is closely related to the populations living in central Balkan and neighboring European regions. The level of allelic diversity found in this study are relevant to facilitate searching for unrelated matched donor and provide a healthy control population from our region that should be useful in the future disease association study. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  10. Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population.

    PubMed

    Lee, K W; Oh, D H; Lee, C; Yang, S Y

    2005-05-01

    High-resolution human leukocyte antigen (HLA) typing exposes the unique patterns of HLA allele and haplotype frequencies in each population. In this study, HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were analyzed in 485 apparently unrelated healthy Korean individuals. A total of 20 HLA-A, 43 HLA-B, 21 HLA-C, 31 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. Eleven alleles (A*0201, A*1101, A*2402, A*3303, B*1501, Cw*0102, Cw*0302, Cw*0303, DQB1*0301, DQB1*0302, and DQB1*0303) were found in more than 10% of the population. In each serologic group, a maximum of three alleles were found with several exceptions (A2, B62, DR4, DR14, and DQ6). In each serologic group exhibiting multiple alleles, two major alleles were present at 62-96% (i.e. A*0201 and A*0206 comprise 85% of A2-positive alleles). Multiple-locus haplotypes estimated by the maximum likelihood method revealed 51 A-C, 43 C-B, 52 B-DRB1, 34 DRB1-DQB1, 48 A-C-B, 42 C-B-DRB1, 46 B-DRB1-DQB1, and 30 A-C-B-DRB1-DQB1 haplotypes with frequencies of more than 0.5%. In spite of their high polymorphism in B and DRB1, identification of relatively small numbers of two-locus (B-C and DRB1-DQB1) haplotypes suggested strong associations of those two loci, respectively. Five-locus haplotypes defined by high-resolution DNA typing correlated well with previously identified serology-based haplotypes in the population. The five most frequent haplotypes were: A*3303-Cw*1403-B*4403-DRB1*1302-DQB1*0604 (4.2%), A*3303-Cw*0701/6-B*4403-DRB1*0701-DQB1*0201/2 (3.0%), A*3303-Cw*0302-B*5801-DRB1*1302-DQB1*0609 (3.0%), A*2402-Cw*0702-B*0702-DRB1*0101-DQB1*0501 (2.9%), and A*3001-Cw*0602-B*1302-DRB1*0701-DQB1*0201/2 (2.7%). Several sets of allele level haplotypes that could not be discriminated by routine HLA-A, -B, and -DRB1 low-resolution typing originated from allelic diversity of A2, B61, DR4, and DR8 serologic groups. Information obtained in this study will be useful for medical and forensic applications as well as in anthropology.

  11. 76 FR 70046 - Airworthiness Directives; Eurocopter France Model AS350B, B1, B2, B3, BA, C, D, and D1; and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... Airworthiness Directives; Eurocopter France Model AS350B, B1, B2, B3, BA, C, D, and D1; and AS355E, F, F1, F2, N... France (Eurocopter) Model AS350B, B1, B2, B3, BA, C, D, and D1 helicopters; and Model AS355E, F, F1, F2... (AD 2003- 22-06), for Eurocopter Model AS350B, B1, B2, B3, BA, C, D, and D1; and Model AS355E, F, F1...

  12. C 1Σ+ , A 1Σ+ , and b 3Π0+ states of LiRb

    NASA Astrophysics Data System (ADS)

    Stevenson, I. C.; Blasing, D. B.; Chen, Y. P.; Elliott, D. S.

    2016-12-01

    We present the first spectroscopic studies of the C 1Σ+ electronic state and the A 1Σ+ -b 3Π0+ complex in 7Li-85Rb. Using resonantly enhanced, two-photon ionization, we observed v =7 , 9, 12, 13, and 26-45 of the C 1Σ+ state. We augment the REMPI data with a form of depletion spectra in regions of dense spectral lines. The A 1Σ+ -b 3Π0+ complex was observed with depletion spectroscopy, depleting to vibrational levels v =0 →29 of the A 1Σ+ state and v =8 →18 of the b 3Π0+ state. For all three series, we determine the term energy and vibrational constants. Finally, we outline several possible future projects based on the data presented here.

  13. Measurement of sigma chi c2 B(chi c2-->J/psi gamma)/sigma chi c1 B(chi c1 -->J/psi gamma) in pp collisions at square root s=1.96 TeV.

    PubMed

    Abulencia, A; Adelman, J; Affolder, T; Akimoto, T; Albrow, M G; Ambrose, D; Amerio, S; Amidei, D; Anastassov, A; Anikeev, K; Annovi, A; Antos, J; Aoki, M; Apollinari, G; Arguin, J-F; Arisawa, T; Artikov, A; Ashmanskas, W; Attal, A; Azfar, F; Azzi-Bacchetta, P; Azzurri, P; Bacchetta, N; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Baroiant, S; Bartsch, V; Bauer, G; Bedeschi, F; Behari, S; Belforte, S; Bellettini, G; Bellinger, J; Belloni, A; Benjamin, D; Beretvas, A; Beringer, J; Berry, T; Bhatti, A; Binkley, M; Bisello, D; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bolla, G; Bolshov, A; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Budroni, S; Burkett, K; Busetto, G; Bussey, P; Byrum, K L; Cabrera, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carillo, S; Carlsmith, D; Carosi, R; Carron, S; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, I; Cho, K; Chokheli, D; Chou, J P; Choudalakis, G; Chuang, S H; Chung, K; Chung, W H; Chung, Y S; Ciljak, M; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Coca, M; Compostella, G; Convery, M E; Conway, J; Cooper, B; Copic, K; Cordelli, M; Cortiana, G; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; Cyr, D; DaRonco, S; Datta, M; D'Auria, S; Davies, T; D'Onofrio, M; Dagenhart, D; de Barbaro, P; De Cecco, S; Deisher, A; De Lentdecker, G; Dell'Orso, M; Delli Paoli, F; Demortier, L; Deng, J; Deninno, M; De Pedis, D; Derwent, P F; Di Giovanni, G P; Dionisi, C; Di Ruzza, B; Dittmann, J R; DiTuro, P; Dörr, C; Donati, S; Donega, M; Dong, P; Donini, J; Dorigo, T; Dube, S; Efron, J; Erbacher, R; Errede, D; Errede, S; Eusebi, R; Fang, H C; Farrington, S; Fedorko, I; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Field, R; Flanagan, G; Foland, A; Forrester, S; Foster, G W; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garcia, J E; Garberson, F; Garfinkel, A F; Gay, C; Gerberich, H; Gerdes, D; Giagu, S; Giannetti, P; Gibson, A; Gibson, K; Gimmell, J L; Ginsburg, C; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Goldstein, J; Golossanov, A; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Griffiths, M; Grinstein, S; Grosso-Pilcher, C; Group, R C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Hamilton, A; Han, B-Y; Han, J Y; Handler, R; Happacher, F; Hara, K; Hare, M; Harper, S; Harr, R F; Harris, R M; Hartz, M; Hatakeyama, K; Hauser, J; Heijboer, A; Heinemann, B; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Holloway, A; Hou, S; Houlden, M; Hsu, S-C; Huffman, B T; Hughes, R E; Husemann, U; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ishizawa, Y; Ivanov, A; Iyutin, B; James, E; Jang, D; Jayatilaka, B; Jeans, D; Jensen, H; Jeon, E J; Jindariani, S; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Karchin, P E; Kato, Y; Kemp, Y; Kephart, R; Kerzel, U; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Klute, M; Knuteson, B; Ko, B R; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kovalev, A; Kraan, A C; Kraus, J; Kravchenko, I; Kreps, M; Kroll, J; Krumnack, N; Kruse, M; Krutelyov, V; Kubo, T; Kuhlmann, S E; Kuhr, T; Kusakabe, Y; Kwang, S; Laasanen, A T; Lai, S; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; LeCompte, T; Lee, J; Lee, J; Lee, Y J; Lee, S W; Lefèvre, R; Leonardo, N; Leone, S; Levy, S; Lewis, J D; Lin, C; Lin, C S; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, T; Lockyer, N S; Loginov, A; Loreti, M; Loverre, P; Lu, R-S; Lucchesi, D; Lujan, P; Lukens, P; Lungu, G; Lyons, L; Lys, J; Lysak, R; Lytken, E; Mack, P; MacQueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maki, T; Maksimovic, P; Malde, S; Manca, G; Margaroli, F; Marginean, R; Marino, C; Marino, C P; Martin, A; Martin, M; Martin, V; Martínez, M; Maruyama, T; Mastrandrea, P; Masubuchi, T; Matsunaga, H; Mattson, M E; Mazini, R; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzemer, S; Menzione, A; Merkel, P; Mesropian, C; Messina, A; Miao, T; Miladinovic, N; Miles, J; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyamoto, A; Moed, S; Moggi, N; Mohr, B; Moore, R; Morello, M; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Mumford, R; Murat, P; Nachtman, J; Nagano, A; Naganoma, J; Nakano, I; Napier, A; Necula, V; Neu, C; Neubauer, M S; Nielsen, J; Nigmanov, T; Nodulman, L; Norniella, O; Nurse, E; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Oldeman, R; Orava, R; Osterberg, K; Pagliarone, C; Palencia, E; Papadimitriou, V; Paramonov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Piedra, J; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Portell, X; Poukhov, O; Pounder, N; Prakoshyn, F; Pronko, A; Proudfoot, J; Ptohos, F; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ranjan, N; Rappoccio, S; Reisert, B; Rekovic, V; Renton, P; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Ruiz, A; Russ, J; Rusu, V; Saarikko, H; Sabik, S; Safonov, A; Sakumoto, W K; Salamanna, G; Saltó, O; Saltzberg, D; Sánchez, C; Santi, L; Sarkar, S; Sartori, L; Sato, K; Savard, P; Savoy-Navarro, A; Scheidle, T; Schlabach, P; Schmidt, E E; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scott, A L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sfyrla, A; Shapiro, M D; Shears, T; Shepard, P F; Sherman, D; Shimojima, M; Shochet, M; Shon, Y; Shreyber, I; Sidoti, A; Sinervo, P; Sisakyan, A; Sjolin, J; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soderberg, M; Soha, A; Somalwar, S; Sorin, V; Spalding, J; Spinella, F; Spreitzer, T; Squillacioti, P; Stanitzki, M; Staveris-Polykalas, A; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Stuart, D; Suh, J S; Sukhanov, A; Sun, H; Suzuki, T; Taffard, A; Takashima, R; Takeuchi, Y; Takikawa, K; Tanaka, M; Tanaka, R; Tecchio, M; Teng, P K; Terashi, K; Thom, J; Thompson, A S; Thomson, E; Tipton, P; Tiwari, V; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Tourneur, S; Trischuk, W; Tsuchiya, R; Tsuno, S; Turini, N; Ukegawa, F; Unverhau, T; Uozumi, S; Usynin, D; Vallecorsa, S; van Remortel, N; Varganov, A; Vataga, E; Vázquez, F; Velev, G; Veramendi, G; Veszpremi, V; Vidal, R; Vila, I; Vilar, R; Vine, T; Vollrath, I; Volobouev, I; Volpi, G; Würthwein, F; Wagner, P; Wagner, R G; Wagner, R L; Wagner, J; Wagner, W; Wallny, R; Wang, S M; Warburton, A; Waschke, S; Waters, D; Weinberger, M; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wright, T; Wu, X; Wynne, S M; Yagil, A; Yamamoto, K; Yamaoka, J; Yamashita, T; Yang, C; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanello, L; Zanetti, A; Zaw, I; Zhang, X; Zhou, J; Zucchelli, S

    2007-06-08

    We measure the ratio of cross section times branching fraction, Rp=sigma chi c2 B(chi c2-->J/psi gamma)/sigma chi c1 B(chi c1-->J/psi gamma), in 1.1 fb(-1) of pp collisions at square root s=1.96 TeV. This measurement covers the kinematic range pT(J/psi)>4.0 GeV/c, |eta(J/psi)<1.0, and pT(gamma)>1.0 GeV/c. For events due to prompt processes, we find Rp=0.395+/-0.016(stat)+/-0.015(syst). This result represents a significant improvement in precision over previous measurements of prompt chi c1,2 hadro production.

  14. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.

    PubMed

    Braun, L; Ghebrehiwet, B; Cossart, P

    2000-04-03

    InlB is a Listeria monocytogenes protein that promotes entry of the bacterium into mammalian cells by stimulating tyrosine phosphorylation of the adaptor proteins Gab1, Cbl and Shc, and activation of phosphatidyl- inositol (PI) 3-kinase. Using affinity chromatography and enzyme-linked immunosorbent assay, we demonstrate a direct interaction between InlB and the mammalian protein gC1q-R, the receptor of the globular part of the complement component C1q. Soluble C1q or anti-gC1q-R antibodies impair InlB-mediated entry. Transient transfection of GPC16 cells, which are non-permissive to InlB-mediated entry, with a plasmid-expressing human gC1q-R promotes entry of InlB-coated beads. Furthermore, several experiments indicate that membrane recruitment and activation of PI 3-kinase involve an InlB-gC1q-R interaction and that gC1q-R associates with Gab1 upon stimulation of Vero cells with InlB. Thus, gC1q-R constitutes a cellular receptor involved in InlB-mediated activation of PI 3-kinase and tyrosine phosphorylation of the adaptor protein Gab1. After E-cadherin, the receptor for internalin, gC1q-R is the second identified mammalian receptor promoting entry of L. monocytogenes into mammalian cells.

  15. The C1Σ+ , A1Σ+ , and b3Π0+ states of LiRb

    NASA Astrophysics Data System (ADS)

    Stevenson, Ian; Blasing, David; Chen, Yong; Elliott, Daniel

    2017-04-01

    We present the first spectroscopic studies of the C1Σ+ electronic state and the A1Σ+ - b3Π0+ complex in 7Li - 85Rb. Using resonantly-enhanced, two-photon ionization, we observed v = 7 , 9, 12, 13 and 26 - 45 of the C1Σ+ state. We augment the REMPI data with a form of depletion spectra in regions of dense spectral lines. The A1Σ+ - b3Π0+ complex was observed with depletion spectroscopy, depleting to vibrational levels v = 0 -> 29 of the A1Σ+ state and v = 8 -> 18 of the b3Π0+ state. For all three series, we determine the term energy and vibrational constants. Finally, we outline several possible future projects in ultracold molecules based on the data presented here.

  16. Frequency distribution of polymorphisms of CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes in the Yakut population.

    PubMed

    Vasilyev, Filipp Filippovich; Danilova, Diana Aleksandrovna; Kaimonov, Vladimir Sergeevich; Chertovskih, Yana Valerievna; Maksimova, Nadezda Romanovna

    2016-01-01

    Allele frequencies of single nucleotide polymorphisms (SNPs) are variable among different populations; therefore the study of SNPs in ethnic groups is important for establishing the clinical significance of the screening of these polymorphisms. The main goal of the research is to study the polymorphisms of CYP2C9, CYP2C19, VKORC1, and SLCO1B1 in Yakuts. Genomic DNA from 229 Yakut subjects were analyzed by real-time polymerase chain reaction (PCR) (SLCO1B1 +521T > C, VKORC1 -1639G>A, CYP2C19 +681G>A, +636G>A, CYP2C9 +430С>T, +1075A>C). Genotype frequencies of polymorphisms in the population of the Yakuts were more characteristic of the Asian population. The results have been included in the software application "Lekgen" that we developed for the interpretation of pharmacogenetic testing. The data of our study obtained on frequency carriers of polymorphisms of genes SLCO1B1, CYP2C19, CYP2C9, VKORC1 among the Yakuts may be useful in developing recommendations for a personalized therapy.

  17. Frequency distribution of polymorphisms of CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes in the Yakut population

    PubMed Central

    Vasilyev, Filipp Filippovich; Danilova, Diana Aleksandrovna; Kaimonov, Vladimir Sergeevich; Chertovskih, Yana Valerievna; Maksimova, Nadezda Romanovna

    2016-01-01

    Allele frequencies of single nucleotide polymorphisms (SNPs) are variable among different populations; therefore the study of SNPs in ethnic groups is important for establishing the clinical significance of the screening of these polymorphisms. The main goal of the research is to study the polymorphisms of CYP2C9, CYP2C19, VKORC1, and SLCO1B1 in Yakuts. Genomic DNA from 229 Yakut subjects were analyzed by real-time polymerase chain reaction (PCR) (SLCO1B1 +521T > C, VKORC1 -1639G>A, CYP2C19 +681G>A, +636G>A, CYP2C9 +430С>T, +1075A>C). Genotype frequencies of polymorphisms in the population of the Yakuts were more characteristic of the Asian population. The results have been included in the software application “Lekgen” that we developed for the interpretation of pharmacogenetic testing. The data of our study obtained on frequency carriers of polymorphisms of genes SLCO1B1, CYP2C19, CYP2C9, VKORC1 among the Yakuts may be useful in developing recommendations for a personalized therapy. PMID:27499796

  18. 75 FR 22508 - Airworthiness Directives; Eurocopter France Model AS350B, BA, B1, B2, B3, C, D, and D1; AS 355E...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-29

    ... Airworthiness Directives; Eurocopter France Model AS350B, BA, B1, B2, B3, C, D, and D1; AS 355E, F, F1, F2, N... (b) None. Applicability (c) This AD applies to Model AS350B, BA, B1, B2, B3, C, D and D1; and AS 355E..., both dated November 16, 2005, is approved by the Director of the Federal Register as of May 14, 2010...

  19. Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis.

    PubMed

    Hevir, N; Vouk, K; Sinkovec, J; Ribič-Pucelj, M; Rižner, T Lanišnik

    2011-05-30

    Endometriosis is a very common disease that is characterized by increased formation of estradiol and disturbed progesterone action. This latter is usually explained by a lack of progesterone receptor B (PR-B) expression, while the role of pre-receptor metabolism of progesterone is not yet fully understood. In normal endometrium, progesterone is metabolized by reductive 20α-hydroxysteroid dehydrogenases (20α-HSDs), 3α/β-HSDs and 5α/β-reductases. The aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are the major reductive 20α-HSDs, while the oxidative reaction is catalyzed by 17β-HSD type 2 (HSD17B2). Also, 3α-HSD and 3β-HSD activities have been associated with the AKR1C isozymes. Additionally, 5α-reductase types 1 and 2 (SRD5A1, SRD5A2) and 5β-reductase (AKR1D1) are responsible for the formation of 5α- and 5β-reduced pregnanes. In this study, we examined the expression of PR-AB and the progesterone metabolizing enzymes in 31 specimens of ovarian endometriosis and 28 specimens of normal endometrium. Real-time PCR analysis revealed significantly decreased mRNA levels of PR-AB, HSD17B2 and SRD5A2, significantly increased mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1, and negligible mRNA levels of AKR1D1. Immunohistochemistry staining of endometriotic tissue compared to control endometrium showed significantly lower PR-B levels in epithelial cells and no significant differences in stromal cells, there were no significant differences in the expression of AKR1C3 and significantly higher AKR1C2 levels were seen only in stromal cells. Our expression analysis data at the mRNA level and partially at the cellular level thus suggest enhanced metabolism of progesterone by SRD5A1 and the 20α-HSD and 3α/β-HSD activities of AKR1C1, AKR1C2 and AKR1C3. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  20. Structure and expression of the human thymocyte antigens CD1a, CD1b, and CD1c

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

    Martin, L.H.; Calabi, F.; Lefebvre, F.A.

    1987-12-01

    The CD1 human antigens are a family of at least three components, CD1a, CD1b, and CD1c, that are characteristic of the cortical stage of thymocyte maturation. CD1a was originally named HTA1 or T6 and thought to be the human equivalent of mouse Tla. The genes coding for all three have not been identified by transfection into mouse cells. The transfectants express the surface antigens that can then be recognized by the corresponding cluster of monoclonal antibodies used to define the three members of CD1. The full sequence of the genomic DNA is described for all three. The intron-exon structure ofmore » CD1a is deduced by comparison with a near-full-length cDNA clone. Similar structures are proposed for the other two, largely based on sequence homology. An unusually long 5'-untranslated exon (280 bases long) is highly conserved between the three genes, suggesting an important but unknown function. CD1c has a duplicated form of this exon that is thought to be spliced out. The major homology between the three antigens is in the ..beta../sub 2/-microglobulin-binding-domain. The general relatedness to major histocompatibility complex class I and class II molecules is significant but low, with no section of higher homology to mouse Tla.« less

  1. Crystal Chemistry and Magnetism of Ternary Actinoid Boron Carbides UB 1- xC 1+ x and U 1- xMxB 2C with M = Sc, Lu, and Th

    NASA Astrophysics Data System (ADS)

    Rogl, P.; Rupp, B.; Felner, I.; Fischer, P.

    1993-06-01

    Within the homogeneous range of uranium monocarbide UB 1- xC 1+ x, the crystal structures of stoichiometric UBC and of the carbon-rich solid solution UB 0.78C 1.22, have been refined from single-crystal X-ray counter data. From X-ray analysis crystal symmetry in both cases is consistent with the centro-symmetric space group Cmcm and there are no indications of superstructure formation. In contrast to the fully ordered atom arrangement revealed for stoichiometric UBC ( a = 0.35899(4), b = 1.19781(12), c = 0.33474(3) nm), random occupation by boron and carbon atoms is observed for the boron site in UB 0.78C 1.22 ( a = 0.35752(4), b = 1.18584(3), c = 0.33881(4) nm). For 279(278) reflections (|F 0| > 3σ) the obtained reliability factors R x = ∑|ΔF|/∑| F0| were R x = 0.069 for UBC and R x = 0.050 for UB 0.78C 1.22. Neutron powder diffraction experiments at 9 and 295 K unambiguously revealed full occupancy by the nonmetal atoms in UB 0.78C 1.22 and prove the statistical occupation of B and C atoms in the B-sites. For the orthorhombic symmetry Cmcm, refinement was not better than R1 = 0.044. A model calculation in monoclinic symmetry C12/ m1, however, resulted in a significant reduction of the residual value to R1 = 0.030, releasing spatial constraints on the boron atoms. Thus the boron-boron chain in Cmcm (B-B = 0.1874 nm) is dissolved into boron pairs (B-B = 0.1706 nm) which are loosely bound at a distance of 0.2043 nm. The formation of C-B-B-C groups corresponds to the structure types of ThBC and Th 3B 2C 3. The magnetic behavior has been investigated in the temperature range from 4.2 K to 1000 K for UB 1- xC 1+ x (UBC-type) and U 1- xMxB 2C (ThB 2C-type for the high temperature modification and 1-UB 2C-type for the low temperature modification) with U partially substituted by Th or Sc, Lu. From magnetic susceptibilities, the alloys UB 1- xC 1+ x reveal temperature independent paramagnetism with typical intermediate valence fluctuation behavior ( TSF ˜ 350 K

  2. The HsiB1C1 (TssB-TssC) Complex of the Pseudomonas aeruginosa Type VI Secretion System Forms a Bacteriophage Tail Sheathlike Structure

    PubMed Central

    Lossi, Nadine S.; Manoli, Eleni; Förster, Andreas; Dajani, Rana; Pape, Tillmann; Freemont, Paul; Filloux, Alain

    2013-01-01

    Protein secretion systems in Gram-negative bacteria evolved into a variety of molecular nanomachines. They are related to cell envelope complexes, which are involved in assembly of surface appendages or transport of solutes. They are classified as types, the most recent addition being the type VI secretion system (T6SS). The T6SS displays similarities to bacteriophage tail, which drives DNA injection into bacteria. The Hcp protein is related to the T4 bacteriophage tail tube protein gp19, whereas VgrG proteins structurally resemble the gp27/gp5 puncturing device of the phage. The tube and spike of the phage are pushed through the bacterial envelope upon contraction of a tail sheath composed of gp18. In Vibrio cholerae it was proposed that VipA and VipB assemble into a tail sheathlike structure. Here we confirm these previous data by showing that HsiB1 and HsiC1 of the Pseudomonas aeruginosa H1-T6SS assemble into tubules resulting from stacking of cogwheel-like structures showing predominantly 12-fold symmetry. The internal diameter of the cogwheels is ∼100 Å, which is large enough to accommodate an Hcp tube whose external diameter has been reported to be 85 Å. The N-terminal 212 residues of HsiC1 are sufficient to form a stable complex with HsiB1, but the C terminus of HsiC1 is essential for the formation of the tubelike structure. Bioinformatics analysis suggests that HsiC1 displays similarities to gp18-like proteins in its C-terminal region. In conclusion, we provide further structural and mechanistic insights into the T6SS and show that a phage sheathlike structure is likely to be a conserved element across all T6SSs. PMID:23341461

  3. β1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function

    PubMed Central

    Kruger, Larisa C.; O'Malley, Heather A.; Hull, Jacob M.; Kleeman, Amanda; Patino, Gustavo A.

    2016-01-01

    Voltage-gated sodium channel (VGSC) β subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, β subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell–cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC β1 and β1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of β1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b+/W) with mice heterozygous for the Scn1b-null allele (Scn1b+/−) to determine whether the C121W mutation results in loss-of-function in vivo. We found that Scn1b+/W mice were more susceptible than Scn1b+/− and Scn1b+/+ mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. β1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, β1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. β1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1bW/W mice. These data, together with our previous results showing that β1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to

  4. Spreading of hepatitis C virus subtypes 1a and 1b through the central region of Argentina.

    PubMed

    Culasso, Andrés Carlos Alberto; Farías, Adrián; Di Lello, Federico Alejandro; Golemba, Marcelo Darío; Ré, Viviana; Barbini, Luciana; Campos, Rodolfo

    2014-08-01

    The recent history of the hepatitis C virus (HCV) subtypes 1a and 1b in the central region of Argentina is hypothesized by phylogeographic reconstruction using coalescent based Bayesian analyses. Direct partial E2 sequences from HCV 1a and 1b infected patients attending different health-care centers of the country were analyzed. The inferred date of the most recent common ancestor (tMRCA) for HCV-1a was: 1962 (between 1943 and 1977) and for HCV-1b was earlier: 1929 (between 1895 and 1953). Diverse ancestral populations were inferred from both subtypes in Córdoba and in Buenos Aires cities and after that, HCV spread within and between larger cities and to other smaller cities. The analyses suggested that HCV-1b was dispersed first and it is currently in a stationary phase whereas HCV-1a was dispersed latter and it is still in a growth phase. Finally, as it was observed in the developed countries, while the transmission of HCV-1b appears to have been somehow prevented, the HCV-1a may still represent a concern in the public health. Further work should be carried out to address their current transmission rate (and its main transmission route) in the Argentinean population. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

    PubMed Central

    Wang, Hong; Wei, Si-Si; Chen, Jie; Chen, Yi-He; Xu, Wei-Ping; Jie, Qi-Qiang; Zhou, Qing; Li, Yi-Gang; Wei, Yi-Dong; Wang, Yue-Peng

    2016-01-01

    Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation. PMID:26918455

  6. Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

    PubMed Central

    Santofimia-Castaño, Patricia; Rizzuti, Bruno; Pey, Ángel L.; Soubeyran, Philippe; Vidal, Miguel; Urrutia, Raúl; Iovanna, Juan L.; Neira, José L.

    2017-01-01

    Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins. PMID:28720707

  7. Fate of avermectin B1a on citrus fruits. 1. Distribution and magnitude of the avermectin B sub 1a and sup 14 C residue on citrus fruits from a field study

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

    Maynard, M.S.; Iwata, Y.; Wislocki, P.G.

    An 8{mu}g/mL solution of ({sup 14}C)avermectin B{sub 1a}, the approximate field application rate, was applied to oranges, lemons, and grapefruit; a 10-fold higher rate was also applied to oranges. Immediately postapplication, {sup 14}C residues were 20-38 ng/g for the fruit treated at the field rate. Most of the residue was recovered in the surface solvent rinse at less than 2 weeks postapplication; however, after this time more of the residue was recovered from the rind fraction. The total recoveries of applied radioactivity were 61-90% and 33-50% at 1 and 12 weeks postapplication, respectively. The level of unextractable rind {sup 14}Cmore » residue from oranges treated at the 10{times} rate and harvested at 12 weeks (a worse case) was 4.9% of the applied dose (<2 ppb at the field rate). The inner pulp samples for all treatments had {sup 14}C residue levels below the detection limit of 0.4-0.8 ppb. The initial depletion half-life of avermectin B{sub 1a} was <1 week, with losses occurring within 30-40 min. For the 1-12-week postapplication period, the avermectin B{sub 1a} and {sup 14}C residue depletion half-lives were 20-38 and 56-98 days, respectively. Differences in the rate of dissipation of avermectin B{sub 1a} due to fruit type and application rate were observed.« less

  8. Species-Specific and Cross-Reactive IgG1 Antibody Binding to Viral Capsid Protein 1 (VP1) Antigens of Human Rhinovirus Species A, B and C

    PubMed Central

    Iwasaki, Jua; Smith, Wendy-Anne; Stone, Shane R.; Thomas, Wayne R.; Hales, Belinda J.

    2013-01-01

    Background Human rhinoviruses (HRV) are associated with upper and lower respiratory illnesses, including severe infections causing hospitalization in both children and adults. Although the clinical significance of HRV infections is now well established, no detailed investigation of the immune response against HRV has been performed. The purpose of this study was to assess the IgG1 antibody response to the three known HRV species, HRV-A, -B and -C in healthy subjects. Methods Recombinant polypeptides of viral capsid protein 1 (VP1) from two genotypes of HRV-A, -B and -C were expressed as glutathione S-transferase (GST) fusion proteins and purified by affinity and then size exclusion chromatography. The presence of secondary structures similar to the natural antigens was verified by circular dichroism analysis. Total and species-specific IgG1 measurements were quantitated by immunoassays and immunoabsorption using sera from 63 healthy adults. Results Most adult sera reacted with the HRV VP1 antigens, at high titres. As expected, strong cross-reactivity between HRV genotypes of the same species was found. A high degree of cross-reactivity between different HRV species was also evident, particularly between HRV-A and HRV-C. Immunoabsorption studies revealed HRV-C specific titres were markedly and significantly lower than the HRV-A and HRV-B specific titres (P<0.0001). A truncated construct of HRV-C VP1 showed greater specificity in detecting anti-HRV-C antibodies. Conclusions High titres of IgG1 antibody were bound by the VP1 capsid proteins of HRV-A, -B and -C, but for the majority of people, a large proportion of the antibody to HRV-C was cross-reactive, especially to HRV-A. The improved specificity found for the truncated HRV-C VP1 indicates species-specific and cross-reactive regions could be defined. PMID:23950960

  9. Association of Neuropeptide Y (NPY), Interleukin-1B (IL1B) Genetic Variants and Correlation of IL1B Transcript Levels with Vitiligo Susceptibility

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Mansuri, Mohmmad Shoab; Singh, Mala; Patel, Hetanshi H.; Agarwal, Nishtha; Shah, Anish M.; Begum, Rasheedunnisa

    2014-01-01

    Background Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. Objectives Aim of the present study was to explore NPY promoter −399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter −511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. Methods PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B −511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. Results Genotype and allele frequencies for NPY −399T/C, +1128T/C and IL1B −511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001) between patients and controls. ‘TC’ haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029), in patients with active than stable vitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. Conclusion Our results suggest that NPY −399T/C, +1128T/C and IL1B −511C/T polymorphisms are associated with vitiligo and IL1B −511C/T SNP influences its transcript levels leading to increased risk for vitiligo in

  10. Cyclisation versus 1,1-Carboboration: Reactions of B(C6F5)3 with Propargyl Amides.

    PubMed

    Melen, Rebecca L; Hansmann, Max M; Lough, Alan J; Hashmi, A Stephen K; Stephan, Douglas W

    2013-09-02

    A series of propargyl amides were prepared and their reactions with the Lewis acidic compound B(C6F5)3 were investigated. These reactions were shown to afford novel heterocycles under mild conditions. The reaction of a variety of N-substituted propargyl amides with B(C6F5)3 led to an intramolecular oxo-boration cyclisation reaction, which afforded the 5-alkylidene-4,5-dihydrooxazolium borate species. Secondary propargyl amides gave oxazoles in B(C6F5)3 mediated (catalytic) cyclisation reactions. In the special case of disubstitution adjacent to the nitrogen atom, 1,1-carboboration is favoured as a result of the increased steric hindrance (1,3-allylic strain) in the 5-alkylidene-4,5-dihydrooxazolium borate species. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Progestin effects on expression of AKR1C1-AKR1C3, SRD5A1 and PGR in the Z-12 endometriotic epithelial cell line.

    PubMed

    Beranič, Nataša; Lanišnik Rižner, Tea

    2013-02-25

    Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. This disease is associated with diminished protective effects of progesterone, which are usually explained by inadequate activation of progesterone receptors and also enhanced pre-receptor metabolism of progesterone. Endometriosis is often treated with progestins, which act as progesterone receptor agonists, although their exact mechanisms of action are not completely understood. The aim of the present study was to investigate how the progestins medroxyprogesterone acetate, dydrogesterone and dienogest, as well as progesterone, impact on the expression of genes of pre-receptor progesterone metabolism in Z-12 epithelial cell line, a model system of peritoneal endometriosis. Our data demonstrate that these progestins affect local pre-receptor metabolism to a different extent. The most favorable effects were seen for dydrogesterone and dienogest, where the first, dydrogesterone, significantly reduced SRD5A1, AKR1C2 and AKR1C3 expression, and additionally had a nonsignificant impact on progesterone receptor B (PR-B) protein levels. This might slow down the first step of pre-receptor metabolism, the conversion of progesterone to 5α-dihydroprogestrone by SRD5A1, and it might also affect further reduction of 3-keto and 20-keto groups catalyzed by AKR1C2 and AKR1C3. Similarly favorable effects were seen for dienogest, which promoted significant reduction of AKR1C1 and AKR1C2 expression and also showed no effect on PR-B protein levels. Different effects were seen for progesterone, which significantly decreased SRD5A1, PR-B and HSD17B2 protein levels. In contrast, treatment with medroxyprogesterone acetate resulted in increased AKR1C1 expression and decreased levels of PR-B, which might lead to enhanced progesterone metabolism and reduced signaling through progesterone receptors. Altogether, our data in this Z-12 cell model suggest that the beneficial effects of treatment

  12. HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia.

    PubMed

    Tan, Lay-Kim; Mohd-Farid, Baharin; Salsabil, Sulaiman; Heselynn, Hussein; Wahinuddin, Sulaiman; Lau, Ing-Soo; Gun, Suk-Chyn; Nor-Suhaila, Sharil; Eashwary, M; Mohd-Shahrir, Mohamed Said; Ainon, Mohd-Mokhtar; Azmillah, Rosman; Muhaini, Othman; Shahnaz, Murad; Too, Chun-Lai

    2016-10-01

    A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p<0.0001), -B (p<0.0001), -DRB1 (p<0.0001) and -DQB1 (p<0.01) loci. Minor deviations from HWEP were detected for HLA-C (p=0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015). Copyright © 2016. Published by Elsevier Inc.

  13. Fourier transform emission spectroscopy of the B 1Π-X 1Sigma + , C 1Sigma + -X 1Sigma + , and G 1Π-X 1Sigma + systems of ScH and ScD

    NASA Astrophysics Data System (ADS)

    Ram, R. S.; Bernath, P. F.

    1996-08-01

    The emission spectra of ScH and ScD have been observed in the 380 nm-2.5 μm spectral region using a Fourier transform spectrometer. The molecules were excited in a scandium hollow cathode lamp operated with neon gas and a trace of hydrogen or deuterium. Three transitions with a common lower state, assigned as the ground X 1Σ+ state, have been observed in the near infrared and visible regions. The ScH bands with 0-0 band origins at 5404, 13 574, and 20 547 cm-1 have been assigned as the B 1Π-X 1Σ+, C 1Σ+-X 1Σ+, and G 1Π-X 1Σ+ transitions, respectively. A rotational analysis of the 0-0, 1-1, 1-0, and 2-1 bands of the B 1Π-X 1Σ+ system, the 0-0 and 1-1 bands of the C 1Σ+-X 1Σ+ system and the 0-0 band of the G 1Π-X 1Σ+ system has been obtained. The principal molecular constants for the X 1Σ+ state of ScH are ΔG(1/2)=1546.9730(14) cm-1, Be=5.425 432(48) cm-1, αe=0.124 802(84) cm-1 and re=1.775 427(8) Å. The corresponding band systems of ScD have also been analyzed. A rotational analysis of the 0-0, 1-1, and 1-0 bands of the B 1Π-X 1Σ+ system, the 0-0, 1-1, 0-1, and 1-2 bands of the C 1Σ+-X 1Σ+ system and the 0-0 band of the G 1Π-X 1Σ+ system has been obtained. The equilibrium molecular constants determined for the ground state of ScD are ωe=1141.2650(31) cm-1, ωexe=12.3799(15) cm-1, Be=2.787 432(41) cm-1, αe=0.045 321(73) cm-1, and re=1.771 219(13) Å. The ScH assignments are supported by recent theoretical predictions made by Anglada et al. [Mol. Phys. 66, 541 (1989)] as well as the experimental results available for ScF and the isovalent YH and LaH molecules. Although some unassigned bands have been attributed to ScH and ScD by previous workers, there have been no previous analyses of ScH or ScD spectra.

  14. Inclusive and exclusive measurements of B decays to χ c 1 and χ c 2 at Belle

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

    Bhardwaj, V.; Miyabayashi, K.; Panzenböck, E.

    2016-03-01

    We report inclusive and exclusive measurements for χ c1 and χ c2 production in B decays. We measure B(B → χ c1X)= (3.03 ± 0.05(stat) ± 0.24(syst)) × 10 more » $-$3 and B(B → χ c2X)= (0.70 ± 0.06(stat) ± 0.10(syst)) × 10 $-$3 . For the first time, χ c2 production in exclusive B decays in the modes B 0 → χ c2π $-$K + and B + → χ c2π +π $-$K + has been observed, along with first evidence for the B + → χ c2π +K$$0\\atop{S}$$ decay mode. For χ c1 production, we report the first observation in the B + → χ c1π +π $-$K +, B 0 → χ c1π +π $-$K$$0\\atop{S}$$ and B 0 → χ c1π 0π $-$K + decay modes. Using these decay modes, we observe a difference in the production mechanism of χ c2 in comparison to χ c1 in B decays. In addition, we report searches for X(3872) and χ c1(2P) in the B + → (χ c1π +π $-$)K + decay 3 mode. The reported results use 772 × 10 6 B$$\\overline{B}$$ events collected at the Υ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e +e $-$ collider.« less

  15. TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-kappaB.

    PubMed

    Garrison, J B; Samuel, T; Reed, J C

    2009-04-02

    Marginal zone mucosa-associated lymphoid tissue (MALT) B-cell lymphoma is the most common extranodal non-Hodgkin lymphoma. The t(11;18)(q21;q21) translocation occurs frequently in MALT lymphomas and creates a chimeric NF-kappaB-activating protein containing the baculoviral IAP repeat (BIR) domains of c-IAP2 (inhibitor of apoptosis protein 2) fused with portions of the MALT1 protein. The BIR1 domain of c-IAP2 interacts directly with TRAF2 (TNFalpha-receptor-associated factor-2), but its role in NF-kappaB activation is still unclear. Here, we investigated the role of TRAF2 in c-IAP2/MALT1-induced NF-kappaB activation. We show the BIR1 domain of c-IAP2 is essential for NF-kappaB activation, whereas BIR2 and BIR3 domains are not. Studies of c-IAP2/MALT1 BIR1 mutant (E47A/R48A) that fails to activate NF-kappaB showed loss of TRAF2 binding, but retention of TRAF6 binding, suggesting that interaction of c-IAP2/MALT1 with TRAF6 is insufficient for NF-kappaB induction. In addition, a dominant-negative TRAF2 mutant or downregulation of TRAF2 achieved by small interfering RNA inhibited NF-kappaB activation by c-IAP2/MALT1 showing that TRAF2 is indispensable. Comparisons of the bioactivity of intact c-IAP2/MALT1 oncoprotein and BIR1 E47A/R48A c-IAP2/MALT1 mutant that cannot bind TRAF2 in a lymphoid cell line provided evidence that TRAF2 interaction is critical for c-IAP2/MALT1-mediated increases in the NF-kappaB activity, increased expression of endogenous NF-kappaB target genes (c-FLIP, TRAF1), and resistance to apoptosis.

  16. Genetic polymorphism of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer risk.

    PubMed

    Xu, Hua; Ding, Qiang; Jiang, Hao-Wen

    2014-01-01

    We aimed to investigate the associations between polymorphisms of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer (PCa) risk. A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to August 3, 2014 was performed. Methodological quality assessment of the trials was based on a standard quality scoring system. The meta-analysis was performed using STATA 12.0. We included 9 studies (1 study for IL-1A, 5 studies for IL-1B, and 3 studies for IL-1RN), and significant association was found between polymorphisms of IL-1B-511 (rs16944) as well as IL-1B-31 (rs1143627) and PCa risk. IL-1B-511 (rs16944) polymorphism was significantly associated with PCa risk in homozygote and recessive models, as well as allele contrast (TT vs CC: OR, 0.74; 95%CI, 0.58-0.94; P=0.012; TT vs TC+CC; OR, 0.79; 95%CI, 0.63-0.98; P=0.033; T vs C: OR, 0.86; 95%CI, 0.77-0.96; P=0.008). The association between IL-1B-31 (rs1143627) polymorphism and PCa risk was weakly significant under a heterozygote model (OR, 1.35; 95%CI, 1.00-1.80; P=0.047). Sequence variants in IL-1B-511 (rs16944) and IL-1B-31 (rs1143627) are significantly associated with PCa risk, which provides additional novel evidence that proinflammatory cytokines and inflammation play an important role in the etiology of PCa.

  17. Polymorphisms in exons 1B and 1C of the type I interleukin-1 receptor gene in patients with endometriosis.

    PubMed

    D'Amora, Paulo; Sato, Hélio; Girão, Manoel J B C; Silva, Ismael D C G; Schor, Eduardo

    2006-09-01

    To study possible correlation between the prevalence of polymorphisms in the type I interleukin-1 receptor gene and pelvic endometriosis. Genotypes of 223 women were analyzed: 109 women with surgically and histologically confirmed endometriosis and 114 healthy women. Distributions of two single-base polymorphisms of the human interleukin-1 receptor type I (IL-1RI) gene were evaluated: PstI, due to a C-->T transition in exon 1B and BsrBI a C-->A transition at position 52 in exon 1C. Polymorphisms were detected by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis (RFLP) resolved on 3% agarose gels stained with ethidium bromide. Genotypes for PstI polymorphisms did not differ significantly among control and endometriosis (P = 0.058). However, in relation to BsrBI polymorphism, protective risk was observed for the development of endometriosis [OR 0.39-IC 95% (0.2-0.9)]. BsrBI heterozygote genotype (C/A) showed protective effect against endometriosis development.

  18. Association of -31T>C and -511 C>T polymorphisms in the interleukin 1 beta (IL1B) promoter in Korean keratoconus patients.

    PubMed

    Kim, So-Hee; Mok, Jee-Won; Kim, Hyun-Seok; Joo, C K

    2008-01-01

    To investigate the genetic association between unrelated Korean keratoconus patients and interleukin 1 alpha (IL1A), interleukin 1 beta (IL1B), and IL1 receptor antagonist (IL1RN) gene polymorphisms. We investigated the association between IL1A (rs1800587, rs2071376, and rs17561), IL1B (rs1143627, rs16944, rs1143634, and rs1143633), and IL1RN (rs419598, rs423904, rs424078, and rs315952, variable number tandem repeat [VNTR]) polymorphisms in 100 unrelated Korean keratoconus patients. One hundred control individuals without any corneal disease were selected from the general population. Polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) analysis and direct sequencing were used to screen for genetic variations in the IL1 gene cluster. Haplotypes for the IL1 gene cluster were constructed using Haploview version 4.0. We analyzed a total of 12 polymorphic sites in the IL1 gene cluster. Among them, the -511 (rs16944) and -31 (rs1143627) positions in the promoter region of IL1B were significantly different between patient and control groups. The C allele of rs16944 (-511C>T, p=0.022, odds ratio of risk [OR]=1.46, 95% confidence intervals [CI] 0.94<2.27) and the T allele of rs1143627 (-31T>C, p=0.025, OR=1.43, 95% CI 0.92<2.22) were associated with a significantly increased risk of keratoconus in Korean patients. Linkage of the two alleles, -31*C and -511*T, was associated with an increased risk for keratoconus with OR=2.38 (p=0.012, 95% CI=1.116-5.046). The *C/*A genotype of rs2071376 in IL1A intron 6 was significantly different between the keratoconus patients and control subjects (p=0.034, OR=0.59, 95% CI 0.32<1.11). Other polymorphisms did not show an association with keratoconus risk. This is the first report of IL1 gene cluster mutation screening in Korean keratoconus patients. Significant differences in allelic frequency of IL1B between keratoconus patients and the control group suggest that IL1B polymorphisms may play a role in the

  19. 48 CFR 1809.206-1 - General. (NASA supplements paragraph (b) and (c))

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true General. (NASA supplements paragraph (b) and (c)) 1809.206-1 Section 1809.206-1 Federal Acquisition Regulations System NATIONAL... Qualification requirements 1809.206-1 General. (NASA supplements paragraph (b) and (c)) (c) If an offeror seeks...

  20. 48 CFR 1809.206-1 - General. (NASA supplements paragraph (b) and (c))

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false General. (NASA supplements paragraph (b) and (c)) 1809.206-1 Section 1809.206-1 Federal Acquisition Regulations System NATIONAL... Qualification requirements 1809.206-1 General. (NASA supplements paragraph (b) and (c)) (c) If an offeror seeks...

  1. 48 CFR 1809.206-1 - General. (NASA supplements paragraph (b) and (c))

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false General. (NASA supplements paragraph (b) and (c)) 1809.206-1 Section 1809.206-1 Federal Acquisition Regulations System NATIONAL... Qualification requirements 1809.206-1 General. (NASA supplements paragraph (b) and (c)) (c) If an offeror seeks...

  2. 48 CFR 1809.206-1 - General. (NASA supplements paragraph (b) and (c))

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 false General. (NASA supplements paragraph (b) and (c)) 1809.206-1 Section 1809.206-1 Federal Acquisition Regulations System NATIONAL... Qualification requirements 1809.206-1 General. (NASA supplements paragraph (b) and (c)) (c) If an offeror seeks...

  3. 48 CFR 1809.206-1 - General. (NASA supplements paragraph (b) and (c))

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false General. (NASA supplements paragraph (b) and (c)) 1809.206-1 Section 1809.206-1 Federal Acquisition Regulations System NATIONAL... Qualification requirements 1809.206-1 General. (NASA supplements paragraph (b) and (c)) (c) If an offeror seeks...

  4. 26 CFR 1.468B-1 - Qualified settlement funds.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 6 2014-04-01 2014-04-01 false Qualified settlement funds. 1.468B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Taxable Year for Which Deductions Taken § 1.468B-1 Qualified settlement...) and (c)(3) of this section or January 1 of the calendar year in which all the requirements of...

  5. 26 CFR 1.468B-1 - Qualified settlement funds.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 6 2011-04-01 2011-04-01 false Qualified settlement funds. 1.468B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Taxable Year for Which Deductions Taken § 1.468B-1 Qualified settlement...) and (c)(3) of this section or January 1 of the calendar year in which all the requirements of...

  6. 26 CFR 1.468B-1 - Qualified settlement funds.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 6 2013-04-01 2013-04-01 false Qualified settlement funds. 1.468B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Taxable Year for Which Deductions Taken § 1.468B-1 Qualified settlement...) and (c)(3) of this section or January 1 of the calendar year in which all the requirements of...

  7. 26 CFR 1.468B-1 - Qualified settlement funds.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 6 2012-04-01 2012-04-01 false Qualified settlement funds. 1.468B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Taxable Year for Which Deductions Taken § 1.468B-1 Qualified settlement...) and (c)(3) of this section or January 1 of the calendar year in which all the requirements of...

  8. Hadronic decays of Ba1(1260 )b1(1235 ) in the perturbative QCD approach

    NASA Astrophysics Data System (ADS)

    Jing, Hao-Yang; Liu, Xin; Xiao, Zhen-Jun

    2017-12-01

    We calculate the branching ratios and polarization fractions of the Ba1b1 decays in the perturbative QCD(pQCD) approach at leading order, where a1(b1) stands for the axial-vector a1(1260 )[b1(1235 )] state. By combining the phenomenological analyses with the perturbative calculations, we find the following results: (a) the large decay rates around 10-5 to 10-6 of the Ba1b1 decays dominated by the longitudinal polarization(except for the B+→b1+a10 mode) are predicted and basically consistent with those in the QCD factorization(QCDF) within errors, which are expected to be tested by the Large Hadron Collider and Belle-II experiments. The large B0→a10b10 branching ratio could provide hints to help explore the mechanism of the color-suppressed decays. (b) the rather different QCD behaviors between the a1 and b1 mesons result in the destructive(constructive) contributions in the nonfactorizable spectator diagrams with a1(b1) emission. Therefore, an interesting pattern of the branching ratios appears for the color-suppressed B0→a10a10,a10b10, and b10b10 modes in the pQCD approach, BR (B0→b10b10)>BR (B0→a10b10)≳BR (B0→a10a10), which is different from BR (B0→b10b10)˜BR (B0→a10b10)≳BR (B0→a10a10) in the QCDF and would be verified at future experiments. (c) the large naive factorization breaking effects are observed in these Ba1b1 decays. Specifically, the large nonfactorizable spectator(weak annihilation) amplitudes contribute to the B0→b1+a1-(B+→a1+b10andB+→b1+a10) mode(s), which demand confirmations via the precise measurements. Furthermore, the different phenomenologies shown among Ba1b1, Ba1a1, and Bb1b1 decays are also expected to be tested stringently, which could shed light on the typical QCD dynamics involved in these modes, even further distinguish those two popular pQCD and QCDF approaches.

  9. MUC1-C ACTIVATES THE TAK1 INFLAMMATORY PATHWAY IN COLON CANCER

    PubMed Central

    Takahashi, Hidekazu; Jin, Caining; Rajabi, Hasan; Pitroda, Sean; Alam, Maroof; Ahmad, Rehan; Raina, Deepak; Hasegawa, Masanori; Suzuki, Yozo; Tagde, Ashujit; Bronson, Roderick T.; Weichselbaum, Ralph; Kufe, Donald

    2015-01-01

    The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1+/−/IL-10−/− mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1→NF-κB pathway, downregulates BCL-XL, and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1→NF-κB signaling contributes to intestinal inflammation and colon cancer progression. PMID:25659581

  10. The Arabidopsis Polycomb Repressive Complex 1 (PRC1) Components AtBMI1A, B, and C Impact Gene Networks throughout All Stages of Plant Development1[OPEN

    PubMed Central

    Zhou, Yue

    2017-01-01

    Polycomb Group regulation in Arabidopsis (Arabidopsis thaliana) is required to maintain cell differentiation and allow developmental phase transitions. This is achieved by the activity of three PcG repressive complex 2s (PRC2s) and the participation of a yet poorly defined PRC1. Previous results showed that apparent PRC1 components perform discrete roles during plant development, suggesting the existence of PRC1 variants; however, it is not clear in how many processes these components participate. We show that AtBMI1 proteins are required to promote all developmental phase transitions and to control cell proliferation during organ growth and development, expanding their proposed range of action. While AtBMI1 function during germination is closely linked to B3 domain transcription factors VAL1/2 possibly in combination with GT-box binding factors, other AtBMI1 regulatory networks require participation of different factor combinations. Conversely, EMF1 and LHP1 bind many H3K27me3 positive genes up-regulated in atbmi1a/b/c mutants; however, loss of their function affects expression of a different subset, suggesting that even if EMF1, LHP1, and AtBMI1 exist in a common PRC1 variant, their role in repression depends on the functional context. PMID:27837089

  11. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells.

    PubMed

    Rajabi, H; Tagde, A; Alam, M; Bouillez, A; Pitroda, S; Suzuki, Y; Kufe, D

    2016-12-15

    Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA methylation patterns are associated with carcinogenesis and cancer cell survival. The oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however, there is no known link between MUC1-C and DNA methylation. Our results demonstrate that MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b promoters in complexes with NF-κB p65 and drives DNMT1 and DNMT3b transcription. In this way, MUC1-C controls global DNA methylation as determined by analysis of LINE-1 repeat elements. The results further demonstrate that targeting MUC1-C downregulates DNA methylation of the CDH1 tumor suppressor gene in association with induction of E-cadherin expression. These findings provide compelling evidence that MUC1-C is of functional importance to induction of DNMT1 and DNMT3b and, in turn, changes in DNA methylation patterns in cancer cells.

  12. Regulation of Fumonisin B1 Biosynthesis and Conidiation in Fusarium verticillioides by a Cyclin-Like (C-Type) Gene, FCC1

    PubMed Central

    Shim, Won-Bo; Woloshuk, Charles P.

    2001-01-01

    Fumonisins are a group of mycotoxins produced in corn kernels by the plant-pathogenic fungus Fusarium verticillioides. A mutant of the fungus, FT536, carrying a disrupted gene named FCC1 (for Fusarium cyclin C1) resulting in altered fumonisin B1 biosynthesis was generated. FCC1 contains an open reading frame of 1,018 bp, with one intron, and encodes a putative 319-amino-acid polypeptide. This protein is similar to UME3 (also called SRB11 or SSN8), a cyclin C of Saccharomyces cerevisiae, and contains three conserved motifs: a cyclin box, a PEST-rich region, and a destruction box. Also similar to the case for C-type cyclins, FCC1 was constitutively expressed during growth. When strain FT536 was grown on corn kernels or on defined minimal medium at pH 6, conidiation was reduced and FUM5, the polyketide synthase gene involved in fumonisin B1 biosynthesis, was not expressed. However, when the mutant was grown on a defined minimal medium at pH 3, conidiation was restored, and the blocks in expression of FUM5 and fumonisin B1 production were suppressed. Our data suggest that FCC1 plays an important role in signal transduction regulating secondary metabolism (fumonisin biosynthesis) and fungal development (conidiation) in F. verticillioides. PMID:11282612

  13. TgrC1 mediates cell-cell adhesion by interacting with TgrB1 via mutual IPT/TIG domains during development of Dictyostelium discoideum.

    PubMed

    Chen, Gong; Wang, Jun; Xu, Xiaoqun; Wu, Xiangfu; Piao, Ruihan; Siu, Chi-Hung

    2013-06-01

    Cell-cell adhesion plays crucial roles in cell differentiation and morphogenesis during development of Dictyostelium discoideum. The heterophilic adhesion protein TgrC1 (Tgr is transmembrane, IPT, IG, E-set, repeat protein) is expressed during cell aggregation, and disruption of the tgrC1 gene results in the arrest of development at the loose aggregate stage. We have used far-Western blotting coupled with MS to identify TgrB1 as the heterophilic binding partner of TgrC1. Co-immunoprecipitation and pull-down studies showed that TgrB1 and TgrC1 are capable of binding with each other in solution. TgrB1 and TgrC1 are encoded by a pair of adjacent genes which share a common promoter. Both TgrB1 and TgrC1 are type I transmembrane proteins, which contain three extracellular IPT/TIG (immunoglobulin, plexin, transcription factor-like/transcription factor immunoglobulin) domains. Antibodies raised against TgrB1 inhibit cell reassociation at the post-aggregation stage of development and block fruiting body formation. Ectopic expression of TgrB1 and TgrC1 driven by the actin15 promoter leads to heterotypic cell aggregation of vegetative cells. Using recombinant proteins that cover different portions of TgrB1 and TgrC1 in binding assays, we have mapped the cell-binding regions in these two proteins to Lys(537)-Ala(783) in TgrB1 and Ile(336)-Val(360) in TgrC1, corresponding to their respective TIG3 and TIG2 domain.

  14. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range

    PubMed Central

    Kalliokoski, Annikka; Neuvonen, Mikko; Neuvonen, Pertti J; Niemi, Mikko

    2008-01-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTOrganic anion transporting polypeptide 1B1 is an influx transporter expressed on the basolateral membrane of hepatocytes.A common single nucleotide polymorphism, c.521T→C (p.Val174Ala), of the SLCO1B1 gene has been associated with increased plasma repaglinide concentrations in healthy volunteers.Previous studies at low repaglinide doses have suggested that the effect of SLCO1B1 c.521T→C polymorphism on the pharmacokinetics of repaglinide could be dose-dependent. WHAT THIS STUDY ADDSRepaglinide peak plasma concentration and area under the plasma concentration–time curve increased linearly along with repaglinide dose ranging from 0.25 to 2 mg in both the predominant c.521TT and rare c.521CC genotype group.The effect of SLCO1B1 c.521T→C polymorphism on repaglinide pharmacokinetics persists over a wide dose range. AIMS To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T→C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent. METHODS Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of ≥1 week. RESULTS The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P ≤ 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC0–∞ increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT

  15. Tissue kallikrein protects neurons from hypoxia/reoxygenation-induced cell injury through Homer1b/c.

    PubMed

    Su, Jingjing; Tang, Yuping; Zhou, Houguang; Liu, Ling; Dong, Qiang

    2012-11-01

    Previous studies have demonstrated that human tissue kallikrein (TK) gene delivery protects against mouse cerebral ischemia/reperfusion (I/R) injury through bradykinin B2 receptor (B2R) activation. We have also reported that exogenous TK administration can suppress glutamate- or acidosis-induced neurotoxicity through the extracellular signal-regulated kinase1/2 (ERK1/2) pathway. To further explore the neuroprotection mechanisms of TK, in the present study we performed immunoprecipitation analysis and identified a scaffolding protein Homer1b/c using MALDI-TOF MS analysis. Here, we tested the hypothesis that TK reduces cell injury induced by oxygen and glucose deprivation/reoxygenation (OGD/R) through activating Homer1b/c. We found that TK increased the expression of Homer1b/c in a concentration- and time-dependent manner. Moreover, TK facilitated the translocation of Homer1b/c to the plasma membrane under OGD/R condition by confocal microscope assays. We also observed that overexpression of Homer1b/c showed the neuroprotection against OGD/R-induced cell injury by enhancing cell survival, reducing LDH release, caspase-3 activity and cell apoptosis. However, the knockdown of Homer1b/c by small interfering RNA showed the opposite effects, indicating that Homer1b/c had protective effects against OGD/R-induced neuronal injury. More interestingly, TK exerted its much more significantly neuroprotective effects after Homer1b/c overexpression, whereas it exerted its reduced effects after Homer1b/c knockdown. In addition, TK pretreatment increased the phosphorylation of the ERK1/2 and Akt-GSK3β through Homer1b/c activation. The beneficial effects of Homer1b/c were abolished by the ERK1/2 or PI3K antagonist. Therefore, we propose novel signaling mechanisms involved in the anti-hypoxic function of TK through activation of Homer1b/c-ERK1/2 and Homer1b/c-PI3K-Akt signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Evidence for the η(b)(2S) and observation of h(b)(1P)→η(b)(1S)γ and h(b)(2P)→η(b)(1S)γ.

    PubMed

    Mizuk, R; Asner, D M; Bondar, A; Pedlar, T K; Adachi, I; Aihara, H; Arinstein, K; Aulchenko, V; Aushev, T; Aziz, T; Bakich, A M; Bay, A; Belous, K; Bhardwaj, V; Bhuyan, B; Bischofberger, M; Bonvicini, G; Bozek, A; Bračko, M; Brodzicka, J; Browder, T E; Chekelian, V; Chen, A; Chen, P; Cheon, B G; Chilikin, K; Chistov, R; Cho, I-S; Cho, K; Choi, S-K; Choi, Y; Dalseno, J; Danilov, M; Doležal, Z; Drásal, Z; Drutskoy, A; Eidelman, S; Epifanov, D; Fast, J E; Gaur, V; Gabyshev, N; Garmash, A; Golob, B; Haba, J; Hara, T; Hayasaka, K; Hayashii, H; Horii, Y; Hoshi, Y; Hou, W-S; Hsiung, Y B; Hyun, H J; Iijima, T; Ishikawa, A; Itoh, R; Iwabuchi, M; Iwasaki, Y; Iwashita, T; Jaegle, I; Julius, T; Kang, J H; Kapusta, P; Kawasaki, T; Kim, H J; Kim, H O; Kim, J H; Kim, K T; Kim, M J; Kim, Y J; Kinoshita, K; Ko, B R; Koblitz, S; Kodyš, P; Korpar, S; Kouzes, R T; Križan, P; Krokovny, P; Kuhr, T; Kumita, T; Kuzmin, A; Kwon, Y-J; Lange, J S; Lee, S-H; Li, J; Libby, J; Liu, C; Liu, Y; Liu, Z Q; Liventsev, D; Louvot, R; Matvienko, D; McOnie, S; Miyabayashi, K; Miyata, H; Mohanty, G B; Mohapatra, D; Moll, A; Muramatsu, N; Mussa, R; Nakao, M; Natkaniec, Z; Ng, C; Nishida, S; Nishimura, K; Nitoh, O; Nozaki, T; Ohshima, T; Okuno, S; Olsen, S L; Onuki, Y; Pakhlov, P; Pakhlova, G; Park, C W; Park, H; Pestotnik, R; Petrič, M; Piilonen, L E; Poluektov, A; Röhrken, M; Sakai, Y; Sandilya, S; Santel, D; Sanuki, T; Sato, Y; Schneider, O; Schwanda, C; Senyo, K; Seon, O; Sevior, M E; Shapkin, M; Shen, C P; Shibata, T-A; Shiu, J-G; Shwartz, B; Sibidanov, A; Simon, F; Smerkol, P; Sohn, Y-S; Sokolov, A; Solovieva, E; Stanič, S; Starič, M; Sumihama, M; Sumiyoshi, T; Tanida, K; Tatishvili, G; Teramoto, Y; Tikhomirov, I; Trabelsi, K; Tsuboyama, T; Uchida, M; Uehara, S; Uglov, T; Unno, Y; Uno, S; Vanhoefer, P; Varner, G; Varvell, K E; Vinokurova, A; Vorobyev, V; Wang, C H; Wang, M-Z; Wang, P; Wang, X L; Watanabe, M; Watanabe, Y; Williams, K M; Won, E; Yabsley, B D; Yamaoka, J; Yamashita, Y; Yuan, C Z; Zhang, Z P; Zhilich, V

    2012-12-07

    We report the first evidence for the η(b)(2S) using the h(b)(2P)→η(b)(2S)γ transition and the first observation of the h(b)(1P)→η(b)(1S)γ and h(b)(2P)→η(b)(1S)γ transitions. The mass and width of the η(b)(1S) and η(b)(2S) are measured to be m(η(b)(1S))=(9402.4±1.5±1.8) MeV/c(2), m(η(b)(2S))=(9999.0±3.5(-1.9)(+2.8)) MeV/c(2), and Γ(η(b)(1S))=(10.8(-3.7-2.0)(+4.0+4.5)) MeV. We also update the h(b)(1P) and h(b)(2P) mass measurements. We use a 133.4 fb(-1) data sample collected at energies near the Υ(5S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider.

  17. A1c Gear: Laboratory quality HbA1c measurement at the point of care.

    PubMed

    Ejilemele, Adetoun; Unabia, Jamie; Ju, Hyunsu; Petersen, John R

    2015-05-20

    HbA1c is an important part of assessing the diabetic control and since the use of point-of-care devices for monitoring HbA1c is increasing, it is important to determine how these devices compare to the central laboratory. One hundred and twenty patient samples were analyzed on the Bio-Rad Variant™II and one POC analyzer (Sakae A1c Gear). Three patient sample pools containing ~5%, ~7%, and ~10% HbA1c levels were run over 20 days. Three reagent lots and three instruments were evaluated for the A1c Gear. The 120 patient samples showed strong correlation (R(2)>0.989) when compared to the Variant™II with means=8.06% and 7.81%, for Variant IIand A1c Gear, respectively. Changing reagent lots or instruments had no impact for the A1c Gear. The ~5%, ~7%, and ~10% pools within-run and between-run imprecision was between 0.87-1.33% and 1.03-1.32%, and 1.41-2.35% and 1.24-1.89% with total imprecision of 1.67-2.35% and 1.61-2.31% for the A1c Gear and Variant II, respectively. The A1c Gear showed a small negative bias (0.25% HbA1c) across HbA1c measurement ranges of <11.5%. This bias was, however, acceptable and not considered to be clinically significant. The A1c Gear meets the criteria of total CV <3% leading us to the conclusion that the A1c Gear can give results as precise as the laboratory at the POC. Copyright © 2015. Published by Elsevier B.V.

  18. MIRK/DYRK1B MEDIATES SURVIVAL DURING THE DIFFERENTIATION OF C2C12 MYOBLASTS 1

    PubMed Central

    Mercer, Stephen E.; Ewton, Daina Z.; Deng, Xiaobing; Lim, Seunghwan; Mazur, Thomas R.; Friedman, Eileen

    2005-01-01

    The kinase Mirk/dyrk1B is essential for the differentiation of C2C12 myoblasts. Mirk reinforces the G0/G1 arrest state in which differentiation occurs by directly phosphorylating and stabilizing p27kip1 and destabilizing cyclin D1. We now demonstrate that Mirk is anti-apoptotic in myoblasts. Knockdown of endogenous Mirk by RNA interference activated caspase 3 and decreased myoblast survival by 75%, while transient overexpression of Mirk increased cell survival. Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and RNA interference experiments demonstrated that Mirk phosphorylates p21 within its nuclear localization domain at Ser153 causing a portion of the typically nuclear p21 to localize in the cytoplasm. Phosphomimetic GFP-p21-S153D was pancellular in both cycling C2C12 myoblasts and NIH3T3 cells. Endogenous Mirk in myotubes, and overexpressed Mirk in NIH3T3 cells were able to cause the pancellular localization of wild-type GFP-p21, but not the non-phosphorylatable mutant GFP-p21-S153A. Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules. Phosphomimetic p21-S153D was more effective than wild-type p21 in blocking the activation of caspase 3. Transient expression of p21-S153D also increased myoblast viability in colony forming assays, while the p21-S153A mutant had no effect. This Mirk-dependent change in p21 intracellular localization is a natural part of myoblast differentiation. Endogenous p21 localized exclusively to the nuclei of proliferating myoblasts, but was also found in the cytoplasm of post-mitotic multinucleated myotubes and adult human skeletal myofibers. PMID:15851482

  19. 29 CFR Appendix B to Subpart C of... - Figures C-1 through C-16

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 9 2013-07-01 2013-07-01 false Figures C-1 through C-16 B Appendix B to Subpart C of Part 1928 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) OCCUPATIONAL SAFETY AND HEALTH STANDARDS FOR AGRICULTURE Roll-Over Protective...

  20. Biological Roles of Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11B1), HSD11B2, and Glucocorticoid Receptor (NR3C1) in Sheep Conceptus Elongation.

    PubMed

    Brooks, Kelsey; Burns, Gregory; Spencer, Thomas E

    2015-08-01

    In sheep, the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) and cortisol. The enzymes, hydroxysteroid (11-beta) dehydrogenase 1 (HSD11B1) and HSD11B2 interconvert cortisone and cortisol. In sheep, HSD11B1 is expressed and active in the conceptus trophectoderm as well as in the endometrial luminal epithelia; in contrast, HSD11B2 expression is most abundant in conceptus trophectoderm. Cortisol is a biologically active glucocorticoid and ligand for the glucocorticoid receptor (NR3C1 or GR) and mineralocorticoid receptor (NR3C2 or MR). Expression of MR is not detectable in either the ovine endometrium or conceptus during early pregnancy. In tissues that do not express MR, HSD11B2 protects cells from the growth-inhibiting and/or proapoptotic effects of cortisol, particularly during embryonic development. In study one, an in utero loss-of-function analysis of HSD11B1 and HSD11B2 was conducted in the conceptus trophectoderm using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous conceptuses were recovered on Day 14 from ewes infused with control morpholino or HSD11B2 MAO. In contrast, HSD11B1 MAO resulted in severely growth-retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In study two, clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing was used to determine the role of GR in conceptus elongation and development. Elongating, filamentous-type conceptuses (12-14 cm in length) were recovered from ewes gestating control embryos (n = 7/7) and gestating GR-edited embryos (n = 6/7). These results support the idea that the effects of HSD11B1-derived cortisol on conceptus elongation are indirectly mediated by the endometrium and are not directly mediated through GR in the trophectoderm. © 2015 by the Society for the Study of Reproduction, Inc.

  1. The effect of SLCO1B1 polymorphism on repaglinide pharmacokinetics persists over a wide dose range.

    PubMed

    Kalliokoski, Annikka; Neuvonen, Mikko; Neuvonen, Pertti J; Niemi, Mikko

    2008-12-01

    To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T-->C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent. Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of > or =1 week. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P < or = 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC(0-infinity) increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype. The effect of SLCO1B1 c.521T-->C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.

  2. Study of infrared emission spectroscopy for the B{sup 1}Δ{sub g}–A{sup 1}Π{sub u} and B{sup ′1}Σ{sub g}{sup +}–A{sup 1}Π{sub u} systems of C{sub 2}

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

    Chen, Wang, E-mail: sc19321@s.okayama-u.ac.jp, E-mail: okakent@okayama-u.ac.jp, E-mail: pbernath@odu.edu; Kawaguchi, Kentarou, E-mail: sc19321@s.okayama-u.ac.jp, E-mail: okakent@okayama-u.ac.jp, E-mail: pbernath@odu.edu; Tang, Jian, E-mail: jtang@okayama-u.ac.jp

    Thirteen bands for the B{sup 1}Δ{sub g}–A{sup 1}Π{sub u} system and eleven bands for the B{sup ′1}Σ{sub g}{sup +}–A{sup 1}Π{sub u} system of C{sub 2} were identified in the Fourier transform infrared emission spectra of hydrocarbon discharges. The B{sup ′1}Σ{sub g}{sup +} v = 4 and the B{sup 1}Δ{sub g} v = 6, 7, and 8 vibrational levels involved in nine bands were studied for the first time. A direct global analysis with Dunham parameters was carried out satisfactorily for the B{sup 1}Δ{sub g}–A{sup 1}Π{sub u} system except for a small perturbation in the B{sup 1}Δ{sub g} v = 6more » level. The calculated rovibrational term energies up to B{sup 1}Δ{sub g} v = 12 showed that the level crossing between the B{sup 1}Δ{sub g} and d{sup 3}Π{sub g} states is responsible for many of the prominent perturbations in the Swan system observed previously. Nineteen forbidden transitions of the B{sup 1}Δ{sub g}–a{sup 3}Π{sub u} transition were identified and the off-diagonal spin-orbit interaction constant A{sub dB} between d{sup 3}Π{sub g} and B{sup 1}Δ{sub g} was derived as 8.3(1) cm{sup −1}. For the B{sup ′1}Σ{sub g}{sup +}–A{sup 1}Π{sub u} system, only individual band analyses for each vibrational level in the B′{sup 1}Σ{sub g}{sup +} state could be done satisfactorily and Dunham parameters obtained from these effective parameters showed that the anharmonic vibrational constant ω{sub e}x{sub e} is anomalously small (nearly zero). Inspection of the RKR (Rydberg-Klein-Rees) potential curves for the B{sup ′1}Σ{sub g}{sup +} and X{sup 1}Σ{sub g}{sup +} states revealed that an avoided crossing or nearly avoided crossing may occur around 30 000 cm{sup −1}, which is responsible for the anomalous molecular constants in these two states.« less

  3. Characterization of C1q in Teleosts

    PubMed Central

    Hu, Yu-Lan; Pan, Xin-Min; Xiang, Li-Xin; Shao, Jian-Zhong

    2010-01-01

    C1qs are key components of the classical complement pathway. They have been well documented in human and mammals, but little is known about their molecular and functional characteristics in fish. In the present study, full-length cDNAs of c1qA, c1qB, and c1qC from zebrafish (Danio rerio) were cloned, revealing the conservation of their chromosomal synteny and organization between zebrafish and other species. For functional analysis, the globular heads of C1qA (ghA), C1qB (ghB), and C1qC (ghC) were expressed in Escherichia coli as soluble proteins. Hemolytic inhibitory assays showed that hemolytic activity in carp serum can be inhibited significantly by anti-C1qA, -C1qB, and -C1qC of zebrafish, respectively, indicating that C1qA, C1qB, and C1qC are involved in the classical pathway and are conserved functionally from fish to human. Zebrafish C1qs also could specifically bind to heat-aggregated zebrafish IgM, human IgG, and IgM. The involvement of globular head modules in the C1q-dependent classical pathway demonstrates the structural and functional conservation of these molecules in the classical pathway and their IgM or IgG binding sites during evolution. Phylogenetic analysis revealed that c1qA, c1qB, and c1qC may be formed by duplications of a single copy of c1qB and that the C1q family is, evolutionarily, closely related to the Emu family. This study improves current understanding of the evolutionary history of the C1q family and C1q-mediated immunity. PMID:20615881

  4. Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer.

    PubMed

    Taskoparan, Betul; Seza, Esin Gulce; Demirkol, Secil; Tuncer, Sinem; Stefek, Milan; Gure, Ali Osmay; Banerjee, Sreeparna

    2017-12-01

    Aldo-keto reductases (including AKR1B1 and AKR1B10) constitute a family of oxidoreductases that have been implicated in the pathophysiology of diabetes and cancer, including colorectal cancer (CRC). Available data indicate that, despite their similarities in structure and enzymatic functions, their roles in CRC may be divergent. Here, we aimed to determine the expression and functional implications of AKR1B1 and AKR1B10 in CRC. AKR1B1 and AKR1B10 gene expression levels were analyzed using publicly available microarray data and ex vivo CRC-derived cDNA samples. Gene Set Enrichment Analysis (GSEA), The Cancer Genome Atlas (TCGA) RNA-seq data and The Cancer Proteome Atlas (TCPA) proteome data were analyzed to determine the effect of high and low AKR1B1 and AKR1B10 expression levels in CRC patients. Proliferation, cell cycle progression, cellular motility, adhesion and inflammation were determined in CRC-derived cell lines in which these genes were either exogenously overexpressed or silenced. We found that the expression of AKR1B1 was unaltered, whereas that of AKR1B10 was decreased in primary CRCs. GSEA revealed that, while high AKR1B1 expression was associated with increased cell cycle progression, cellular motility and inflammation, high AKR1B10 expression was associated with a weak inflammatory phenotype. Functional studies carried out in CRC-derived cell lines confirmed these data. Microarray data analysis indicated that high expression levels of AKR1B1 and AKR1B10 were significantly associated with shorter and longer disease-free survival rates, respectively. A combined gene expression signature of AKR1B10 (low) and AKR1B1 (high) showed a better prognostic stratification of CRC patients independent of confounding factors. Despite their similarities, the expression levels and functions of AKR1B1 and AKR1B10 are highly divergent in CRC, and they may have prognostic implications.

  5. Characterization of ursodeoxycholic and norursodeoxycholic acid as substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and NTCP.

    PubMed

    König, Jörg; Klatt, Sabine; Dilger, Karin; Fromm, Martin F

    2012-08-01

    Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock-out mice. Uptake of UDCA and norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA are substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and Na(+) -taurocholate co-transporting polypeptide (NTCP), which are localized in the basolateral membrane of hepatocytes. Uptake of [(3) H]UDCA and [(14) C]norUDCA into Human embryonic kidney (HEK) cells stably expressing OATP1B1, OATP1B3, OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter-transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1-, OATP1B3- and OATP2B1-mediated UDCA and norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK-NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34-fold. NorUDCA was not significantly transported by NTCP. The low uptake rates suggest that OATP1B1, OATP1B3, OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and norUDCA in human beings. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

  6. Crystal structures of fission yeast histone chaperone Asf1 complexed with the Hip1 B-domain or the Cac2 C terminus.

    PubMed

    Malay, Ali D; Umehara, Takashi; Matsubara-Malay, Kazuko; Padmanabhan, Balasundaram; Yokoyama, Shigeyuki

    2008-05-16

    The assembly of core histones onto eukaryotic DNA is modulated by several histone chaperone complexes, including Asf1, CAF-1, and HIRA. Asf1 is a unique histone chaperone that participates in both the replication-dependent and replication-independent pathways. Here we report the crystal structures of the apo-form of fission yeast Asf1/Cia1 (SpAsf1N; residues 1-161) as well as its complexes with the B-domain of the fission yeast HIRA orthologue Hip1 (Hip1B) and the C-terminal region of the Cac2 subunit of CAF-1 (Cac2C). The mode of the fission yeast Asf1N-Hip1B recognition is similar to that of the human Asf1-HIRA recognition, suggesting that Asf1N recognition of Hip1B/HIRA is conserved from yeast to mammals. Interestingly, Hip1B and Cac2C show remarkably similar interaction modes with Asf1. The binding between Asf1N and Hip1B was almost completely abolished by the D37A and L60A/V62A mutations in Asf1N, indicating the critical role of salt bridge and van der Waals contacts in the complex formation. Consistently, both of the aforementioned Asf1 mutations also drastically reduced the binding to Cac2C. These results provide a structural basis for a mutually exclusive Asf1-binding model of CAF-1 and HIRA/Hip1, in which Asf1 and CAF-1 assemble histones H3/H4 (H3.1/H4 in vertebrates) in a replication-dependent pathway, whereas Asf1 and HIRA/Hip1 assemble histones H3/H4 (H3.3/H4 in vertebrates) in a replication-independent pathway.

  7. Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A

    PubMed Central

    Gupta, Swati; Fahiminiya, Somayyeh; Wang, Tracy; Dempsey Nunez, Laura; Rosenblatt, David S.; Gibson, William T.; Gilfix, Brian; Bergeron, John J. M.; Jerome-Majewska, Loydie A.

    2016-01-01

    Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (p.M400I) and MAN1B1 c.1000C>T (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-COL1A1 retention in the endoplasmic reticulum (ER). The mutation we identified in MAN1B1 was previously associated with reduced MAN1B1 protein and congenital disorders of glycosylation (CDG). CDG patients are also short, are obese, and have abnormal glycan remodeling. Molecular analysis of fibroblasts from the family revealed normal levels of SEC23A in all cells and reduced levels of MAN1B1 in cells with heterozygous or homozygous mutations in SEC23A and MAN1B1. Secretion of pro-COL1A1 was increased in fibroblasts from the siblings and patients, and pro-COL1A1 was retained in Golgi of heterozygous and homozygous mutant cells, although intracellular pro-COL1A1 was increased in patient fibroblasts only. We postulate that increased pro-COL1A1 secretion is responsible for tall stature in these patients and an unaffected sibling, and not previously discovered in patients with mutations in either SEC23A or MAN1B1. The patients in this study share biochemical and cellular characteristics consistent with mutations in MAN1B1 and SEC23A, indicating a digenic disease. PMID:27148587

  8. [Establishment of A1E3 and B1C4 monoclonal antibody-based ELISA for detecting circulating antigen of Schistosoma japonicum and its preliminary application].

    PubMed

    Cai, Yu-Chun; Chen, Shao-Hong; Tian, Li-Guang; Chu, Yan-Hong; Lu, Yan; Chen, Mu-Xin; Ai, Lin; Zhou, Yang; Chen, Jia-Xu

    2014-02-01

    To establish A1E3 and B1C4 monoclonal antibody-based ELISA for detecting circulating antigen of Schistosoma japonicum and explore its application value in the field. The characteristics of A1E3 and B1C4 monoclonal antibodies were analyzed by SDS-PAGE and Western blotting. The SEA-based ELISA was used to evaluate the titers of A1E3 and B1C4. The orthogonal test was used to determine the best concentration of coating antibody B1C4 and optimal working concentration of A1E3-HRP. Under the optimal conditions, the serum samples of 20 acute schistosomiasis cases, 46 chronic schistosomiasis cases, and 20 control sera were tested to evaluate its detection sensitivity and specificity. Seventy-two antibody positive serum samples from Jiangling County of Hubei Province were detected and compared to a commercially available ELISA kit, to evaluate the detection effects of this method. The results of SDS-PAGE demonstrated that the purified A1E3 and B1C4 contained a clear heavy chain with molecular weight of 88,000 and 52,000 respectively and had the same light chain with molecular weight of 20,000; while Western blotting demonstrated that A1E3 and B1C4 could be recognized by SEA and serum samples of acute schistosomiasis cases. The SEA-based ELISA demonstrated the titers of B1C4 and A1E3 were 1:10(5) and 1:30,000, respectively. The serum samples from all the acute cases and 86.9% of the chronic cases showed a positive reaction. All of the control sera from healthy persons gave a negative response. The positive rates of the double monoclonal antibody ELISA and commercial ELISA for detecting the circulating antigen were 45.8% and 43.1% respectively, and there was no significant difference between the results of the two methods. A1E3 and B1C4 monoclonal antibody-based ELISA is established successfully. It exhibits a high sensitivity and specificity in detecting circulating antigen of Schistosoma japonicum.

  9. MISR Level 1A CCD, 1B1, 1B2, and Browse Products

    Atmospheric Science Data Center

    2013-04-01

    ... ESDT Product File Name Prefix Current Quality Designations MI1B2E MISR_AM1_GRP_ELLIPSOID_GM, ... should be used. All calibration files for the life of the mission have been reprocessed using the best available calibration. ...

  10. HIV-1 Gp120 clade B/C induces a GRP78 driven cytoprotective mechanism in astrocytoma

    PubMed Central

    López, Sheila N.; Rodríguez-Valentín, Madeline; Rivera, Mariela; Rodríguez, Maridaliz; Babu, Mohan; Cubano, Luis A.; Xiong, Huangui; Wang, Guangdi; Kucheryavykh, Lilia; Boukli, Nawal M.

    2017-01-01

    HIV-1 clades are known to be one of the key factors implicated in modulating HIV-associated neurocognitive disorders. HIV-1 B and C clades account for the majority of HIV-1 infections, clade B being the most neuropathogenic. The mechanisms behind HIV-mediated neuropathogenesis remain the subject of active research. We hypothesized that HIV-1 gp120 clade B and C proteins may exert differential proliferation, cell survival and NeuroAIDS effects in human astrocytoma cells via the Unfolded Protein Response, an endoplasmic reticulum- based cytoprotective mechanism. The differential effect of gp120 clade B and C was evaluated using for the first time a Tandem Mass Tag isobaric labeling quantitative proteomic approach. Flow cytometry analyses were performed for cell cycle and cell death identification. Among the proteins differentiated by HIV-1 gp120 proteins figure cytoskeleton, oxidative stress, UPR markers and numerous glycolytic metabolism enzymes. Our results demonstrate that HIV-1 gp120 B induced migration, proliferative and protective responses granted by the expression of GRP78, while HIV-1 gp120 C induced the expression of key inflammatory and pro-apoptotic markers. These novel findings put forward the first evidence that GRP78 is a key player in HIV-1 clade B and C neuropathogenic discrepancies and can be used as a novel target for immunotherapies. PMID:28978127

  11. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a...

  12. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a...

  13. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a...

  14. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part— (a...

  15. Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor-Electrophile Conjugate.

    PubMed

    Punthasee, Puminan; Laciak, Adrian R; Cummings, Andrea H; Ruddraraju, Kasi Viswanatharaju; Lewis, Sarah M; Hillebrand, Roman; Singh, Harkewal; Tanner, John J; Gates, Kent S

    2017-04-11

    Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism. The inactivation occurred with a second-order rate constant of (1.7 ± 0.3) × 10 2 M -1 min -1 . Mass spectrometric analysis of the inactivated enzyme indicated that the primary site of modification was C121, a residue distant from the active site. Previous work provided evidence that covalent modification of the allosteric residue C121 can cause inactivation of PTP1B [Hansen, S. K., Cancilla, M. T., Shiau, T. P., Kung, J., Chen, T., and Erlanson, D. A. (2005) Biochemistry 44, 7704-7712]. Overall, our results are consistent with an unusual enzyme inactivation process in which noncovalent binding of the inhibitor-electrophile conjugate to the active site of PTP1B protects the nucleophilic catalytic C215 residue from covalent modification, thus allowing inactivation of the enzyme via selective modification of allosteric residue C121.

  16. Blockade of PD-1/B7-H1 Interaction Restores Effector CD8+ T Cell Responses in a Hepatitis C Virus Core Murine Model1

    PubMed Central

    Lukens, John R.; Cruise, Michael W.; Lassen, Matthew G.; Hahn, Young S.

    2010-01-01

    The impaired function of CD8+ T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8+ T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8+ T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8+ T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-γ, TNF-α, and granzyme B production by CD8+ T cells. In addition, the impaired CD8+ T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8+ T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8+ T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection. PMID:18354211

  17. Impact of hepatitis C virus recombinant form RF1_2k/1b on treatment outcomes within the Georgian national hepatitis C elimination program.

    PubMed

    Karchava, Marine; Chkhartishvili, Nikoloz; Sharvadze, Lali; Abutidze, Akaki; Dvali, Natia; Gatserelia, Lana; Dzigua, Lela; Bolokadze, Natalia; Dolmazashvili, Ekaterine; Kotorashvili, Adam; Imnadze, Paata; Gamkrelidze, Amiran; Tsertsvadze, Tengiz

    2018-01-01

    Hepatitis C virus (HCV) recombinant form RF1_2k/1b is common in ethnic Georgians. This chimera virus contains genomic fragments of genotype 2 and genotype 1 and is misclassified as genotype 2 by standard genotyping. We aimed to identify RF1_2k/1b strains among genotype 2 patients and assess its impact on treatment outcomes. The study included 148 patients with HCV genotype 2 as determined by 5-untranslated region/core genotyping assay. RF1_2k/1b was identified by sequencing the non-structural protein 5B region. Patients were treated within the national hepatitis C elimination program with sofosbuvir/ribavirin (SOF/RBV), interferon (IFN)/SOF/RBV, or ledipasvir (LDV)/SOF/RBV. Of 148 patients, 103 (69.5%) had RF1_ 2k/1b. Sustained virologic response (SVR) data was available for 136 patients (RF1_ 2k/1b, n = 103; genotype 2, n = 33). Sustained virologic response was achieved in more genotype 2 patient than in RF1_2k/1b patients (97.0% vs. 76.7%, P = 0.009). Twelve weeks of LDV/SOF/RBV treatment was highly effective (100% SVR) in both genotypes. Among RF1_2k/1b patients, LDV/SOF/RBV for 12 weeks was superior (100% SVR) to SOF/RBV for 12 weeks (56.4%, P < 0.0001) or 20 weeks (79.2%, P = 0.05). Twelve weeks of IFN/SOF/RBV also showed better response than SOF/RBV for 12 weeks (88.9% vs. 56.4%, P = 0.02) in these patients. High prevalence of the RF1_2k/1b strain can significantly affect treatment outcomes. Treatment with IFN/SOF/RBV and especially LDV/SOF/RBV ensured significantly higher SVR in patients infected with RF1_2k/1b strain compared to standard HCV genotype 2 treatment with SOF/RBV. There is a need to reassess existing methods for the management of HCV genotype 2 infections, especially in areas with high prevalence of the RF1_2k/1b strain. © 2017 The Japan Society of Hepatology.

  18. Liquid chromatography/fluorescence method for emamectin B1a and desmethylamino-emamectin B1a residues in lobster tissue.

    PubMed

    Tauber, Ronald; Gillan, Niall; Crouch, Louis; Greenhalgh, Roy

    2006-01-01

    A liquid chromatography (LC)/fluorescence procedure was validated for emamectin (EM B1a) and desmethylamino-emamectin (DMAEM B1a) residues in lobster tissue. They were extracted by shaking and sonicating with 1% ammonium acetate-methanol in the presence of sand. The extract was concentrated, partitioned with ethyl acetate, and cleaned up on a propylsulfonic cation exchange cartridge. The analytes were eluted from the cartridge with 5% ammonium hydroxide-methyl acetate, the eluate was concentrated, and the solvent was changed to dry 20% ethyl acetate-acetonitrile before derivatization with trifluoroacetic anhydride-N-methylimidizole. The products were analyzed by LC-fluorescence, and no interference [>limit of detection (LOD)] was detected in the control samples. Lobster tissues fortified with EM B1a and DMAEM B1a at 0.5, 5, 10, 25, and 50 ng/g gave overall mean recoveries of 96.7 +/- 12.4%, relative standard deviation (RSD) = 12.8% for EM B1 and 83.6 +/- 12.1%, RSD = 14.5% for DMAEM B1a. Regression analysis of the calibration data gave slopes of 0.90 (EM B1a) and 0.71 (DMAEM B1a) with an r2 = 0.99 for both compounds. The calculated LOD and limit of quantification (LOQ) for EM B1a were 1.10 and 3.32 ng/g, respectively, and for DMAEM B1a were 0.762 and 2.31 ng/g, respectively. Residues of EM B1a and DMAEM B1a in fortified lobster tissues stored at -20 degrees C showed that residues were stable for 10-12 months. No loss of EM B1a and DMAEM B1a residues was observed after 3 freeze/thaw cycles of fortified tissue in a 5-day period.

  19. High prevalence of hepatitis B virus genotype C/C1 in the Minangkabau ethnic group in Indonesia

    PubMed Central

    2013-01-01

    Background The Minangkabau is one of the major ethnic groups in Indonesia. Previous studies with a limited number of samples have shown a different prevalence of HBV/C in the Minangkabau compared to the Indonesian population in general. The aim of this study was to assess the HBV genotype distribution pattern and the prevalence of pre-S, T1753V and A1762T/G1764A mutations among the Minangkabau HBV carriers. The samples were collected from Padang, West Sumatera and from western Java. Mixed primers for specific genotypes were used to determine the HBV genotype. Pre-S or S genes were amplified, sequenced and aligned with reference sequences from GenBank to derive a phylogenetic tree for subgenotyping. Pre-S genes were also analyzed for mutations. The basal core promoter (BCP) region was amplified and directly sequenced to analyze T1753V and A1762T/G1764A mutations. Results The predominant HBV genotype among the Minangkabau HBV carriers (n=117) was C (72.6%) followed by B (24.8%) and co-infection with B and C (2.6%). The prevalence of pre-S mutations, including both the pre-S deletion and pre-S2 start codon mutation, was 41.0%, and the T1753V and A1762T/G1764A mutations were found in 51.9% and 71.2% respectively. HBV/C1 was the predominant HBV subgenotype in the Minangkabau HBV carriers, and was found in 66.2%, followed by B3, B7, C8, B2, B9, C2, and C10 (18.3%, 7.0%, 2.8%, 1.4%, 1.4%, 1.4%, and 1.4% respectively). From samples that were found to be co-infected with HBV B and C, two samples were successfully cloned and subgenotyped, including one with mixed subgenotypes of B3 and C1, and another one with mixed subgenotypes of B7, C1, putative intergenotypic of B/A, and C/A. Furthermore, three samples from donors of non-Minangkabau ethnicity from Padang were found to be infected with an intragenotypic recombination form, including a putative recombinant of B8/B3 and B9/B7. Conclusion HBV/C with subgenotype C1 was the predominant HBV genotype among HBV carriers of

  20. Expression of fusion IL2-B7.1(IgV+C) and effects on T lymphocytes.

    PubMed

    Kong, Linghong; Li, Yaochen; Yang, Ye; Li, Kangsheng

    2007-12-01

    The search for an effective immunotherapeutic treatment for tumors is an important area of cancer research. To prepare a more effective form of the bifunctional fusion protein IL2-B7.1(IgV+C) and analyze its effect on the stimulation of T lymphocyte proliferation, we used DNAStar 5.03 software to predict the structural diversity and biochemical character of IL2-B7.1(IgV+C). We then prepared fusion protein IL2-B7.1(IgV+C) by establishing its prokaryotic expression system, and tested its effect on the stimulation of T lymphocytes in vitro. The results indicated that IL2-B7.1(IgV+C) correctly formed a secondary structure in which both IL2 and B7.1(IgV+C) maintained their original hydrophilicity and epitopes. Western blot analysis revealed that IL2-B7.1(IgV+C) was efficiently expressed. Our analysis of CTLL-2 and T-cell proliferation showed that recombinant human (rh) IL2-B7.1(IgV+C) exerted the combined stimulating effects of both rhIL2 and rh B7.1(IgV+C) on cell proliferation, and that these effects could be blocked by adding either anti-IL2 or anti-B7.1 monoclonal antibodies. A >2-fold increase in [3H]TdR incorporation compared with that of cells treated with recombinant protein IL2, or B7.1(IgV+C) alone, revealed that rhIL2-B7.1(IgV+C) had dose-dependent synergetic effects on T-cell activation in the presence of anti-CD3 monoclonal antibody. We concluded that the augmented potency of rhIL2-B7.1(IgV+C) resulted in a stronger stimulation of T-cell proliferation than either rhB7.1(IgV+C) or rhIL2 alone.

  1. Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis.

    PubMed

    Vatansever, Sezgin; Tekin, Fatih; Salman, Esin; Altintoprak, Ender; Coskunol, Hakan; Akarca, Ulus Salih

    2015-05-17

    No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p>0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population.

  2. Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB.

    PubMed

    Guo, Yun-Yun; Lu, Yi; Zheng, Yuan; Chen, Xiao-Rong; Dong, Jun-Lu; Yuan, Rong-Rong; Huang, Shu-Hong; Yu, Hui; Wang, Yue; Chen, Zhe-Yu; Su, Bo

    2017-06-21

    Multiple studies have established that brain-derived neurotrophic factor (BDNF) plays a critical role in the regulation of synaptic plasticity via its receptor, TrkB. In addition to being phosphorylated, TrkB has also been demonstrated to be ubiquitinated. However, the mechanisms of TrkB ubiquitination and its biological functions remain poorly understood. In this study, we demonstrate that ubiquitin C-terminal hydrolase L1 (UCH-L1) promotes contextual fear conditioning learning and memory via the regulation of ubiquitination of TrkB. We provide evidence that UCH-L1 can deubiquitinate TrkB directly. K460 in the juxtamembane domain of TrkB is the primary ubiquitination site and is regulated by UCH-L1. By using a peptide that competitively inhibits the association between UCH-L1 and TrkB, we show that the blockade of UCH-L1-regulated TrkB deubiquitination leads to increased BDNF-induced TrkB internalization and consequently directs the internalized TrkB to the degradation pathway, resulting in increased degradation of surface TrkB and attenuation of TrkB activation and its downstream signaling pathways. Moreover, injection of the peptide into the DG region of mice impairs hippocampus-dependent memory. Together, our results suggest that the ubiquitination of TrkB is a mechanism that controls its downstream signaling pathways via the regulation of its endocytosis and postendocytic trafficking and that UCH-L1 mediates the deubiquitination of TrkB and could be a potential target for the modulation of hippocampus-dependent memory. SIGNIFICANCE STATEMENT Ubiquitin C-terminal hydrolase L1 (UCH-L1) has been demonstrated to play important roles in the regulation of synaptic plasticity and learning and memory. TrkB, the receptor for brain-derived neurotrophic factor, has also been shown to be a potent regulator of synaptic plasticity. In this study, we demonstrate that UCH-L1 functions as a deubiquitinase for TrkB. The blockage of UCH-L1-regulated deubiquitination of TrkB

  3. INDUCTION OF CYP1A1 AD CYP1B1 AND FORMATION OF DNA ADDUCTS IN C57BL/6, BALB/C, AND F1 MICE FOLLOWING IN UTERO EXPOSURE TO 3-METHYLCHOLANTHRENE

    EPA Science Inventory

    Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3�m...

  4. Receptor specificity and trigemino-vascular inhibitory actions of a novel 5-HT1B/1D receptor partial agonist, 311C90 (zolmitriptan).

    PubMed

    Martin, G R; Robertson, A D; MacLennan, S J; Prentice, D J; Barrett, V J; Buckingham, J; Honey, A C; Giles, H; Moncada, S

    1997-05-01

    1. 311C90 (zolmitriptan zomig: (S)-4[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone) is a novel 5-HT1B/1D receptor agonist with proven efficacy in the acute treatment of migraine. Here, we describe the receptor specificity of the drug and its actions on trigeminal-evoked plasma protein extravasation into the dura mater of the anaesthetized guinea-pig. 2. At the "5-HT1B-like' receptor mediating vascular contraction (rabbit saphenous vein), the compound was a potent (p[A50] = 6.79 +/- 0.06) partial agonist achieving 77 +/- 4% of the maximum effect to 5-hydroxytryptamine (5-HT). In the same experiments, sumatriptan (p[A50] = 6.48 +/- 0.04) was half as potent as 311C90 and produced 97 +/- 2% of the 5-HT maximum effect. Studies in which receptor inactivation methods were used to estimate the affinity (pKA) and efficacy relative to 5-HT (tau rel) for each agonist confirmed that 311C90 exhibits higher affinity than sumatriptan (pKA = 6.63 +/- 0.04 and 6.16 +/- 0.03, respectively) and that both drugs are partial agonists relative to 5-HT (tau rel = 0.61 +/- 0.03 and 0.63 +/- 0.10, respectively, compared to 5-HT = 1.0). 3. Consistent with its effects in rabbit saphenous vein, 311C90 also produced concentration-dependent contractions of primate basilar artery and human epicardial coronary artery rings. In basilar artery, agonist potency (p[A50] = 6.92 +/- 0.07) was similar to that demonstrated in rabbit saphenous vein, again being 2-3 fold higher than for sumatriptan (p[A50] = 6.46 +/- 0.03). Both agonists produced about 50% of the maximum response obtained with 5-HT in the same preparations. In rings of human coronary artery, the absolute potency of 311C90 and sumatriptan was higher than in primate basilar artery (p[A50] = 7.3 +/- 0.1 and 6.7 +/- 0.1, respectively), but maximum effects relative to 5-HT were lower (37 +/- 8% and 35 +/- 7%, respectively). In both types of vessel, the inability of 5-HT1B/1D agonists to achieve the same maximum as the

  5. 26 CFR 1.475(c)-1 - Definitions-dealer in securities.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-customer relationship. Whether a taxpayer is transacting business with customers is determined on the basis... a dealer in securities under section 475(c)(1)(B), and the counterparties are its customers. Example...)(1)(B), and the other banks in the interbank market are its customers. Example 3. B engages in...

  6. DISC1, PDE4B, and NDE1 at the centrosome and synapse

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

    Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz

    Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependantmore » Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.« less

  7. Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.

    PubMed

    Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha; Jin, Caining; Alam, Maroof; Bouillez, Audrey; Hata, Tsuyoshi; Tagde, Ashujit; Keating, Amy; Kharbanda, Surender; Singh, Harpal; Kufe, Donald

    2018-01-01

    B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

  8. Molecular Variation at the HLA-A, B, C, DRB1, DQA1, and DQB1 Loci in Full Heritage American Indians in Arizona: Private Haplotypes and Their Evolution

    PubMed Central

    Williams, Robert; Chen, Yao-Fong; Endres, Robert; Middleton, Derek; Trucco, Massimo; Knowler, William

    2009-01-01

    A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only 5 allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two “private” alleles, B*5102 and B*4005, that are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the 6 most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members. PMID:19845915

  9. Molecular variation at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in full heritage American Indians in Arizona: private haplotypes and their evolution.

    PubMed

    Williams, R; Chen, Y-F; Endres, R; Middleton, D; Trucco, M; Williams, J Dunn; Knowler, W

    2009-12-01

    A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high-resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only five allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two 'private' alleles, B*5102 and B*4005, which are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the six most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high-frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members.

  10. BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes.

    PubMed

    Xu, Qi; Luo, Jiao; Wu, Ning; Zhang, Renshuai; Shi, Dayong

    2018-01-01

    Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Observation of the Decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-}.

    PubMed

    Aaij, R; Adeva, B; Adinolfi, M; Ajaltouni, Z; Akar, S; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves, A A; Amato, S; Amerio, S; Amhis, Y; An, L; Anderlini, L; Andreassi, G; Andreotti, M; Andrews, J E; Appleby, R B; Archilli, F; d'Argent, P; Arnau Romeu, J; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Baalouch, M; Babuschkin, I; Bachmann, S; Back, J J; Badalov, A; Baesso, C; Baker, S; Balagura, V; Baldini, W; Baranov, A; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Baryshnikov, F; Baszczyk, M; Batozskaya, V; Battista, V; Bay, A; Beaucourt, L; Beddow, J; Bedeschi, F; Bediaga, I; Beiter, A; Bel, L J; Bellee, V; Belloli, N; Belous, K; Belyaev, I; Ben-Haim, E; Bencivenni, G; Benson, S; Beranek, S; Berezhnoy, A; Bernet, R; Bertolin, A; Betancourt, C; Betti, F; Bettler, M-O; van Beuzekom, M; Bezshyiko, Ia; Bifani, S; Billoir, P; Birnkraut, A; Bitadze, A; Bizzeti, A; Blake, T; Blanc, F; Blouw, J; Blusk, S; Bocci, V; Boettcher, T; Bondar, A; Bondar, N; Bonivento, W; Bordyuzhin, I; Borgheresi, A; Borghi, S; Borisyak, M; Borsato, M; Bossu, F; Boubdir, M; Bowcock, T J V; Bowen, E; Bozzi, C; Braun, S; Britton, T; Brodzicka, J; Buchanan, E; Burr, C; Bursche, A; Buytaert, J; Cadeddu, S; Calabrese, R; Calvi, M; Calvo Gomez, M; Camboni, A; Campana, P; Campora Perez, D H; Capriotti, L; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carniti, P; Carson, L; Carvalho Akiba, K; Casse, G; Cassina, L; Castillo Garcia, L; Cattaneo, M; Cavallero, G; Cenci, R; Chamont, D; Charles, M; Charpentier, Ph; Chatzikonstantinidis, G; Chefdeville, M; Chen, S; Cheung, S F; Chobanova, V; Chrzaszcz, M; Chubykin, A; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coco, V; Cogan, J; Cogneras, E; Cogoni, V; Cojocariu, L; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombs, G; Coquereau, S; Corti, G; Corvo, M; Costa Sobral, C M; Couturier, B; Cowan, G A; Craik, D C; Crocombe, A; Cruz Torres, M; Cunliffe, S; Currie, R; D'Ambrosio, C; Da Cunha Marinho, F; Dall'Occo, E; Dalseno, J; Davis, A; De Aguiar Francisco, O; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Serio, M; De Simone, P; Dean, C T; Decamp, D; Deckenhoff, M; Del Buono, L; Dembinski, H-P; Demmer, M; Dendek, A; Derkach, D; Deschamps, O; Dettori, F; Dey, B; Di Canto, A; Di Nezza, P; Dijkstra, H; Dordei, F; Dorigo, M; Dosil Suárez, A; Dovbnya, A; Dreimanis, K; Dufour, L; Dujany, G; Dungs, K; Durante, P; Dzhelyadin, R; Dziewiecki, M; Dziurda, A; Dzyuba, A; Déléage, N; Easo, S; Ebert, M; Egede, U; Egorychev, V; Eidelman, S; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; Ely, S; Esen, S; Evans, H M; Evans, T; Falabella, A; Farley, N; Farry, S; Fay, R; Fazzini, D; Ferguson, D; Fernandez, G; Fernandez Prieto, A; Ferrari, F; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fini, R A; Fiore, M; Fiorini, M; Firlej, M; Fitzpatrick, C; Fiutowski, T; Fleuret, F; Fohl, K; Fontana, M; Fontanelli, F; Forshaw, D C; Forty, R; Franco Lima, V; Frank, M; Frei, C; Fu, J; Funk, W; Furfaro, E; Färber, C; Gabriel, E; Gallas Torreira, A; Galli, D; Gallorini, S; Gambetta, S; Gandelman, M; Gandini, P; Gao, Y; Garcia Martin, L M; García Pardiñas, J; Garra Tico, J; Garrido, L; Garsed, P J; Gascon, D; Gaspar, C; Gavardi, L; Gazzoni, G; Gerick, D; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gianì, S; Gibson, V; Girard, O G; Giubega, L; Gizdov, K; Gligorov, V V; Golubkov, D; Golutvin, A; Gomes, A; Gorelov, I V; Gotti, C; Govorkova, E; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graverini, E; Graziani, G; Grecu, A; Greim, R; Griffith, P; Grillo, L; Gruber, L; Gruberg Cazon, B R; Grünberg, O; Gushchin, E; Guz, Yu; Gys, T; Göbel, C; Hadavizadeh, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hamilton, B; Han, X; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; Hatch, M; He, J; Head, T; Heister, A; Hennessy, K; Henrard, P; Henry, L; van Herwijnen, E; Heß, M; Hicheur, A; Hill, D; Hombach, C; Hopchev, P H; Huard, Z-C; Hulsbergen, W; Humair, T; Hushchyn, M; Hutchcroft, D; Idzik, M; Ilten, P; Jacobsson, R; Jalocha, J; Jans, E; Jawahery, A; Jiang, F; John, M; Johnson, D; Jones, C R; Joram, C; Jost, B; Jurik, N; Kandybei, S; Karacson, M; Kariuki, J M; Karodia, S; Kecke, M; Kelsey, M; Kenzie, M; Ketel, T; Khairullin, E; Khanji, B; Khurewathanakul, C; Kirn, T; Klaver, S; Klimaszewski, K; Klimkovich, T; Koliiev, S; Kolpin, M; Komarov, I; Kopecna, R; Koppenburg, P; Kosmyntseva, A; Kotriakhova, S; Kozachuk, A; Kozeiha, M; Kravchuk, L; Kreps, M; Krokovny, P; Kruse, F; Krzemien, W; Kucewicz, W; Kucharczyk, M; Kudryavtsev, V; Kuonen, A K; Kurek, K; Kvaratskheliya, T; Lacarrere, D; Lafferty, G; Lai, A; Lanfranchi, G; Langenbruch, C; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Leflat, A; Lefrançois, J; Lefèvre, R; Lemaitre, F; Lemos Cid, E; Leroy, O; Lesiak, T; Leverington, B; Li, T; Li, Y; Li, Z; Likhomanenko, T; Lindner, R; Lionetto, F; Liu, X; Loh, D; Longstaff, I; Lopes, J H; Lucchesi, D; Lucio Martinez, M; Luo, H; Lupato, A; Luppi, E; Lupton, O; Lusiani, A; Lyu, X; Machefert, F; Maciuc, F; Maev, O; Maguire, K; Malde, S; Malinin, A; Maltsev, T; Manca, G; Mancinelli, G; Manning, P; Maratas, J; Marchand, J F; Marconi, U; Marin Benito, C; Marinangeli, M; Marino, P; Marks, J; Martellotti, G; Martin, M; Martinelli, M; Martinez Santos, D; Martinez Vidal, F; Martins Tostes, D; Massacrier, L M; Massafferri, A; Matev, R; Mathad, A; Mathe, Z; Matteuzzi, C; Mauri, A; Maurice, E; Maurin, B; Mazurov, A; McCann, M; McNab, A; McNulty, R; Meadows, B; Meier, F; Melnychuk, D; Merk, M; Merli, A; Michielin, E; Milanes, D A; Minard, M-N; Mitzel, D S; Mogini, A; Molina Rodriguez, J; Monroy, I A; Monteil, S; Morandin, M; Morello, M J; Morgunova, O; Moron, J; Morris, A B; Morris, A P; Mountain, R; Muheim, F; Mulder, M; Mussini, M; Müller, D; Müller, J; Müller, K; Müller, V; Naik, P; Nakada, T; Nandakumar, R; Nandi, A; Nasteva, I; Needham, M; Neri, N; Neubert, S; Neufeld, N; Neuner, M; Nguyen, T D; Nguyen-Mau, C; Nieswand, S; Niet, R; Nikitin, N; Nikodem, T; Nogay, A; O'Hanlon, D P; Oblakowska-Mucha, A; Obraztsov, V; Ogilvy, S; Oldeman, R; Onderwater, C J G; Ossowska, A; Otalora Goicochea, J M; Owen, P; Oyanguren, A; Pais, P R; Palano, A; Palutan, M; Papanestis, A; Pappagallo, M; Pappalardo, L L; Pappenheimer, C; Parker, W; Parkes, C; Passaleva, G; Pastore, A; Patel, M; Patrignani, C; Pearce, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perret, P; Pescatore, L; Petridis, K; Petrolini, A; Petrov, A; Petruzzo, M; Picatoste Olloqui, E; Pietrzyk, B; Pikies, M; Pinci, D; Pistone, A; Piucci, A; Placinta, V; Playfer, S; Plo Casasus, M; Poikela, T; Polci, F; Poli Lener, M; Poluektov, A; Polyakov, I; Polycarpo, E; Pomery, G J; Ponce, S; Popov, A; Popov, D; Popovici, B; Poslavskii, S; Potterat, C; Price, E; Prisciandaro, J; Prouve, C; Pugatch, V; Puig Navarro, A; Punzi, G; Qian, C; Qian, W; Quagliani, R; Rachwal, B; Rademacker, J H; Rama, M; Ramos Pernas, M; Rangel, M S; Raniuk, I; 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    2017-08-11

    The first observation of the decays Λ_{b}^{0}→χ_{c1}pK^{-} and Λ_{b}^{0}→χ_{c2}pK^{-} is reported using a data sample corresponding to an integrated luminosity of 3.0  fb^{-1}, collected by the LHCb experiment in pp collisions at center-of-mass energies of 7 and 8 TeV. The following ratios of branching fractions are measured: B(Λ_{b}^{0}→χ_{c1}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.242±0.014±0.013±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→J/ψpK^{-})=0.248±0.020±0.014±0.009,B(Λ_{b}^{0}→χ_{c2}pK^{-})/B(Λ_{b}^{0}→χ_{c1}pK^{-})=1.02±0.10±0.02±0.05,where the first uncertainty is statistical, the second systematic, and the third due to the uncertainty on the branching fractions of the χ_{c1}→J/ψγ and χ_{c2}→J/ψγ decays. Using both decay modes, the mass of the Λ_{b}^{0} baryon is also measured to be m_{Λ_{b}^{0}}=5619.44±0.28±0.26  MeV/c^{2}, where the first and second uncertainties are statistical and systematic, respectively.

  12. STM investigations of Au(1 1 1) electrodes coated with vitamin B 12 derivatives

    NASA Astrophysics Data System (ADS)

    Szőcs, E.; Durrer, L.; Luginbühl, R.; Simic, N.; Viana, A. S.; Abrantes, L. M.; Keese, R.; Siegenthaler, H.

    2006-01-01

    Vitamin B 12 derivatives immobilized at flame-annealed Au(1 1 1) electrode surfaces have been investigated in close correlation with their structural properties and spatial arrangement at the electrode substrate by scanning tunneling microscopy (STM) in air and in aqueous 0.1 M NaClO 4 solution. The investigated compounds were symmetrical (B 12C 10S-SC 10B 12) and nonsymmetrical (B 12C 10S-SC 10) dialkyl disulfide derivatives of vitamin B 12, attached to the electrode surfaces by the S-Au bond. The ex situ and in situ STM experiments show the formation of a surface layer, whose packing density and structure is presumably controlled by the spatial arrangement of the large cobyrinate head groups. In presence of the symmetrical B 12 compound, a disordered surface layer is observed. Voltammetric investigations show that, in 0.1 M NaClO 4, this layer becomes unstable at potentials approximately ⩽ -1000 mV vs. MSE and is almost completely removed at more negative potentials. The STM imaging properties of the nonsymmetrical B 12 surface layer show a significant dependence on the tunneling distance. In particular, at small tunneling distances, a highly regular hexagonal surface pattern is observed that suggests strongly the presence of an ordered surface assembly. Modeling of the B 12 head group has been performed to provide information for a structure-related interpretation of the high-resolution STM images. The investigations are first STM results obtained at such B 12 modified electrodes.

  13. SLCO1B1 variants and statin-induced myopathy--a genomewide study.

    PubMed

    Link, E; Parish, S; Armitage, J; Bowman, L; Heath, S; Matsuda, F; Gut, I; Lathrop, M; Collins, R

    2008-08-21

    Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin

  14. Aldo-keto Reductase 1B15 (AKR1B15)

    PubMed Central

    Weber, Susanne; Salabei, Joshua K.; Möller, Gabriele; Kremmer, Elisabeth; Bhatnagar, Aruni; Adamski, Jerzy; Barski, Oleg A.

    2015-01-01

    Aldo-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues. PMID:25577493

  15. 26 CFR 1.267(b)-1 - Relationships.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 3 2011-04-01 2011-04-01 false Relationships. 1.267(b)-1 Section 1.267(b)-1...) INCOME TAXES (CONTINUED) Items Not Deductible § 1.267(b)-1 Relationships. (a) In general. (1) The persons... partnership separately. Therefore, if the other person and a partner are within any one of the relationships...

  16. 26 CFR 1.267(b)-1 - Relationships.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Relationships. 1.267(b)-1 Section 1.267(b)-1...) INCOME TAXES Items Not Deductible § 1.267(b)-1 Relationships. (a) In general. (1) The persons referred to... partnership separately. Therefore, if the other person and a partner are within any one of the relationships...

  17. 34 CFR 5b.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 1 2011-07-01 2011-07-01 false Definitions. 5b.1 Section 5b.1 Education Office of the Secretary, Department of Education PRIVACY ACT REGULATIONS § 5b.1 Definitions. As used in this part: (a... Education. (c) Department means the Department of Education. (d) Disclosure means the availability or...

  18. Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages.

    PubMed

    Xu, Xiaolong; Guo, Yuhong; Zhao, Jingxia; He, Shasha; Wang, Yan; Lin, Yan; Wang, Ning; Liu, Qingquan

    2017-09-01

    Current data have shown that punicalagin (PUN), an ellagitannin isolated from pomegranate, possesses anti-inflammatory and anti-oxidant properties; however, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC 50 value of 1.04μM. Results from NPOI further showed that the K on and K off of PUN-PTP1B complex were 3.38e2M -1 s -1 and 4.13e-3s -1 , respectively. The active site Arg24 of PTP1B was identified as a key binding site of PUN by computation simulation and point mutation. Moreover, inhibition of PTP1B by PUN promoted an M2c-like macrophage polarization and enhanced anti-inflammatory cytokines expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1-like macrophage marker genes, such as Tlr4, Irf1/2, Hmgb1, and Stat1 were down-regulated, while M2 marker genes, including Tmem171, Gpr35, Csf1, Il1rn, Cebpb, Fos, Vegfα, Slc11a1, and Bhlhe40 were up-regulated in PUN-treated macrophages. Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 polarization and IL-10 secretion. In addition, phosphorylation of both Akt and STAT3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated anti-inflammatory and anti-oxidant activities and provided new therapeutic strategies for inflammatory diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Investigation of the Herzberg (C1Σ+→A1Π) band system in 12C17O

    NASA Astrophysics Data System (ADS)

    Hakalla, Rafał

    2015-10-01

    The C→A (0,1), (0,2) and (0,3) rovibronic bands of the less-abundant 12C17O isotopologue are studied in high resolution using a high-accuracy dispersive optical spectroscopy in the region of 22,800-26,100 cm-1. Calibration with respect to simultaneously recorded thorium atomic lines, obtained from several overlapped orders of the spectrum in the visible range, as well as a stainless steel hollow-cathode molecular lamp with two anodes, yields an absolute accuracy of wavenumbers measurements of about 0.0025 cm-1 for the CO spectra. All 261 spectra lines of the Herzberg band system in 12C17O, up to Jmax=34, were precisely measured and rotationally analyzed. As a result, the merged rotational constants and rotational equilibrium constants for the C1Σ+ Rydberg state, as well as the band origins, the isotope shifts, the RKR turning points, Franck-Condon factors, relative intensities, and r-centroids of the C→A system in the 12C17O isotopologue were obtained. An experimental RKR potential energy curve and vibrational levels of the C1Σ+ state in 12C17O together with highly excited k3Π, c3Π, E1Π, B1Σ+ and D‧1Σ+ states lying in the region between the first dissociation limit and the ionization potential of CO were plotted. A detailed investigation of possible perturbations that should occur in the C1Σ+(υ=0) Rydberg state of less-abundant 12C17O isotopologue in the close vicinity of the k3Π(υ=1, 2) and c3Π(υ=0) states in the region 92,000 cm-1 was performed. In the A1Π, υ=3 state of 12C17O, extensive, multi-state rotational perturbations were found and analyzed. Also, a global isotopic analysis of the C1Σ+ Rydberg state was carried out in the 12C16O, 12C17O, 13C16O, 12C18O, 13C17O, and 13C18O as well as in 14C16O and 14C18O isotopologues. This analysis enabled us to determine, amongst others, the vibrational equilibrium constants in 12C17O for the C1Σ+ state, to improve these constants in the 12C16O, 13C16O, 12C18O, 13C17O, and 13C18O isotopologues and

  20. Hemoglobin A1c (HbA1c) Test: MedlinePlus Lab Test Information

    MedlinePlus

    ... medlineplus.gov/labtests/hemoglobina1chba1ctest.html Hemoglobin A1c (HbA1c) Test To use the sharing features on this page, ... enable JavaScript. What is a hemoglobin A1c (HbA1c) test? A hemoglobin A1c (HbA1c) test measures the amount ...

  1. Two novel disease-causing variants in BMPR1B are associated with brachydactyly type A1.

    PubMed

    Racacho, Lemuel; Byrnes, Ashley M; MacDonald, Heather; Dranse, Helen J; Nikkel, Sarah M; Allanson, Judith; Rosser, Elisabeth; Underhill, T Michael; Bulman, Dennis E

    2015-12-01

    Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2-5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that cause BDA2. These findings demonstrate that BMPR1B is another gene involved with the pathogenesis of BDA1 and illustrates the continuum of phenotypes between BDA1 and BDA2.

  2. MUC1-C activates BMI1 in human cancer cells.

    PubMed

    Hiraki, M; Maeda, T; Bouillez, A; Alam, M; Tagde, A; Hinohara, K; Suzuki, Y; Markert, T; Miyo, M; Komura, K; Ahmad, R; Rajabi, H; Kufe, D

    2017-05-18

    B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→︀BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16 INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16 INK4a expression. In support of these results, analysis of three gene expresssion data sets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing.

  3. Spectroscopy of the X^1Σ^+, A^1Π and B^1Σ^+ Electronic States of MgS

    NASA Astrophysics Data System (ADS)

    Caron, Nicholas; Tokaryk, Dennis W.; Adam, Allan G.; Linton, Colan

    2016-06-01

    The spectra of some astrophysical sources contain signatures from molecules containing magnesium or sulphur atoms. Therefore, we have extended previous studies of the diatomic molecule MgS, which is a possible candidate for astrophysical detection. Microwave spectra of X^1Σ^+ , the ground electronic state, were reported in 1989 and 1997, and the B^1Σ^+-X^1Σ^+ electronic absorption spectrum in the blue was last studied in 1970. We have investigated the B^1Σ^+-X^1Σ^+ 0-0 spectrum of MgS at high resolution under jet-cooled conditions in a laser-ablation molecular source, and have obtained laser-induced fluorescence spectra from four isotopologues. Dispersed fluorescence from this source identified the low-lying A^1Π state near 4520 wn. We also created MgS in a Broida oven, with the help of a stream of activated nitrogen, and took rotationally resolved dispersed fluorescence spectra of the B^1Σ^+-A^1Π transition with a grating spectrometer by laser excitation of individual rotational levels of the B^1Σ^+ state via the B^1Σ^+-X^1Σ^+ transition. These spectra provide a first observation and analysis of the A^1Π state. S. Takano, S. Yamamoto and S. Saito, Chem. Phys. Lett. 159, 563-566 (1989) K. A. Walker and M. C. L. Gerry, J. Mol. Spectrosc 182, 178-183 (1997) M. Marcano and R. F. Barrow, Trans. Faraday Soc. 66, 2936-2938 (1970)

  4. Congenital glaucoma and CYP1B1: an old story revisited.

    PubMed

    Alsaif, Hessa S; Khan, Arif O; Patel, Nisha; Alkuraya, Hisham; Hashem, Mais; Abdulwahab, Firdous; Ibrahim, Niema; Aldahmesh, Mohammed A; Alkuraya, Fowzan S

    2018-03-19

    Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.

  5. BPAG1a and b associate with EB1 and EB3 and modulate vesicular transport, Golgi apparatus structure, and cell migration in C2.7 myoblasts.

    PubMed

    Poliakova, Kseniia; Adebola, Adijat; Leung, Conrad L; Favre, Bertrand; Liem, Ronald K H; Schepens, Isabelle; Borradori, Luca

    2014-01-01

    BPAG1a and BPAG1b (BPAG1a/b) constitute two major isoforms encoded by the dystonin (Dst) gene and show homology with MACF1a and MACF1b. These proteins are members of the plakin family, giant multi-modular proteins able to connect the intermediate filament, microtubule and microfilament cytoskeletal networks with each other and to distinct cell membrane sites. They also serve as scaffolds for signaling proteins that modulate cytoskeletal dynamics. To gain better insights into the functions of BPAG1a/b, we further characterized their C-terminal region important for their interaction with microtubules and assessed the role of these isoforms in the cytoskeletal organization of C2.7 myoblast cells. Our results show that alternative splicing does not only occur at the 5' end of Dst and Macf1 pre-mRNAs, as previously reported, but also at their 3' end, resulting in expression of additional four mRNA variants of BPAG1 and MACF1. These isoform-specific C-tails were able to bundle microtubules and bound to both EB1 and EB3, two microtubule plus end proteins. In the C2.7 cell line, knockdown of BPAG1a/b had no major effect on the organization of the microtubule and microfilament networks, but negatively affected endocytosis and maintenance of the Golgi apparatus structure, which became dispersed. Finally, knockdown of BPAG1a/b caused a specific decrease in the directness of cell migration, but did not impair initial cell adhesion. These data provide novel insights into the complexity of alternative splicing of Dst pre-mRNAs and into the role of BPAG1a/b in vesicular transport, Golgi apparatus structure as well as in migration in C2.7 myoblasts.

  6. BPAG1a and b Associate with EB1 and EB3 and Modulate Vesicular Transport, Golgi Apparatus Structure, and Cell Migration in C2.7 Myoblasts

    PubMed Central

    Poliakova, Kseniia; Adebola, Adijat; Leung, Conrad L.; Favre, Bertrand; Liem, Ronald K. H.; Schepens, Isabelle; Borradori, Luca

    2014-01-01

    BPAG1a and BPAG1b (BPAG1a/b) constitute two major isoforms encoded by the dystonin (Dst) gene and show homology with MACF1a and MACF1b. These proteins are members of the plakin family, giant multi-modular proteins able to connect the intermediate filament, microtubule and microfilament cytoskeletal networks with each other and to distinct cell membrane sites. They also serve as scaffolds for signaling proteins that modulate cytoskeletal dynamics. To gain better insights into the functions of BPAG1a/b, we further characterized their C-terminal region important for their interaction with microtubules and assessed the role of these isoforms in the cytoskeletal organization of C2.7 myoblast cells. Our results show that alternative splicing does not only occur at the 5′ end of Dst and Macf1 pre-mRNAs, as previously reported, but also at their 3′ end, resulting in expression of additional four mRNA variants of BPAG1 and MACF1. These isoform-specific C-tails were able to bundle microtubules and bound to both EB1 and EB3, two microtubule plus end proteins. In the C2.7 cell line, knockdown of BPAG1a/b had no major effect on the organization of the microtubule and microfilament networks, but negatively affected endocytosis and maintenance of the Golgi apparatus structure, which became dispersed. Finally, knockdown of BPAG1a/b caused a specific decrease in the directness of cell migration, but did not impair initial cell adhesion. These data provide novel insights into the complexity of alternative splicing of Dst pre-mRNAs and into the role of BPAG1a/b in vesicular transport, Golgi apparatus structure as well as in migration in C2.7 myoblasts. PMID:25244344

  7. Logarithmic phase Escherichia coli K1 efficiently avoids serum killing by promoting C4bp-mediated C3b and C4b degradation

    PubMed Central

    Wooster, David G; Maruvada, Ravi; Blom, Anna M; Prasadarao, Nemani V

    2006-01-01

    Meningitis caused by Escherichia coli K1 is a serious illness in neonates with neurological sequelae in up to 50% of survivors. A high degree of bacteremia is required for E. coli K1 to cross the blood–brain barrier, which suggests that the bacterium must evade the host defence mechanisms and survive in the bloodstream. We previously showed that outer membrane protein A (OmpA) of E. coli binds C4b-binding protein (C4bp), an inhibitor of complement activation via the classical pathway. Nevertheless, the exact mechanism by which E. coli K1 survives in serum remains elusive. Here, we demonstrate that log phase (LP) OmpA+E. coli K1 avoids serum bactericidal activity more effectively than postexponential phase bacteria. OmpA–E. coli cannot survive in serum grown to either phase. The increased serum resistance of LP OmpA+E. coli is the result of increased binding of C4bp, with a concomitant decrease in the deposition of C3b and the downstream complement proteins responsible for the formation of the membrane attack complex. C4bp bound to E. coli K1 acts as a cofactor to factor I in the cleavage of both C3b and C4b, which shuts down the ensuing complement cascade. Accordingly, a peptide corresponding to the complement control protein domain 3 of C4bp sequence, was able to compete with C4bp binding to OmpA and cause increased deposition of C3b. Thus, binding of C4bp appears to be responsible for survival of E. coli K1 in human serum. PMID:16556262

  8. A New Orbit for Comet C/1865 B1 (Great Southern Comet of 1865)

    NASA Astrophysics Data System (ADS)

    Branham, Richard L., Jr.

    2018-04-01

    Comet C/1865 B1 (Great southern comet of 1865), observed only in the southern hemisphere, is one of a large number of comets with parabolic orbits. Given that there are 202 observations in right ascension and 165 in declination it proves possible to calculate a better orbit than that Körber published in 1887, the orbit used in various catalogs and data bases. C/1865 B1's orbit is hyperbolic and statistically distinguishable from a parabola. This object, therefore, cannot be considered an NEO. The comet has a small perihelion distance of 0.026 AU.

  9. Generation of Bayesian prediction models for OATP-mediated drug-drug interactions based on inhibition screen of OATP1B1, OATP1B1∗15 and OATP1B3.

    PubMed

    van de Steeg, E; Venhorst, J; Jansen, H T; Nooijen, I H G; DeGroot, J; Wortelboer, H M; Vlaming, M L H

    2015-04-05

    Human organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3 are important hepatic uptake transporters. Early assessment of OATP1B1/1B3-mediated drug-drug interactions (DDIs) is therefore important for successful drug development. A promising approach for early screening and prediction of DDIs is computational modeling. In this study we aimed to generate a rapid, single Bayesian prediction model for OATP1B1, OATP1B1∗15 and OATP1B3 inhibition. Besides our previously generated HEK-OATP1B1 and HEK-OATP1B1∗15 cells, we now generated and characterized HEK-OATP1B3 cells. Using these cell lines we investigated the inhibitory potential of 640 FDA-approved drugs from a commercial library (10μM) on the uptake of [(3)H]-estradiol-17β-d-glucuronide (1μM) by OATP1B1, OATP1B1∗15, and OATP1B3. Using a cut-off of ⩾60% inhibition, 8% and 7% of the 640 drugs were potent OATP1B1 and OATP1B1∗15 inhibitors, respectively. Only 1% of the tested drugs significantly inhibited OATP1B3, which was not sufficient for Bayesian modeling. Modeling of OATP1B1 and OATP1B1∗15 inhibition revealed that presence of conjugated systems and (hetero)cycles with acceptor/donor atoms in- or outside the ring enhance the probability of a molecule binding these transporters. The overall performance of the model for OATP1B1 and OATP1B1∗15 was ⩾80%, including evaluation with a true external test set. Our Bayesian classification model thus represents a fast, inexpensive and robust means of assessing potential binding of new chemical entities to OATP1B1 and OATP1B1∗15. As such, this model may be used to rank compounds early in the drug development process, helping to avoid adverse effects in a later stage due to inhibition of OATP1B1 and/or OATP1B1∗15. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Symbiotic effects of a lipase-secreting bacterium, Burkholderia arboris SL1B1, and a glycerol-assimilating yeast, Candida cylindracea SL1B2, on triacylglycerol degradation.

    PubMed

    Matsuoka, Hiroshi; Miura, Atsuto; Hori, Katsutoshi

    2009-04-01

    Although microbial degradation of oils and fats has been developed for application in wastewater treatment, microbial degraders are not always effective in the field, for example, in grease-traps installed for the treatment of wastewater from restaurants and food industries. Wastewater in grease-traps is usually in a pH range of 5.5 to 6.5 due to hydrolysis of triacylglycerol (TAG). Because many microorganisms commercialized for use in grease-traps cannot grow at pH 6.0, we screened oil-degrading microorganisms from the environment by growing in a medium at pH 6.0 containing canola oil as the sole carbon source. We succeeded in isolating the bacterial strain Burkholderia arboris SL1B1, which secretes lipase and assimilates fatty acids, and the yeast strain Candida cylindracea SL1B2, which assimilates glycerol. The former cannot utilize glycerol as a carbon source while the latter shows only faint lipase activity that cannot support its active growth on TAG. Canola oil was degraded rapidly by a pure culture of SL1B1 at pH 6.0. However, the degradation was markedly enhanced by a mixed culture of SL1B1 and SL1B2, although lipase activity during cultivation was similar between the pure and mixed cultures. This suggests that the reversible reaction proceeds in the direction of hydrolysis of TAG due to consumption of the reaction product, glycerol, by the symbiotic yeast strain. The optimum pH and temperature of lipase secreted by B. arboris SL1B1 were 8.0 and 60 degrees C, respectively. This lipase showed highly thermal stability; the residual activity after incubation at 70 degrees C for 2 h did not decline.

  11. Linkage of genes for laminin B1 and B2 subunits on chromosome 1 in mouse.

    PubMed

    Elliott, R W; Barlow, D; Hogan, B L

    1985-08-01

    We have used cDNA clones for the B1 and B2 subunits of laminin to find restriction fragment length DNA polymorphisms for the genes encoding these polypeptides in the mouse. Three alleles were found for LamB2 and two for LamB1 among the inbred mouse strains. The segregation of these polymorphisms among recombinant inbred strains showed that these genes are tightly linked in the central region of mouse Chromosome 1 between Sas-1 and Ly-m22, 7.4 +/- 3.2 cM distal to the Pep-3 locus. There is no evidence in the mouse for pseudogenes for these proteins.

  12. 26 CFR 1.1092(c)-1 - Qualified covered calls.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... lowest qualified benchmark is determined using the adjusted applicable stock price, as defined in § 1... (CONTINUED) INCOME TAXES Wash Sales of Stock Or Securities § 1.1092(c)-1 Qualified covered calls. (a) In.... Under section 1092(d)(3)(B)(i)(I), stock is personal property if the stock is part of a straddle that...

  13. Laboratory diagnosis of von Willebrand disease type 1/2E (2A subtype IIE), type 1 Vicenza and mild type 1 caused by mutations in the D3, D4, B1-B3 and C1-C2 domains of the von Willebrand factor gene. Role of von Willebrand factor multimers and the von Willebrand factor propeptide/antigen ratio.

    PubMed

    Gadisseur, Alain; Berneman, Zwi; Schroyens, Wilfried; Michiels, Jan Jacques

    2009-01-01

    Autosomal dominant von Willebrand disease (VWD) type 1/2E is a quantitative/qualitative defect in the von Willebrand factor (VWF) caused by heterozygous cysteine and non-cysteine mutations in the D3 domain of the VWF gene and results in a secretion-multimerization-clearance defect in mutant VWF with the loss of large VWF multimers not due to proteolysis. The multimers of patients with dominant VWD type 1/2E due to mutations in the D3 domain show an aberrant triplet structure with lack of outer bands but with pronounced inner bands of the triplet structure combined with a relative decrease in large multimers reflecting heterozygosity for multimerization defects. There is a good response to desmopressin (DDAVP) followed by rapid clearance of VWF:antigen (Ag), factor VIII coagulant activity (FVIII:C) and VWF:ristocetin cofactor activity (RCo) as the main cause of VWD type 1 or 2 with typical 2E multimeric pattern (VWD type 1/2E). Cysteine mutations in the D3 domains (C1130, C1149 and C1190) show pronounced features of VWD 1/2E with the relative loss of large and relative increase in small VWF multimers with abnormal triplet structure in heterozygotes. Such abnormalities are less pronounced in patients with a milder form of VWD type 1 due to non-cysteine mutations W1144G, T1156M and W1120S in the D3 domain. VWD type 1 Vicenza is caused by the R1205H mutation in the D3 domain and characterized by equally low levels of FVIII:C, VWF:Ag and VWF:RCo. The response to DDAVP in VWD Vicenza is good for FVIII:C, VWF:Ag and VWF:RCo, which is followed by a rapid clearance in less than a few hours of FVIII:C and VWF parameters. The ratios for FVIII:C/VWF:Ag, VWF:RCo/Ag and VWF:CB/Ag remain normal before and after DDAVP indicating that VWD Vicenza clearly differs from VWD type 1, 1/2E and 2M. A new set of missense mutations in D4, B1-B3 and C1-C2 domains has been discovered as the cause of a mild VWD type 1 secretion defect with normal VWF multimers or smeary VWF multimeric pattern

  14. 75 FR 16664 - Airworthiness Directives; Turbomeca ARRIEL 1B, 1D, 1D1, 2B, and 2B1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-02

    ... limited to, Eurocopter AS 350 B, AS 350 BA, AS 350 B1, AS 350 B2, AS 350 B3, and EC 130 B4 helicopters... an aviation product. The MCAI describes the unsafe condition as: During production of Arriel 1 and... by Turbom[eacute]ca. Potentially non-conforming PT blades have been traced as having been installed...

  15. 18 CFR 1b.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 1 2011-04-01 2011-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF... pipelines, electric utilities and hydroelectric projects. [43 FR 27174, June 23, 1978, as amended by Order...

  16. Spi-C has opposing effects to PU.1 on gene expression in progenitor B cells.

    PubMed

    Schweitzer, Brock L; Huang, Kelly J; Kamath, Meghana B; Emelyanov, Alexander V; Birshtein, Barbara K; DeKoter, Rodney P

    2006-08-15

    The Ets transcription factor Spi-C, expressed in B cells and macrophages, is closely related to PU.1 and has the ability to recognize the same DNA consensus sequence. However, the function of Spi-C has yet to be determined. The purpose of this study is to further examine Spi-C activity in B cell development. First, using retroviral vectors to infect PU.1(-/-) fetal liver progenitors, Spi-C was found to be inefficient at inducing cytokine-dependent proliferation and differentiation of progenitor B (pro-B) cells or macrophages relative to PU.1 or Spi-B. Next, Spi-C was ectopically expressed in fetal liver-derived, IL-7-dependent pro-B cell lines. Wild-type (WT) pro-B cells ectopically expressing Spi-C (WT-Spi-C) have several phenotypic characteristics of pre-B cells such as increased CD25 and decreased c-Kit surface expression. In addition, WT-Spi-C pro-B cells express increased levels of IgH sterile transcripts and reduced levels of expression and transcription of the FcgammaRIIb gene. Gel-shift analysis suggests that Spi-C, ectopically expressed in pro-B cells, can bind PU.1 consensus sites in the IgH intronic enhancer and FcgammaRIIb promoter. Transient transfection analysis demonstrated that PU.1 functions to repress the IgH intronic enhancer and activate the FcgammaRIIb promoter, while Spi-C opposes these activities. WT-Spi-C pro-B cells have reduced levels of dimethylation on lysine 9 of histone H3 within the IgH 3' regulatory region, indicating that Spi-C can contribute to removal of repressive features in the IgH locus. Overall, these studies suggest that Spi-C may promote B cell differentiation by modulating the activity of PU.1-dependent genes.

  17. Targeting the disordered C-terminus of PTP1B with an allosteric inhibitor

    PubMed Central

    Krishnan, Navasona; Koveal, Dorothy; Miller, Daniel H.; Xue, Bin; Akshinthala, Sai Dipikaa; Kragelj, Jaka; Jensen, Malene Ringkjøbing; Gauss, Carla-Maria; Page, Rebecca; Blackledge, Martin; Muthuswamy, Senthil K.; Peti, Wolfgang; Tonks, Nicholas K.

    2014-01-01

    PTP1B, a validated therapeutic target for diabetes and obesity, plays a critical positive role in HER2 signaling in breast tumorigenesis. Efforts to develop therapeutic inhibitors of PTP1B have been frustrated by the chemical properties of the active site. We defined a novel mechanism of allosteric inhibition that targets the C-terminal, non-catalytic segment of PTP1B. We present the first ensemble structure of PTP1B containing this intrinsically disordered segment, within which we identified a binding site for the small molecule inhibitor, MSI-1436. We demonstrate binding to a second site close to the catalytic domain, with cooperative effects between the two sites locking PTP1B in an inactive state. MSI-1436 antagonized HER2 signaling, inhibited tumorigenesis in xenografts and abrogated metastasis in the NDL2 mouse model of breast cancer, validating inhibition of PTP1B as a therapeutic strategy in breast cancer. This new approach to inhibition of PTP1B emphasizes the potential of disordered segments of proteins as specific binding sites for therapeutic small molecules. PMID:24845231

  18. Allorecognition, via TgrB1 and TgrC1, mediates the transition from unicellularity to multicellularity in the social amoeba Dictyostelium discoideum

    PubMed Central

    Hirose, Shigenori; Santhanam, Balaji; Katoh-Kurosawa, Mariko; Shaulsky, Gad; Kuspa, Adam

    2015-01-01

    The social amoeba Dictyostelium discoideum integrates into a multicellular organism when individual starving cells aggregate and form a mound. The cells then integrate into defined tissues and develop into a fruiting body that consists of a stalk and spores. Aggregation is initially orchestrated by waves of extracellular cyclic adenosine monophosphate (cAMP), and previous theory suggested that cAMP and other field-wide diffusible signals mediate tissue integration and terminal differentiation as well. Cooperation between cells depends on an allorecognition system comprising the polymorphic adhesion proteins TgrB1 and TgrC1. Binding between compatible TgrB1 and TgrC1 variants ensures that non-matching cells segregate into distinct aggregates prior to terminal development. Here, we have embedded a small number of cells with incompatible allotypes within fields of developing cells with compatible allotypes. We found that compatibility of the allotype encoded by the tgrB1 and tgrC1 genes is required for tissue integration, as manifested in cell polarization, coordinated movement and differentiation into prestalk and prespore cells. Our results show that the molecules that mediate allorecognition in D. discoideum also control the integration of individual cells into a unified developing organism, and this acts as a gating step for multicellularity. PMID:26395484

  19. Modulation of intracellular Ca(2+) via alpha(1B)-adrenoreceptor signaling molecules, G alpha(h) (transglutaminase II) and phospholipase C-delta 1.

    PubMed

    Kang, Sung Koo; Kim, Dae Kyong; Damron, Derek S; Baek, Kwang Jin; Im, Mie-Jae

    2002-04-26

    We characterized the alpha(1B)-adrenoreceptor (alpha(1B)-AR)-mediated intracellular Ca(2+) signaling involving G alpha(h) (transglutaminase II, TGII) and phospholipase C (PLC)-delta 1 using DDT1-MF2 cell. Expression of wild-type TGII and a TGII mutant lacking transglutaminase activity resulted in significant increases in a rapid peak and a sustained level of intracellular Ca(2+) concentration ([Ca(2+)](i)) in response to activation of the alpha(1B)-AR. Expression of a TGII mutant lacking the interaction with the receptor or PLC-delta 1 substantially reduced both the peak and sustained levels of [Ca(2+)](i). Expression of TGII mutants lacking the interaction with PLC-delta 1 resulted in a reduced capacitative Ca(2+) entry. Reduced expression of PLC-delta 1 displayed a transient elevation of [Ca(2+)](i) and a reduction in capacitative Ca(2+) entry. Expression of the C2-domain of PLC-delta 1, which contains the TGII interaction site, resulted in reduction of the alpha(1B)-AR-evoked peak increase in [Ca(2+)](i), while the sustained elevation in [Ca(2+)](i) and capacitative Ca(2+) entry remained unchanged. These findings demonstrate that stimulation of PLC-delta 1 via coupling of the alpha(1B)-AR with TGII evokes both Ca(2+) release and capacitative Ca(2+) entry and that capacitative Ca(2+) entry is mediated by the interaction of TGII with PLC-delta 1.

  20. A1C

    MedlinePlus

    A1C is a blood test for type 2 diabetes and prediabetes. It measures your average blood glucose, or blood sugar, level over the past 3 ... A1C alone or in combination with other diabetes tests to make a diagnosis. They also use the ...

  1. Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.

    PubMed

    Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

    2016-05-24

    Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.

  2. Regulation of HSD17B1 and SRD5A1 in lymphocytes.

    PubMed

    Zhou, Z; Speiser, P W

    1999-11-01

    We previously reported lymphocyte expression of genes encoding enzymes required for steroid metabolism; however, only 17beta-HSD and 5alpha-reductase showed significant enzyme activity. We now investigate regulation of lymphocyte expression for genes encoding 17beta-HSD and 5alpha-reductase. Cultured human T and B lymphoid cell lines and peripheral blood mononuclear cells were treated with known regulators of steroidogenic gene expression including forskolin, PMA, ionomycin, various steroids, interleukin (IL)-4, and IL-6. Treatment with 10 or 50 microM forskolin resulted in a 20-60% reduction of expression for HSD17B1 (encoding 17beta-HSD I) in T and B lymphoid cell lines and peripheral blood mononuclear cells, although such a change was not observed in the expression of SRD5A1 (encoding 5alpha-reductase I). No significant changes were found when cells were treated for 24 h with various concentrations of PMA or ionomycin. Incubation with 10(-9) to 10(-7) M androstenedione or estradiol increased expression of HSD17B1, while testosterone decreased the expression of this gene. SRD5A1 expression was increased in the presence of 5alpha-DHT although no consistent changes were observed when the cells were treated with testosterone. Other steroids, including dexamethasone, progesterone, and 6-hydroxypregnanolone, produced no effects on expression of either HSD17B1 or SRD5A1. Treatment with 0.1-10 ng/ml of IL-4 or IL-6 also did not effect significant changes in gene expression. These data implicate the involvement of the cAMP-protein kinase signal transduction pathway in regulating lymphocyte expression of HSD17B1. Furthermore, it appears that lymphocyte HSD17B1 and SRD5A1 are regulated to some extent by specific steroids. Copyright 1999 Academic Press.

  3. MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai

    PubMed Central

    2010-01-01

    Background Genome-wide association studies (GWAS) in White Europeans have shown that genetic variation rs10830963 in melatonin receptor 1B gene (MTNR1B) is associated with fasting glucose and type 2 diabetes, which has also been replicated in several Asian populations. As a variant in the gene involved in the regulation of circadian rhythms, the effect of the variant on sleep status remains unknown. This study aimed to investigate the effects of MTNR1B rs10830963 on fasting glucose, type 2 diabetes and sleep status in Chinese Hans. Methods MTNR1B rs10830963 was genotyped in a population-based cohort including 3,210 unrelated Chinese Hans from Beijing and Shanghai, and tested for associations with risk of type 2 diabetes, diabetes-related traits and sleep status. Results We confirmed the associations of MTNR1B rs10830963 with fasting glucose (beta = 0.11 mmol/l, 95%CI [0.03, 0.18], P = 0.005), glycated hemoglobin (HbA1c) (beta = 0.07%, 95%CI [0.02,0.12], P = 0.004) and homeostasis model assessment of beta-cell function (HOMA-B) (beta = -5.01%, 95%CI [-8.24,-1.77], P = 0.003) in the Shanghai, but not in the Beijing subpopulation (P ≥ 0.58). The effect size of MTNR1B rs10830963 on fasting glucose in Shanghai Chinese Hans was comparable to that reported from other Asian populations. We found no evidence of associations with type 2 diabetes (OR 1.05 [0.90-1.23], P = 0.54), homeostasis model assessment of insulin sensitivity (HOMA-S) (P = 0.86) or sleep status (P ≥ 0.44). Conclusions A common variant in MTNR1B was associated with fasting glucose, HbA1C and HOMA-B but not with sleep status in Chinese Hans from Shanghai, strengthening the role of MTNR1B rs10830963 in fasting glycemia and impaired beta-cell function. PMID:20398260

  4. Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype.

    PubMed

    Chikata, Takayuki; Murakoshi, Hayato; Koyanagi, Madoka; Honda, Kazutaka; Gatanaga, Hiroyuki; Oka, Shinichi; Takiguchi, Masafumi

    2017-12-12

    HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  5. Prolonged neutropenia after irinotecan-based chemotherapy in a child with polymorphisms of UGT1A1 and SLCO1B1.

    PubMed

    Sakaguchi, S; Garcia-Bournissen, F; Kim, R; Schwarz, U I; Nathan, P C; Ito, S

    2009-12-01

    Genetic polymorphisms of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and SLCO1B1 coding organic anion-transporter polypeptide 1B1, are independent risk factors known to increase irinotecan toxicity in adults. Although combined occurrence of polymorphisms in these 2 genes is likely to influence susceptibility to irinotecan toxicity, data are scarce, especially in children. We report an 11-year-old female with severe and prolonged neutropenia after irinotecan-based chemotherapy. The patient's genotyping revealed polymorphisms in both UGT1A1 and SLCO1B1. To our knowledge, this is the first case report of combined genotyping of both UGT1A1 and SLCO1B1 in a child with severe irinotecan toxicity.

  6. Coxiella burnetii Avirulent Nine Mile Phase II Induces Caspase-1-Dependent Pyroptosis in Murine Peritoneal B1a B Cells.

    PubMed

    Schoenlaub, Laura; Cherla, Rama; Zhang, Yan; Zhang, Guoquan

    2016-12-01

    Our recent study demonstrated that virulent Coxiella burnetii Nine Mile phase I (NMI) is capable of infecting and replicating within peritoneal B1a cells and that B1a cells play an important role in host defense against C. burnetii infection in mice. However, it remains unknown if avirulent Nine Mile phase II (NMII) can infect and replicate in B1a cells and whether NMI and NMII can differentially interact with B1a cells. In this study, we examined if NMI and NMII can differentially modulate host cell apoptotic signaling in B1a cells. The results showed that NMII induced dose-dependent cell death in murine peritoneal B1a cells but NMI did not, suggesting that NMI and NMII may differentially activate host cell apoptotic signaling in B1a cells. Western blotting indicated that NMII-induced B1a cell death was not dependent on either caspase-3 or PARP-1 cleavage, but cleavage of caspase-1 was detected in NMII-infected B1a cells. In addition, inhibition or deficiency of caspase-1 activity blocked NMII-induced B1a cell death. These results suggest that NMII induces a caspase-1-dependent pyroptosis in murine peritoneal B1a cells. We also found that heat-killed NMII and type 4 secretion system (T4SS) mutant NMII were unable to induce B1a cell death and that NMII infection did not induce cell death in peritoneal B1a cells from Toll-like receptor 2 (TLR-2)- or NLRP3 inflammasome-deficient mice. These data suggest that NMII-induced caspase-1-dependent pyroptosis may require its T4SS and activation of the TLR-2 and NLRP3 signaling pathways. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  7. Bruton's tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-gamma2 activation.

    PubMed

    Inabe, Kazunori; Miyawaki, Toshio; Longnecker, Richard; Matsukura, Hiroyoshi; Tsukada, Satoshi; Kurosaki, Tomohiro

    2002-03-13

    Bruton's tyrosine kinase (Btk) is essential for B cell development and B cell antigen receptor (BCR) function. Recent studies have shown that Btk plays an important role in BCR-mediated c-Jun NH(2)-terminal kinase (JNK) 1 activation; however, the mechanism by which Btk participates in the JNK1 response remains elusive. Here we show that the BCR-mediated Rac1 activation is significantly inhibited by loss of Btk, while this Rac1 activation is not affected by loss of phospholipase C-gamma2 (PLC-gamma2). Since PLC-gamma2 is also required for BCR-mediated JNK1 response, our results suggest that Btk regulates Rac1 pathway as well as PLC-gamma2 pathway, both of which contribute to the BCR-mediated JNK1 response.

  8. Bu-2470, a new peptide antibiotic complex. II. Structure determination of Bu-2470 A, B1, B2a and B2b.

    PubMed

    Sugawara, K; Yonemoto, T; Konishi, M; Matsumoto, K; Miyaki, T; Kawaguchi, H

    1983-06-01

    The structures of Bu-2470 A, B1, B2a, and B2b have been determined. Bu-2470 A is a simple octapeptide having no fatty acid moiety, while Bu-2470 B1, B2a and B2b are octapeptides that have been acylated with a beta-hydroxy C11 or C10 fatty acid. The octapeptide structure of Bu-2470 components was found identical with that of octapeptin C1, hence generic names of octapeptin C0, C2, C3 and C4 are proposed for Bu-2470 A, B1, B2a and B2b, respectively.

  9. [11C]AZ10419096 - a full antagonist PET radioligand for imaging brain 5-HT1B receptors.

    PubMed

    Lindberg, Anton; Nag, Sangram; Schou, Magnus; Takano, Akihiro; Matsumoto, Junya; Amini, Nahid; Elmore, Charles S; Farde, Lars; Pike, Victor W; Halldin, Christer

    2017-11-01

    The serotonergic system is widely present in all regions of the central nervous system (CNS) and plays a key modulatory role in many of its functions. Positron emission tomography (PET) is used to study several serotonin receptors in CNS in vivo. The G-protein coupled receptor 5-HT 1B is mostly present in the occipital cortex and in midbrain and is linked to several psychiatric disorders. There is evidence that agonist PET radioligands for neuroreceptors are more sensitive to endogenous neurotransmitters than antagonists. Our previously developed 5-HT 1B receptor PET radioligand, [ 11 C]AZ10419369, is now considered a partial agonist. In this work we are aiming to develop a full antagonist PET radioligand for imaging brain 5-HT 1B receptors, and evaluate its sensitivity to increased endogenous serotonin concentration. [ 11 C]AZ10419096 was synthesized by rapid methylation of the prepared corresponding N-desmethyl precursor with [ 11 C]methyl triflate. Five PET measurements were performed in cynomolgus monkeys, consisting of two at baseline, one after treatment of a monkey with a 5-HT 1B antagonist, AR-A000002, and two in which fenfluramine was administered during scanning to induce endogenous serotonin release. [ 11 C]AZ10419096 was synthesized in high yield and purity within 30 min, including purification, formulation and sterile filtration. The baseline PET measurements demonstrated [ 11 C]AZ10419096 to have favorable radioligand characteristics, including high specific binding in brain regions that have high 5-HT 1B density, such as occipital cortex and globus pallidus, as well as subsequent rapid elimination from brain and a minor abundance of lipophilic radiometabolites in plasma. AR-A00002 completely blocked radioligand receptor-specific binding. Fenfluramine produced a distinct displacement of radioligand consistent with an expected increase of synaptic endogenous serotonin concentration. [ 11 C]AZ10419096, a full 5-HT 1B antagonist PET radioligand

  10. Identification of high-risk Listeria monocytogenes serotypes in lineage I (serotype 1/2a, 1/2c, 3a and 3c) using multiplex PCR

    USDA-ARS?s Scientific Manuscript database

    Aims: Using molecular subtyping techniques, Listeria monocytogenes is divided into three major phylogenetic lineages, and a multiplex PCR method can differentiate five L. monocytogenes subgroups: 1/2a-3a, 1/2c-3c, 1/2b-3b-7, 4b-4d-4e, and 4a-4c. In the current study, we conducted genome comparison...

  11. Contribution of HLA-A/B/C/DRB1/DQB1 common haplotypes to donor search outcome in unrelated hematopoietic stem cell transplantation.

    PubMed

    Pédron, Béatrice; Guérin-El Khourouj, Valérie; Dalle, Jean-Hugues; Ouachée-Chardin, Marie; Yakouben, Karima; Corroyez, France; Auvrignon, Anne; Petit, Arnaud; Landman-Parker, Judith; Leverger, Guy; Baruchel, André; Sterkers, Ghislaine

    2011-11-01

    In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies ≥0.19% in patient families of European origin and that split into ≤2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding ≥9/10 HLA-matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 × 10(-6)) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into ≥3 groups of probability with ≥1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches. Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  12. B-1 phagocytes: the myeloid face of B-1 cells.

    PubMed

    Popi, Ana Flavia

    2015-12-01

    The relationship between malignant B cells and macrophages has long been established. Furthermore, evolutionary studies have demonstrated that B cells from early vertebrates have both phagocytic and antibody production capabilities. In addition to their lymphoid nature, B-1 cells retain several myeloid characteristics. Various reports have demonstrated that B-1 cells can differentiate into phagocytes. However, descriptions of B-1 cells as a novel phagocyte cell member are rarely found in the literature. This review aims to present the available data regarding B-1 cell-derived phagocytes and also discusses how their existence might be relevant to hematopoiesis and immune responses. © 2015 New York Academy of Sciences.

  13. Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling

    PubMed Central

    Thomas, Remy; van der Weyden, Louise; Rauch, Dan; Ratner, Lee; Nyborg, Jennifer K.; Ramos, Juan Carlos; Takai, Yoshimi; Shembade, Noula

    2015-01-01

    Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells. PMID:25774694

  14. Zebrafish Lmx1b.1 and Lmx1b.2 are required for maintenance of the isthmic organizer.

    PubMed

    O'Hara, F Patrick; Beck, Ernestine; Barr, Lauren K; Wong, Lily L; Kessler, Daniel S; Riddle, Robert D

    2005-07-01

    The mesencephalic and metencephalic region (MMR) of the vertebrate central nervous system develops in response to signals produced by the isthmic organizer (IsO). We have previously reported that the LIM homeobox transcription factor Lmx1b is expressed within the chick IsO, where it is sufficient to maintain expression of the secreted factor wnt1. In this paper, we show that zebrafish express two Lmx1b orthologs, lmx1b.1 and lmx1b.2, in the rostral IsO, and demonstrate that these genes are necessary for key aspects of MMR development. Simultaneous knockdown of Lmx1b.1 and Lmx1b.2 using morpholino antisense oligos results in a loss of wnt1, wnt3a, wnt10b, pax8 and fgf8 expression at the IsO, leading ultimately to programmed cell death and the loss of the isthmic constriction and cerebellum. Single morpholino knockdown of either Lmx1b.1 or Lmx1b.2 has no discernible effect on MMR development. Maintenance of lmx1b.1 and lmx1b.2 expression at the isthmus requires the function of no isthmus/pax2.1, as well as Fgf signaling. Transient misexpression of Lmx1b.1 or Lmx1b.2 during early MMR development induces ectopic wnt1 and fgf8 expression in the MMR, as well as throughout much of the embryo. We propose that Lmx1b.1- and Lmx1b.2-mediated regulation of wnt1, wnt3a, wnt10b, pax8 and fgf8 maintains cell survival in the isthmocerebellar region.

  15. Characterization of a ( sub 3 H)-5-hydroxtyryptamine binding site in rabbit caudate nucleus that differs from the 5-HT sub 1A , 5-HT sub 1B , 5-HT sub 1C and 5-HT sub 1D subtypes

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

    Xiong, Wencheng; Nelson, D.L.

    1989-01-01

    ({sup 3}H)5-HT binding sites were analyzed in membranes prepared from the rabbit caudate nucleus (CN). ({sup 3}H)5-HT labeled both 5-HT{sub 1A} and 5-HT{sub 1C} recognition sites, defined by nanomolar affinity for 8-OH-DPAT and mesulergine respectively; however, these represented only a fraction of total specific ({sup 3}H)5-HT binding. Saturation experiments of ({sup 3}H)5-HT binding in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine to block 5-HT{sub 1A} and 5-HT{sub 1C} sites revealed that non-5-HT{sub 1A}/non-5-HT{sub 1C} sites represented about 60% of the total 5-HT{sub 1} sites and that they exhibited saturable, high affinity, and homogeneous binding. The pharmacological profilemore » of the non-5-HT{sub 1A}/non-5-HT{sub 1C} sites (designated 5-HT{sub 1R}) also differed from that of 5-HT{sub 1B} and 5-HT{sub 2} sites, but was similar to that of the 5-HT{sub 1D} site. However, significant differences existed between the 5-HT{sub 1D} and 5-HT{sub 1B} sites for their K{sub i} values for spiperone, spirilene, metergoline, and methiothepin. The study of modulatory agents also showed differences between the 5-HT{sub 1R} and 5-HT{sub 1D} sites. In addition, calcium enhanced the effects of GTP on the 5-HT{sub 1R} sites, whereas calcium inhibited the GTP effect on the 5-HT{sub 1D} sites.« less

  16. Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations

    PubMed Central

    Sychev, Dmitrij Alekseevitch; Shuev, Grigorij Nikolaevich; Suleymanov, Salavat Shejhovich; Ryzhikova, Kristina Anatol’evna; Mirzaev, Karin Badavievich; Grishina, Elena Anatol’evna; Snalina, Natalia Evgenievna; Sozaeva, Zhannet Alimovna; Grabuzdov, Anton Mikhailovich; Matsneva, Irina Andreevna

    2017-01-01

    Background The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. Materials and methods We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data. Results After performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy–Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians. Conclusion In the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of

  17. Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

    NASA Astrophysics Data System (ADS)

    Heinrich, Edith; Getoff, Nikola

    2003-06-01

    Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and β-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N 2O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer.

  18. Human aldo-keto reductases 1B1 and 1B10: a comparative study on their enzyme activity toward electrophilic carbonyl compounds.

    PubMed

    Shen, Yi; Zhong, Linlin; Johnson, Stephen; Cao, Deliang

    2011-05-30

    Aldo-keto reductase family 1 member B1 (AKR1B1, 1B1 in brief) and aldo-keto reductase family 1 member B10 (AKR1B10, 1B10 in brief) are two proteins with high similarities in their amino acid sequences, stereo structures, and substrate specificity. However, these two proteins exhibit distinct tissue distributions; 1B10 is primarily expressed in the gastrointestinal tract and adrenal gland, whereas 1B1 is ubiquitously present in all tissues/organs, suggesting their difference in biological functions. This study evaluated in parallel the enzyme activity of 1B1 and 1B10 toward alpha, beta-unsaturated carbonyl compounds with cellular and dietary origins, including acrolein, crotonaldehyde, 4-hydroxynonenal, trans-2-hexenal, and trans-2,4-hexadienal. Our results showed that 1B10 had much better enzyme activity and turnover rates toward these chemicals than 1B1. By detecting the enzymatic products using high-performance liquid chromatography, we measured their activity to carbonyl compounds at low concentrations. Our data showed that 1B10 efficiently reduced the tested carbonyl compounds at physiological levels, but 1B1 was less effective. Ectopically expressed 1B10 in 293T cells effectively eliminated 4-hydroxynonenal at 5 μM by reducing to 1,4-dihydroxynonene, whereas endogenously expressed 1B1 did not. The 1B1 and 1B10 both showed enzyme activity to glutathione-conjugated carbonyl compounds, but 1B1 appeared more active in general. Together our data suggests that 1B10 is more effectual in eliminating free electrophilic carbonyl compounds, but 1B1 seems more important in the further detoxification of glutathione-conjugated carbonyl compounds. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. The effect of organic anion-transporting polypeptides 1B1, 1B3 and 2B1 on the antitumor activity of flavopiridol in breast cancer cells.

    PubMed

    Brenner, Stefan; Riha, Juliane; Giessrigl, Benedikt; Thalhammer, Theresia; Grusch, Michael; Krupitza, Georg; Stieger, Bruno; Jäger, Walter

    2015-01-01

    The contribution of organic anion transporting polypeptides (OATPs) to the cellular uptake of flavopiridol was investigated in OATP1B1-, OATP1B3- and OATP2B1-expressing Chinese hamster ovary (CHO) cells. Uptake of flavopiridol into these cells showed typical Michaelis-Menten kinetics with much higher transport capacity for OATP1B3 compared to OATP1B1 and OATP2B1 (Vmax/Km, 33.9 vs. 8.84 and 2.41 µl/mg/min, respectively). The predominant role of OATPs was further supported by a dramatic inhibition of flavopiridol uptake in the presence of the OATP substrate rifampicin. Uptake of flavopiridol by OATPs also seems to be an important determinant in breast cancer cells. The much higher mRNA level for OATP1B1 found in wild-type compared to ZR-75-1 OATP1B1 knockdown cells correlated with higher flavopiridol initial uptake leading to 4.6-fold decreased IC50 values in the cytotoxicity assay (IC50, 1.45 vs. 6.64 µM). Cell cycle profile also showed a clear incidence for a stronger cell cycle arrest in the G2/M phase for ZR-75-1 wild-type cells compared to OATP1B1 knockdown cells, further indicating an active uptake via OATP1B1. In conclusion, our results revealed OATP1B1, OATP1B3 and OATP2B1 as uptake transporters for flavopiridol in cancer cells, which may also apply in patients during cancer therapy.

  20. The boron transporter BnaC4.BOR1;1c is critical for inflorescence development and fertility under boron limitation in Brassica napus.

    PubMed

    Zhang, Quan; Chen, Haifei; He, Mingliang; Zhao, Zhuqing; Cai, Hongmei; Ding, Guangda; Shi, Lei; Xu, Fangsen

    2017-09-01

    Boron (B) is an essential micronutrient for plants, but the molecular mechanisms underlying the uptake and distribution of B in allotetraploid rapeseed (Brassica napus) are unclear. Here, we identified a B transporter of rapeseed, BnaC4.BOR1;1c, which is expressed in shoot nodes and involved in distributing B to the reproductive organs. Transgenic Arabidopsis plants containing a BnaC4.BOR1;1c promoter-driven GUS reporter gene showed strong GUS activity in roots, nodal regions of the shoots and immature floral buds. Overexpressing BnaC4.BOR1;1c in Arabidopsis wild type or in bor1-1 mutants promoted wild-type growth and rescued the bor1-1 mutant phenotype. Conversely, knockdown of BnaC4.BOR1;1c in a B-efficient rapeseed line reduced B accumulation in flower organs, eventually resulting in severe sterility and seed yield loss. BnaC4.BOR1;1c RNAi plants exhibited large amounts of disintegrated stigma papilla cells with thickened cell walls accompanied by abnormal proliferation of lignification under low-B conditions, indicating that the sterility may be a result of altered cell wall properties in flower organs. Taken together, our results demonstrate that BnaC4.BOR1;1c is a AtBOR1-homologous B transporter gene expressing in both roots and shoot nodes that is essential for the developing inflorescence tissues, which highlights its diverse functions in allotetraploid rapeseed compared with diploid model plant Arabidopsis. © 2017 John Wiley & Sons Ltd.

  1. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies.

    PubMed

    Kayman-Kurekci, Gulsum; Talim, Beril; Korkusuz, Petek; Sayar, Nilufer; Sarioglu, Turkan; Oncel, Ibrahim; Sharafi, Parisa; Gundesli, Hulya; Balci-Hayta, Burcu; Purali, Nuhan; Serdaroglu-Oflazer, Piraye; Topaloglu, Haluk; Dincer, Pervin

    2014-07-01

    We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A- and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. HLA Association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival.

    PubMed

    Loiseau, Pascale; Busson, Marc; Balere, Marie-Lorraine; Dormoy, Anne; Bignon, Jean-Denis; Gagne, Katia; Gebuhrer, Lucette; Dubois, Valérie; Jollet, Isabelle; Bois, Monique; Perrier, Pascale; Masson, Dominique; Moine, Agnès; Absi, Léna; Reviron, Denis; Lepage, Virginia; Tamouza, Ryad; Toubert, Antoine; Marry, Evelyne; Chir, Zina; Jouet, Jean-Pierre; Blaise, Didier; Charron, Dominique; Raffoux, Colette

    2007-08-01

    HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P=.046, hazard ratio [HR]=1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P=.003, HR=1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P=.002, HR=2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

  3. An APC/C-Cdh1 Biosensor Reveals the Dynamics of Cdh1 Inactivation at the G1/S Transition.

    PubMed

    Ondracka, Andrej; Robbins, Jonathan A; Cross, Frederick R

    2016-01-01

    B-type cyclin-dependent kinase activity must be turned off for mitotic exit and G1 stabilization. B-type cyclin degradation is mediated by the anaphase-promoting complex/cyclosome (APC/C); during and after mitotic exit, APC/C is dependent on Cdh1. Cdh1 is in turn phosphorylated and inactivated by cyclin-CDK at the Start transition of the new cell cycle. We developed a biosensor to assess the cell cycle dynamics of APC/C-Cdh1. Nuclear exit of the G1 transcriptional repressor Whi5 is a known marker of Start; APC/C-Cdh1 is inactivated 12 min after Whi5 nuclear exit with little measurable cell-to-cell timing variability. Multiple phosphorylation sites on Cdh1 act in a redundant manner to repress its activity. Reducing the number of phosphorylation sites on Cdh1 can to some extent be tolerated for cell viability, but it increases variability in timing of APC/C-Cdh1 inactivation. Mutants with minimal subsets of phosphorylation sites required for viability exhibit striking stochasticity in multiple responses including budding, nuclear division, and APC/C-Cdh1 activity itself. Multiple cyclin-CDK complexes, as well as the stoichiometric inhibitor Acm1, contribute to APC/C-Cdh1 inactivation; this redundant control is likely to promote rapid and reliable APC/C-Cdh1 inactivation immediately following the Start transition.

  4. Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1.

    PubMed

    Ballou, W Ripley; Reed, Jennifer L; Noble, William; Young, Neal S; Koenig, Scott

    2003-02-15

    A recombinant human parvovirus B19 vaccine (MEDI-491; MedImmune) composed of the VP1 and VP2 capsid proteins and formulated with MF59C.1 adjuvant was evaluated in a randomized, double-blind, phase 1 trial. Parvovirus B19-seronegative adults (n=24) received either 2.5 or 25 microg MEDI-491 at 0, 1, and 6 months. MEDI-491 was safe and immunogenic. All volunteers developed neutralizing antibody titers that peaked after the third immunization and were sustained through study day 364.

  5. ARID1B is a specific vulnerability in ARID1A-mutant cancers.

    PubMed

    Helming, Katherine C; Wang, Xiaofeng; Wilson, Boris G; Vazquez, Francisca; Haswell, Jeffrey R; Manchester, Haley E; Kim, Youngha; Kryukov, Gregory V; Ghandi, Mahmoud; Aguirre, Andrew J; Jagani, Zainab; Wang, Zhong; Garraway, Levi A; Hahn, William C; Roberts, Charles W M

    2014-03-01

    Recent studies have revealed that ARID1A, encoding AT-rich interactive domain 1A (SWI-like), is frequently mutated across a variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, an ARID1A homolog whose gene product is mutually exclusive with ARID1A in SWI/SNF complexes, as the number 1 gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation in both cancer cells and primary cells. We also find that ARID1A and ARID1B are frequently co-mutated in cancer but that ARID1A-deficient cancers retain at least one functional ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.

  6. ARID1B is a specific vulnerability in ARID1A-mutant cancers

    PubMed Central

    Helming, Katherine C.; Wang, Xiaofeng; Wilson, Boris G.; Vazquez, Francisca; Haswell, Jeffrey R.; Manchester, Haley E.; Kim, Youngha; Kryukov, Gregory V.; Ghandi, Mahmoud; Aguirre, Andrew J.; Jagani, Zainab; Wang, Zhong; Garraway, Levi A.; Hahn, William C.; Roberts, Charles W. M.

    2014-01-01

    Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers. PMID:24562383

  7. Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling.

    PubMed

    Cao, Lei; Tian, Ye; Jiang, Yi; Zhang, Ge-Juan; Lei, Hui; Di, Zheng-Li

    2015-01-01

    Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown-induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway. © 2015 S. Karger AG, Basel.

  8. Targeting MUC1-C suppresses polycomb repressive complex 1 in multiple myeloma.

    PubMed

    Tagde, Ashujit; Markert, Tahireh; Rajabi, Hasan; Hiraki, Masayuki; Alam, Maroof; Bouillez, Audrey; Avigan, David; Anderson, Kenneth; Kufe, Donald

    2017-09-19

    The polycomb repressive complex 1 (PRC1) includes the BMI1, RING1 and RING2 proteins. BMI1 is required for survival of multiple myeloma (MM) cells. The MUC1-C oncoprotein is aberrantly expressed by MM cells, activates MYC and is also necessary for MM cell survival. The present studies show that targeting MUC1-C with (i) stable and inducible silencing and CRISPR/Cas9 editing and (ii) the pharmacologic inhibitor GO-203, which blocks MUC1-C function, downregulates BMI1, RING1 and RING2 expression. The results demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism. MUC1-C thus promotes MYC occupancy on the BMI1 promoter and thereby activates BMI1 expression. We also show that the MUC1-C→MYC pathway induces RING2 expression. Moreover, in contrast to BMI1 and RING2, we found that MUC1-C drives RING1 by an NF-κB p65-dependent mechanism. Targeting MUC1-C and thereby the suppression of these key PRC1 proteins was associated with downregulation of the PRC1 E3 ligase activity as evidenced by decreases in ubiquitylation of histone H2A. Targeting MUC1-C also resulted in activation of the PRC1-repressed tumor suppressor genes, PTEN, CDNK2A and BIM . These findings identify a heretofore unrecognized role for MUC1-C in the epigenetic regulation of MM cells.

  9. The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells

    PubMed Central

    Grötsch, Bettina; Brachs, Sebastian; Lang, Christiane; Luther, Julia; Derer, Anja; Schlötzer-Schrehardt, Ursula; Bozec, Aline; Fillatreau, Simon; Berberich, Ingolf; Hobeika, Elias; Reth, Michael; Wagner, Erwin F.; Schett, Georg

    2014-01-01

    The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell–specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression. PMID:25288397

  10. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme.

    PubMed

    Siuciak, J A; McCarthy, S A; Chapin, D S; Reed, T M; Vorhees, C V; Repaske, D R

    2007-07-01

    PDE1B is a calcium-dependent cyclic nucleotide phosphodiesterase that is highly expressed in the striatum. In order to investigate the physiological role of PDE1B in the central nervous system, PDE1B knockout mice (C57BL/6N background) were assessed in behavioral tests and their brains were assayed for monoamine content. In a variety of well-characterized behavioral tasks, including the elevated plus maze (anxiety-like behavior), forced swim test (depression-like behavior), hot plate (nociception) and two cognition models (passive avoidance and acquisition of conditioned avoidance responding), PDE1B knockout mice performed similarly to wild-type mice. PDE1B knockout mice showed increased baseline exploratory activity when compared to wild-type mice. When challenged with amphetamine (AMPH) and methamphetamine (METH), male and female PDE1B knockout mice showed an exaggerated locomotor response. Male PDE1B knockout mice also showed increased locomotor responses to higher doses of phencyclidine (PCP) and MK-801; however, this effect was not consistently observed in female knockout mice. In the striatum, increased dopamine turnover (DOPAC/DA and HVA/DA ratios) was found in both male and female PDE1B knockout mice. Striatal serotonin (5-HT) levels were also decreased in PDE1B knockout mice, although levels of the metabolite, 5HIAA, were unchanged. The present studies demonstrate increased striatal dopamine turnover in PDE1B knockout mice associated with increased baseline motor activity and an exaggerated locomotor response to dopaminergic stimulants such as methamphetamine and amphetamine. These data further support a role for PDE1B in striatal function.

  11. Endophilin B1

    PubMed Central

    Cheung, Zelda H

    2009-01-01

    Endophilin B1 is a member of the endophilin family that is localized predominantly to intracellular membranes. Also known as Bax-interacting factor-1 (Bif-1), this protein has been observed to regulate the membrane dynamics of various intracellular compartments, such as the control of mitochondrial morphology and autophagosome formation in fibroblast. Endophilin B1 is expressed in the brain, but its functions in neurons had remained unknown. Recently, we have observed a novel role of endophilin B1 in neurons where it controls the trafficking of TrkA, cognate receptor for the prototypic neurotrophin nerve growth factor (NGF). Knock-down of endophilin B1 expression induces precocious targeting of NGF/TrkA to late endosomes and lysosomes, thereby leading to reduced TrkA levels. This is accompanied by marked attenuation of NGF-induced gene transcription and neurite outgrowth. Our observations suggest that endophilin B1 regulates TrkA level and downstream functions by controlling the movement of TrkA to late endosomes/lysosomes, possibly acting at the level of early endosomes. PMID:19704909

  12. ALDH1B1 links alcohol consumption and diabetes.

    PubMed

    Singh, Surendra; Chen, Ying; Matsumoto, Akiko; Orlicky, David J; Dong, Hongbin; Thompson, David C; Vasiliou, Vasilis

    2015-08-07

    Aldehyde dehydrogenase 1B1 (ALDH1B1) is a mitochondrial enzyme sharing 65% and 72% sequence identity with ALDH1A1 and ALDH2 proteins, respectively. Compared to the latter two ALDH isozymes, little is known about the physiological functions of ALDH1B1. Studies in humans indicate that ALDH1B1 may be associated with alcohol sensitivity and stem cells. Our recent in vitro studies using human ALDH1B1 showed that it metabolizes acetaldehyde and retinaldehyde. To investigate the in vivo role of ALDH1B1, we generated and characterized a global Aldh1b1 knockout mouse line. These knockout (KO) mice are fertile and show overtly good health. However, ethanol pharmacokinetic analysis revealed ∼40% increase in blood acetaldehyde levels in KO mice. Interestingly, the KO mice exhibited higher fasting blood glucose levels. Collectively, we show for the first time the functional in vivo role of ALDH1B1 in acetaldehyde metabolism and in maintaining glucose homeostasis. This mouse model is a valuable tool to investigate the mechanism by which alcohol may promote the development of diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Protein tyrosine phosphatase 1B (PTP1B) is required for cardiac lineage differentiation of mouse embryonic stem cells.

    PubMed

    Eshkiki, Zahra Shokati; Ghahremani, Mohammad Hossein; Shabani, Parisa; Firuzjaee, Sattar Gorgani; Sadeghi, Asie; Ghanbarian, Hossein; Meshkani, Reza

    2017-01-01

    Protein tyrosine phosphatase 1B (PTP1B) has been shown to regulate multiple cellular events such as differentiation, cell growth, and proliferation; however, the role of PTP1B in differentiation of embryonic stem (ES) cells into cardiomyocytes remains unexplored. In the present study, we investigated the effects of PTP1B inhibition on differentiation of ES cells into cardiomyocytes. PTP1B mRNA and protein levels were increased during the differentiation of ES cells into cardiomyocytes. Accordingly, a stable ES cell line expressing PTP1B shRNA was established. In vitro, the number and size of spontaneously beating embryoid bodies were significantly decreased in PTP1B-knockdown cells, compared with the control cells. Decreased expression of cardiac-specific markers Nkx2-5, MHC-α, cTnT, and CX43, as assessed by real-time PCR analysis, was further confirmed by immunocytochemistry of the markers. The results also showed that PTP1B inhibition induced apoptosis in both differentiated and undifferentiated ES cells, as presented by increasing the level of cleaved caspase-3, cytochrome C, and cleaved PARP. Further analyses revealed that PTP1B inhibition did not change proliferation and pluripotency of undifferentiated ES cells. Taken together, the data presented here suggest that PTP1B is essential for proper differentiation of ES cells into cardiomyocytes.

  14. Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers.

    PubMed

    Matsunaga, Toshiyuki; Hojo, Aki; Yamane, Yumi; Endo, Satoshi; El-Kabbani, Ossama; Hara, Akira

    2013-02-25

    Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used for treatment of patients with solid tumors formed in various organs including the lung, prostate and cervix, but is much less sensitive in colon and breast cancers. One major factor implicated in the ineffectiveness has been suggested to be acquisition of the CDDP resistance. Here, we established the CDDP-resistant phenotypes of human colon HCT15 cells by continuously exposing them to incremental concentrations of the drug, and monitored expressions of aldo-keto reductases (AKRs) 1A1, 1B1, 1B10, 1C1, 1C2 and 1C3. Among the six AKRs, AKR1C1 and AKR1C3 are highly induced with the CDDP resistance. The resistance lowered the sensitivity toward cellular damages evoked by oxidative stress-derived aldehydes, 4-hydroxy-2-nonenal and 4-oxo-2-nonenal that are detoxified by AKR1C1 and AKR1C3. Overexpression of AKR1C1 or AKR1C3 in the parental HCT15 cells mitigated the cytotoxicity of the aldehydes and CDDP. Knockdown of both AKR1C1 and AKR1C3 in the resistant cells or treatment of the cells with specific inhibitors of the AKRs increased the sensitivity to CDDP toxicity. Thus, the two AKRs participate in the mechanism underlying the CDDP resistance probably via detoxification of the aldehydes resulting from enhanced oxidative stress. The resistant cells also showed an enhancement in proteolytic activity of proteasome accompanied by overexpression of its catalytic subunits (PSMβ9 and PSMβ10). Pretreatment of the resistant cells with a potent proteasome inhibitor Z-Leu-Leu-Leu-al augmented the CDDP sensitization elicited by the AKR inhibitors. Additionally, the treatment of the cells with Z-Leu-Leu-Leu-al and the AKR inhibitors induced the expressions of the two AKRs and proteasome subunits. Collectively, these results suggest the involvement of up-regulated AKR1C1, AKR1C3 and proteasome in CDDP resistance of colon cancers and support a chemotherapeutic role for their inhibitors. Copyright © 2012 Elsevier Ireland

  15. PeaTAR1B: Characterization of a Second Type 1 Tyramine Receptor of the American Cockroach, Periplaneta americana

    PubMed Central

    Balfanz, Sabine

    2017-01-01

    The catecholamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. In insects; these neuroactive substances are functionally replaced by the phenolamines octopamine and tyramine. Phenolamines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Type 1 tyramine receptors are better activated by tyramine than by octopamine. In contrast; type 2 tyramine receptors are almost exclusively activated by tyramine. Functionally; activation of type 1 tyramine receptors leads to a decrease in the intracellular concentration of cAMP ([cAMP]i) whereas type 2 tyramine receptors can mediate Ca2+ signals or both Ca2+ signals and effects on [cAMP]i. Here; we report that the American cockroach (Periplaneta americana) expresses a second type 1 tyramine receptor (PeaTAR1B) in addition to PeaTAR1A (previously called PeaTYR1). When heterologously expressed in flpTM cells; activation of PeaTAR1B by tyramine leads to a concentration-dependent decrease in [cAMP]i. Its activity can be blocked by a series of established antagonists. The functional characterization of two type 1 tyramine receptors from P. americana; PeaTAR1A and PeaTAR1B; which respond to tyramine by changing cAMP levels; is a major step towards understanding the actions of tyramine in cockroach physiology and behavior; particularly in comparison to the effects of octopamine. PMID:29084141

  16. PeaTAR1B: Characterization of a Second Type 1 Tyramine Receptor of the American Cockroach, Periplaneta americana.

    PubMed

    Blenau, Wolfgang; Balfanz, Sabine; Baumann, Arnd

    2017-10-30

    The catecholamines norepinephrine and epinephrine regulate important physiological functions in vertebrates. In insects; these neuroactive substances are functionally replaced by the phenolamines octopamine and tyramine. Phenolamines activate specific guanine nucleotide-binding (G) protein-coupled receptors (GPCRs). Type 1 tyramine receptors are better activated by tyramine than by octopamine. In contrast; type 2 tyramine receptors are almost exclusively activated by tyramine. Functionally; activation of type 1 tyramine receptors leads to a decrease in the intracellular concentration of cAMP ([cAMP] i ) whereas type 2 tyramine receptors can mediate Ca 2+ signals or both Ca 2+ signals and effects on [cAMP] i . Here; we report that the American cockroach ( Periplaneta americana ) expresses a second type 1 tyramine receptor (PeaTAR1B) in addition to PeaTAR1A (previously called PeaTYR1). When heterologously expressed in flpTM cells; activation of PeaTAR1B by tyramine leads to a concentration-dependent decrease in [cAMP] i . Its activity can be blocked by a series of established antagonists. The functional characterization of two type 1 tyramine receptors from P. americana ; PeaTAR1A and PeaTAR1B; which respond to tyramine by changing cAMP levels; is a major step towards understanding the actions of tyramine in cockroach physiology and behavior; particularly in comparison to the effects of octopamine.

  17. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). 57.22235 Section 57.22235 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION... Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the...

  18. 30 CFR 57.22235 - Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Actions at 1.0 percent methane (I-C, II-A, II-B... AND NONMETAL MINES Safety Standards for Methane in Metal and Nonmetal Mines Ventilation § 57.22235 Actions at 1.0 percent methane (I-C, II-A, II-B, and IV mines). (a) If methane reaches 1.0 percent in the...

  19. WATER IN COMETS 71P/CLARK AND C/2004 B1 (LINEAR) WITH SPITZER

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

    Bockelee-Morvan, Dominique; Woodward, Charles E.; Kelley, Michael S.

    2009-05-10

    We present 5.5-7.6 {mu}m spectra of comets 71P/Clark (2006 May 27.56 UT, r{sub h} = 1.57 AU pre-perihelion) and C/2004 B1 (LINEAR) (2005 October 15.22 UT, r{sub h} = 2.21 AU pre-perihelion and 2006 May 16.22 UT, r{sub h} = 2.06 AU post-perihelion) obtained with the Spitzer Space Telescope. The {nu}{sub 2} vibrational band of water is detected with a signal-to-noise ratio of 11-50. Fitting the spectra using a fluorescence model of water emission yields a water rotational temperature of < 18 K for 71P/Clark and {approx_equal}14 {+-} 2 K (pre-perihelion) and 23 {+-} 4 K (post-perihelion) for C/2004 B1more » (LINEAR). The water ortho-to-para ratio in C/2004 B1 (LINEAR) is measured to be 2.31 {+-} 0.18, which corresponds to a spin temperature of 26{sup +3} {sub -2} K. Water production rates are derived. The agreement between the water model and the measurements is good, as previously found for Spitzer spectra of C/2003 K4 (LINEAR). The Spitzer spectra of these three comets do not show any evidence for emission from polycyclic aromatic hydrocarbons and carbonate minerals, in contrast to results reported for comets 9P/Tempel 1 and C/1995 O1 (Hale-Bopp)« less

  20. 5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

    PubMed Central

    Wu, Hua-Li; Pang, Si-Lin; Liu, Qiong-Zhen; Wang, Qian; Cai, Min-Xuan; Shang, Jing

    2014-01-01

    Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A

  1. 26 CFR 1.681(b)-1 - Cross reference.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Cross reference. 1.681(b)-1 Section 1.681(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Miscellaneous § 1.681(b)-1 Cross reference. For disallowance of certain charitable, etc...

  2. Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

    PubMed Central

    Verma, Anjali; Rajagopalan, Pavithra; Lotke, Rishikesh; Varghese, Rebu; Selvam, Deepak; Kundu, Tapas K.

    2016-01-01

    ABSTRACT Of the various genetic subtypes of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), only in subtype C of HIV-1 is a genetically variant NF-κB binding site found at the core of the viral promoter in association with a subtype-specific Sp1III motif. How the subtype-associated variations in the core transcription factor binding sites (TFBS) influence gene expression from the viral promoter has not been examined previously. Using panels of infectious viral molecular clones, we demonstrate that subtype-specific NF-κB and Sp1III motifs have evolved for optimal gene expression, and neither of the motifs can be replaced by a corresponding TFBS variant. The variant NF-κB motif binds NF-κB with an affinity 2-fold higher than that of the generic NF-κB site. Importantly, in the context of an infectious virus, the subtype-specific Sp1III motif demonstrates a profound loss of function in association with the generic NF-κB motif. An additional substitution of the Sp1III motif fully restores viral replication, suggesting that the subtype C-specific Sp1III has evolved to function with the variant, but not generic, NF-κB motif. A change of only two base pairs in the central NF-κB motif completely suppresses viral transcription from the provirus and converts the promoter into heterochromatin refractory to tumor necrosis factor alpha (TNF-α) induction. The present work represents the first demonstration of functional incompatibility between an otherwise functional NF-κB motif and a unique Sp1 site in the context of an HIV-1 promoter. Our work provides important leads as to the evolution of the HIV-1 subtype C viral promoter with relevance for gene expression regulation and viral latency. IMPORTANCE Subtype-specific genetic variations provide a powerful tool to examine how these variations offer a replication advantage to specific viral subtypes, if any. Only in subtype C of HIV-1 are two genetically distinct

  3. Quasi-two-dimensional fluctuations in the magnetization of L a 1.9 C a 1.1 C u 2 O 6 + δ superconductors

    DOE PAGES

    Shi, Xiaoya; Dimitrov, I. K.; Ozaki, Toshinori; ...

    2017-11-01

    We report the results of magnetization measurements with the magnetic field applied along the c axis on superconducting La 1.9Ca 1.1Cu 2O 6+δ single crystals processed under ultrahigh oxygen pressure. Strong fluctuation effects were found in both low- and high-field regimes. Scaling analysis of the high-field magnetization data near the critical temperature (T c = 53.5K) region reveals the characteristics of critical fluctuation behavior of quasi-two-dimensional (2D) superconductivity, described by Ginzburg-Landau theory using the lowest Landau level approximation. Low-field magnetic susceptibility data can be successfully explained by the Lawrence-Doniach model for a quasi-2D superconductor, from which we obtained the amore » b plane Ginzburg-Landau coherence length of this system, ξ ab(0) = 11.8 ± 0.9 Å . The coherence length along the c axis, ξ c(0), is estimated to be about 1.65 Å, which is in between those of 2D cuprate systems, such as Bi 2Sr 2Ca 2Cu 3O 10 and Bi 2Sr 2CaCu 2O 8, and quasi-three-dimensional (3D) cuprate systems, such as overdoped La 2-xSr xCuO 4 and YBa 2Cu 3O 7-δ. Our studies suggest a strong interplay among the fluctuation effects, dimensionalities, and the ratios of the interlayer Cu-O plane spacing, s , to the c-axis coherence lengths. A high s/ξ c(0) was observed in the high-pressure oxygenated La 1.9Ca 1.1Cu 2O 6+δ, and that apparently drives this system to behave more like a quasi-2D superconductor.« less

  4. Quasi-two-dimensional fluctuations in the magnetization of L a 1.9 C a 1.1 C u 2 O 6 + δ superconductors

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

    Shi, Xiaoya; Dimitrov, I. K.; Ozaki, Toshinori

    We report the results of magnetization measurements with the magnetic field applied along the c axis on superconducting La 1.9Ca 1.1Cu 2O 6+δ single crystals processed under ultrahigh oxygen pressure. Strong fluctuation effects were found in both low- and high-field regimes. Scaling analysis of the high-field magnetization data near the critical temperature (T c = 53.5K) region reveals the characteristics of critical fluctuation behavior of quasi-two-dimensional (2D) superconductivity, described by Ginzburg-Landau theory using the lowest Landau level approximation. Low-field magnetic susceptibility data can be successfully explained by the Lawrence-Doniach model for a quasi-2D superconductor, from which we obtained the amore » b plane Ginzburg-Landau coherence length of this system, ξ ab(0) = 11.8 ± 0.9 Å . The coherence length along the c axis, ξ c(0), is estimated to be about 1.65 Å, which is in between those of 2D cuprate systems, such as Bi 2Sr 2Ca 2Cu 3O 10 and Bi 2Sr 2CaCu 2O 8, and quasi-three-dimensional (3D) cuprate systems, such as overdoped La 2-xSr xCuO 4 and YBa 2Cu 3O 7-δ. Our studies suggest a strong interplay among the fluctuation effects, dimensionalities, and the ratios of the interlayer Cu-O plane spacing, s , to the c-axis coherence lengths. A high s/ξ c(0) was observed in the high-pressure oxygenated La 1.9Ca 1.1Cu 2O 6+δ, and that apparently drives this system to behave more like a quasi-2D superconductor.« less

  5. Synthesis and characterization of aluminum- and gallium-bridged [1.1]chromarenophanes and [1.1]molybdarenophanes.

    PubMed

    Lund, Clinton L; Schachner, Jörg A; Burgess, Ian J; Quail, J Wilson; Schatte, Gabriele; Müller, Jens

    2008-07-07

    The synthesis and structural characterization of the first [1.1]chromarenophanes and the first [1.1]molybdarenophanes are described. A salt-metathesis reaction of [2-(Me 2NCH 2)C 6H 4]AlCl 2 with freshly prepared [Cr(LiC 6H 5) 2].TMEDA (TMEDA = N, N, N', N'-tetramethylethylenediamine) resulted in the dialumina[1.1]chromarenophane [{2-(Me 2NCH 2)C 6H 4}Al(eta (6)-C 6H 5) 2Cr] 2 ( 2a). The poor solubility of 2a in organic solvents prompted us to synthesize the new intramolecularly coordinated aluminum- and gallium dichlorides [5- tBu-2-(Me 2NCH 2)C 6H 3]ECl 2 [E = Al ( 3a), Ga ( 3b)] in which the phenyl group was equipped with a tert-butyl group. Salt-metathesis reactions of 3a and 3b, respectively, with freshly prepared [M(LiC 6H 5) 2].TMEDA (M = Cr, Mo) resulted in four new [1.1]metallarenophanes of the general type [{5- tBu-2-(Me 2NCH 2)C 6H 3}E(eta (6)-C 6H 5) 2M] 2 [E = Al, M = Cr ( 4a); E = Ga, M = Cr ( 4b); E = Al, M = Mo ( 5a); E = Ga, M = Mo ( 5b)]. 2a, 4a, b, and 5a, b have been structurally characterized by single-crystal analysis [ 2a.1/2C 6H 12: C 48H 56Al 2Cr 2N 2, monoclinic, P2 1/ c, a = 9.9117(9) A, b = 19.9361(16) A, c = 10.638(2) A, alpha = 90 degrees , beta = 112.322(5) degrees , gamma = 90 degrees , Z = 2; 4a.2C 6H 6: C 62H 72Al 2Cr 2N 2, monoclinic, P2 1/ c, a = 10.9626(9) A, b = 19.3350(18) A, c = 12.4626(9) A, alpha = 90 degrees , beta = 100.756(5) degrees , gamma = 90 degrees , Z = 2; 4b.2C 6H 6: C 62H 72Cr 2Ga 2N 2, monoclinic, P2 1/ c, a = 10.8428(2) A, b = 19.4844(4) A, c = 12.4958(2) A, alpha = 90 degrees , beta = 100.6187 degrees , gamma = 90 degrees , Z = 2; 5a.2C 6H 6: C 62H 72Al 2Mo 2N 2, triclinic, P1, a = 10.4377(4) A, b = 11.6510(4) A, c = 11.6514(4) A, alpha = 73.545(3) degrees , beta = 89.318(2) degrees , gamma = 76.120(2) degrees , Z = 1; 5b.2C 6H 6: C 62H 72Ga 2Mo 2N 2, triclinic, P1, a = 10.3451(5) A, b = 11.6752(6) A, c = 11.6900(5) A, alpha = 73.917(3) degrees , beta = 89.550(3) degrees , gamma = 76.774(2) degrees , Z = 1

  6. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1

    PubMed Central

    Bassan, Merav; Liu, Hongguang; Madsen, Kenneth L.; Armsen, Wencke; Zhou, Jiayi; DeSilva, Tara; Chen, Weizhi; Paradise, Allison; Brasch, Michael A.; Staudinger, Jeff; Gether, Ulrik; Irwin, Nina; Rosenberg, Paul A.

    2015-01-01

    Synaptic plasticity is implemented by the interaction of glutamate receptors with PDZ domain proteins. Glutamate transporters provide the only known mechanism of clearance of glutamate from excitatory synapses, and GLT1 is the major glutamate transporter. We show here that GLT1 interacts with the PDZ domain protein PICK1, which plays a critical role in regulating the expression of glutamate receptors at excitatory synapses. A yeast two-hybrid screen of a neuronal library using the carboxyl tail of GLT1b yielded clones expressing PICK1. The GLT1b C-terminal peptide bound to PICK1 with high affinity (Ki = 6.5 ± 0.4 μm) in an in vitro fluorescence polarization assay. We also tested peptides based on other variants of GLT1 and other glutamate transporters. GLT1b co-immunoprecipitated with PICK1 from rat brain lysates and COS7 cell lysates derived from cells transfected with plasmids expressing PICK1 and GLT1b. In addition, expression of GLT1b in COS7 cells changed the distribution of PICK1, bringing it to the surface. GLT1b and PICK1 co-localized with each other and with synaptic markers in hippocampal neurons in culture. Phorbol ester, an activator of protein kinase C (PKC), a known PICK1 interactor, had no effect on glutamate transport in rat forebrain neurons in culture. However, we found that exposure of neurons to a myristolated decoy peptide with sequence identical to the C-terminal sequence of GLT1b designed to block the PICK1–GLT1b interaction rendered glutamate transport into neurons responsive to phorbol ester. These results suggest that the PICK1–GLT1b interaction regulates the modulation of GLT1 function by PKC. PMID:18184314

  7. 15-HETE "modulates" expression of C3b receptor (CR1) antigen on peripheral blood B-lymphocytes.

    PubMed

    Cook, J; Delebassée, S; Aldigier, J C; Gualde, N; Kazatchkine, M

    1986-08-01

    We have studied the effect of the lipoxygenase metabolite, 15-HETE, on the expression of the human C3b receptor (CR1) by a B-lymphocyte enriched population of human peripheral blood leukocytes. The number of CR1 antigenic sites expressed by B-lymphocytes isolated from HLA typed donors was determined by equilibrium binding studies using an 125 I-labelled mouse monoclonal anti CR1 antibody before and after 16 hrs incubation in RPMI alone or containing 10(-6)M, 10(-7)M or 10(-8)M final concentration of 15-HETE. In B44- subjects CR1 expression on B cells increased 63% after incubation in RPMI alone. This increase was inhibited in the presence of 10(-6)M and 10(-7)M 15-HETE (23% and 30% increase respectively). In contrast, B44+ individuals showed a smaller increase in CR1 numbers when incubated in RPMI alone. In the presence of 15-HETE CR1 antigenic sites continued to increase. When B44+ subjects were classified as A29+ or A29-, donors that were A29+ B44+ accounted for the augmentation observed while A29- B44+ individuals did not differ from individuals that were A29- B44-.

  8. 26 CFR 1.669(b)-1 - Information requirements.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Information requirements. 1.669(b)-1 Section 1... Beginning Before January 1, 1969 § 1.669(b)-1 Information requirements. The election of a beneficiary who is... following information with respect to the operation and accounts of the foreign trust created by a U.S...

  9. Sequence variations of the partially dominant DELLA gene Rht-B1c in wheat and their functional impacts

    PubMed Central

    Ma, Zhengqiang

    2013-01-01

    Rht-B1c, allelic to the DELLA protein-encoding gene Rht-B1a, is a natural mutation documented in common wheat (Triticum aestivum). It confers variation to a number of traits related to cell and plant morphology, seed dormancy, and photosynthesis. The present study was conducted to examine the sequence variations of Rht-B1c and their functional impacts. The results showed that Rht-B1c was partially dominant or co-dominant for plant height, and exhibited an increased dwarfing effect. At the sequence level, Rht-B1c differed from Rht-B1a by one 2kb Veju retrotransposon insertion, three coding region single nucleotide polymorphisms (SNPs), one 197bp insertion, and four SNPs in the 1kb upstream sequence. Haplotype investigations, association analyses, transient expression assays, and expression profiling showed that the Veju insertion was primarily responsible for the extreme dwarfing effect. It was found that the Veju insertion changed processing of the Rht-B1c transcripts and resulted in DELLA motif primary structure disruption. Expression assays showed that Rht-B1c caused reduction of total Rht-1 transcript levels, and up-regulation of GATA-like transcription factors and genes positively regulated by these factors, suggesting that one way in which Rht-1 proteins affect plant growth and development is through GATA-like transcription factor regulation. PMID:23918966

  10. Measurement of sigma(Lambda(b)0) / sigma(anti-B 0) x B(Lambda0(b) ---> Lambda+(c) pi-) / B(anti-B0 ---> D+ pi-) in p anti-p collisions at S**(1/2) = 1.96-TeV

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

    Abulencia, A.; Acosta, D.; Adelman, Jahred A.

    2006-01-01

    The authors present the first observation of the baryon decay {Lambda}{sub b}{sup 0} {yields} {Lambda}{sub c}{sup +} {pi}{sup -} followed by {Lambda}{sub c}{sup +} {yields} pK{sup -} {pi}{sup +} in 106 pb{sup -1} p{bar p} collisions at {radical}s = 1.96 TeV in the CDF experiment. IN order to reduce systematic error, the measured rate for {Lambda}{sub b}{sup 0} decay is normalized to the kinematically similar meson decay {bar B}{sup 0} {yields} D{sup +}{pi}{sup -} followed by D{sup +} {yields} {pi}{sup +}K{sup -}{pi}{sup +}. They report the ratio of production cross sections ({sigma}) times the ratio of branching fractions ({Beta}) formore » the momentum region integrated above p{sub T} > 6 GeV/c and pseudorapidity range |{eta}| < 1.3: {sigma}(p{bar p} {yields} {Lambda}{sub b}{sup 0}X)/{sigma}(p{bar p} {yields} {bar B}{sup 0} X) x {Beta}({Lambda}{sub b}{sup 0} {yields} {Lambda}{sub c}{sup +}{pi}{sup -})/{Beta}({bar B}{sup 0} {yields} D{sup +}{pi}{sup -}) = 0.82 {+-} 0.08(stat) {+-} 0.11(syst) {+-} 0.22 ({Beta}({Lambda}{sub c}{sup +} {yields} pK{sup -} {pi}{sup +})).« less

  11. 26 CFR 1.642(c)-1 - Unlimited deduction for amounts paid for a charitable purpose.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the election was made, (iii) The office of the district director, or the service center, where the....642(c)-1 Unlimited deduction for amounts paid for a charitable purpose. (a) In general. (1) Any part... election, to a related estate, as defined under § 1.645-1(b), for the amount so paid. (2) In determining...

  12. Near Full-Length Identification of a Novel HIV-1 CRF01_AE/B/C Recombinant in Northern Myanmar.

    PubMed

    Zhou, Yan-Heng; Chen, Xin; Liang, Yue-Bo; Pang, Wei; Qin, Wei-Hong; Zhang, Chiyu; Zheng, Yong-Tang

    2015-08-01

    The Myanmar-China border appears to be the "hot spot" region for the occurrence of HIV-1 recombination. The majority of the previous analyses of HIV-1 recombination were based on partial genomic sequences, which obviously cannot reflect the reality of the genetic diversity of HIV-1 in this area well. Here, we present a near full-length characterization of a novel HIV-1 CRF01_AE/B/C recombinant isolated from a long-distance truck driver in Northern Myanmar. It is the first description of a near full-length genomic sequence in Myanmar since 2003, and might be one of the most complicated HIV-1 chimeras ever detected in Myanmar, containing four CRF01_AE, six B segments, and five C segments separated by 14 breakpoints throughout its genome. The discovery and characterization of this new CRF01_AE/B/C recombinant indicate that intersubtype recombination is ongoing in Myanmar, continuously generating new forms of HIV-1. More work based on near full-length sequence analyses is urgently needed to better understand the genetic diversity of HIV-1 in these regions.

  13. Human Leukocyte Antigen-A, B, C, DRB1, and DQB1 Allele and Haplotype Frequencies in a Subset of 237 Donors in the South African Bone Marrow Registry

    PubMed Central

    Ingram, Charlotte; Schlaphoff, Terry; Borrill, Veronica; Christoffels, Alan

    2018-01-01

    Human leukocyte antigen- (HLA-) A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR). Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC) format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A∗02:02g (0.096), B∗07:02g (0.082), C∗07:02g (0.180), DQB1∗06:02 (0.157), and DRB1∗15:01 (0.072). The most common haplotype was A∗03:01g~B∗07:02g~C∗07:02g~DQB1∗06:02~DRB1∗15:01 (0.067), which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies. PMID:29850621

  14. Administration and Stenographic Career Ladders, AFS 702x0/A/B/C and 702X1.

    DTIC Science & Technology

    1980-04-01

    MEN mIIIIIIIII hhhllllhlhhl UNITED STATES AIR FORCE _Si -j𔃽.- 0 ADMINISTRATION AND5$TENOGRAPHIC -CAREER LADDERS AIS 702XO/ A /B/C AND 702X1 -J AFPT- 9...7J2-389 ( ,/ " ’ _ LA. -IAPRI 180 This document has n a :’.-pro+ved1 + ,for pil s’ s ;i - , OqCUPATIONAL ANALYSIS PROGRAM USAF OCCUPATIONAL...79 APPENDIX A O--------------------------------------------- 80 Acc22~C~For 1 -* ii L PREFACE This report presents the results of a detailed Air

  15. 26 CFR 1.6038B-1 - Reporting of certain transfers to foreign corporations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... be filed by a control group member (as defined in § 1.367(a)-7(f)(1)) or final distributee (as.... transferor of each control group member. (B) A calculation of the gain recognized (if any) by the U.S... by each control group member under § 1.367(a)-7(c)(3). (C) The date on which the U.S. transferor and...

  16. 26 CFR 1.6038B-1 - Reporting of certain transfers to foreign corporations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... be filed by a control group member (as defined in § 1.367(a)-7(f)(1)) or final distributee (as.... transferor of each control group member. (B) A calculation of the gain recognized (if any) by the U.S... by each control group member under § 1.367(a)-7(c)(3). (C) The date on which the U.S. transferor and...

  17. Walleye dermal sarcoma virus Orf B functions through receptor for activated C kinase (RACK1) and protein kinase C

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

    Daniels, Candelaria C.; Rovnak, Joel; Quackenbush, Sandra L.

    2008-06-05

    Walleye dermal sarcoma virus is a complex retrovirus that is associated with walleye dermal sarcomas that are seasonal in nature. Fall developing tumors contain low levels of spliced accessory gene transcripts A and B, suggesting a role for the encoded proteins, Orf A and Orf B, in oncogenesis. In explanted tumor cells the 35 kDa Orf B accessory protein is localized to the cell periphery in structures similar to focal adhesions and along actin stress fibers. Similar localization was observed in mammalian cells. The cellular protein, receptor for activated C kinase 1 (RACK1), bound Orf B in yeast two-hybrid assaysmore » and in cell culture. Sequence analysis of walleye RACK1 demonstrated high conservation to other known RACK1 sequences. RACK1 binds to activated protein kinase C (PKC). Orf B associates with PKC{alpha}, which is constitutively activated and localized at the membrane. Activated PKC promoted cell survival, proliferation, and increased cell viability in Orf B-expressing cells.« less

  18. 26 CFR 1.677(b)-1 - Trusts for support.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Trusts for support. 1.677(b)-1 Section 1.677(b... (CONTINUED) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.677(b)-1 Trusts for support. (a) Section 677(b) provides that a grantor is not treated as the owner of a trust merely because its...

  19. Magterpenoids A-C, Three Polycyclic Meroterpenoids with PTP1B Inhibitory Activity from the Bark of Magnolia officinalis var. biloba.

    PubMed

    Li, Chuan; Li, Chuang-Jun; Ma, Jie; Chen, Fang-You; Li, Li; Wang, Xiao-Liang; Ye, Fei; Zhang, Dong-Ming

    2018-06-15

    Magterpenoid A (1), possessing a rare 4,6,11-trioxatricyclo[5.3.1.0 1,5 ]undecane framework with an irregular monoterpenoid moiety, magterpenoid B (2), with an unprecedented 6/6/6/6 polycyclic skeleton, and magterpenoid C (3), a novel terpenoid quinone with a C6-C3 unit, were isolated from the bark of Magnolia officinalis var. biloba. Plausible biogenetic pathways of 1-3 are presented. Compounds 1 and 3 exhibited significant PTP1B inhibitory activities with IC 50 values of 1.44 and 0.81 μM, respectively.

  20. 75 FR 27411 - Airworthiness Directives; Turbomeca Arriel 1B, 1D, 1D1, and 1S1 Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-17

    .... That AD requires initial and repetitive relative position checks of the gas generator 2nd stage turbine... repetitive replacements of 2nd stage turbines on Arriel 1B, 1D, and 1D1 engines. This AD requires lowering the initial and repetitive thresholds for replacement of 2nd stage turbines on Arriel 1B, 1D, and 1D1...

  1. Leu432Val polymorphism in CYP1B1 as a susceptible factor towards predisposition to primary open-angle glaucoma

    PubMed Central

    Banerjee, Deblina; Mookherjee, Suddhasil; Banerjee, Antara; Sen, Abhijit; Variation Consortium, the Indian Genome

    2008-01-01

    Purpose Defects in cytochrome P450 1B1 (CYP1B1) cause primary congenital glaucoma. However, defects in the gene have also been reported in primary open-angle glaucoma (POAG). Since POAG is primarily a complex disease, we examined the potential of coding single nucleotide polymorphisms (cSNPs) in the gene for association with the disease. Methods Five coding SNPs – c.514 C>G (Arg48Gly), c.727 G>T (Ala119Ser), c.1666 C>G (Leu432Val), c.1719 C>T (Asp449Asp), and c.1730 A>G (Asn453Ser) – were genotyped in 264 unrelated POAG patients and 95 controls. In addition, 542 normal individuals selected from various ethnic groups representing the Indian population were also genotyped for these cSNPs. The patterns of linkage disequilibrium between the SNPs and haplotype variations for comparison between POAG patients and controls as well as different ethnic groups of the Indian population were determined using Haploview. Allelic variants of Leu432Val were cloned by site-directed mutagenesis of normal CYP1B1 cDNA, which were used for transfection of retinal pigment epithelium (RPE) cells. The generation of reactive oxygen species (ROS) was quantified by measuring fluorescence emission by degradation of CM-H2DCFDA using a fluoremeter. Results The c.1666G allele of the Leu432Val in CYP1B1 showed a statistically significant higher representation among POAG patients compared to controls (p=0.0001; Odds ratio=6.027; 95% CI: 3.863–9.401) suggesting it to be a potential risk allele toward disease predisposition. Analysis of genotype frequencies of the polymorphism between the two groups demonstrated GG as a potential risk genotype (p=0.0001; Odds ratio=15.505; 95% CI: 5.529–43.474) for the disease. CYP1B1 Val432 was estimated to generate higher ROS in RPE cells compared to its allelic variant (Leu432; p=0.0245 for 15 min and p=0.0197 for 30 min). Comparison of haplotype diversities revealed CGGTA as the risk haplotype for the disease (p=0.0001, by Fisher’s exact test

  2. 16 CFR Figure 1 to Part 1213 - Wedge Block for Tests in § 1213.4(a), (b), and (c)

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Wedge Block for Tests in § 1213.4(a), (b), and (c) 1 Figure 1 to Part 1213 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION CONSUMER... 1 to Part 1213—Wedge Block for Tests in § 1213.4(a), (b), and (c) ER22DE99.007 ...

  3. The antioxidant effects of vitamin A, C, and E on aflatoxin B1-induced oxidative stress in human lymphocytes.

    PubMed

    Alpsoy, L; Yildirim, A; Agar, G

    2009-03-01

    The aim of this study was to investigate the possible protective role of vitamin A, C, and E on aflatoxin B(1)-induced in human lymphocytes using biochemical approaches. The control group received dimethyl sulfoxide, the second group of cultures were administered aflatoxin B(1) (AFB(1)) at a dose of 5 muM. The other group of cultures were treated with AFB(1)+vitamin A (0.5 and 1.0 and 1.5 microM) and AFB(1)+vitamin C (25, 50, and 100 microM) and AFB(1)+vitamin E (40, 100, and 200 microM). The results of this experiment show that AFB(1) significantly decreased the level of GSH and the activities of superoxide dismutase and GPx and increased level of malondialdehyde. Simultaneous supplementation with vitamin A, C, and E restored these parameters to that of normal range. In conclusion, vitamin A, C, and E exhibited protective effects in human lymphocytes by inhibiting AFB(1)-induced ROS generation.

  4. AP-11B-adaptin mediates endosomal synaptic vesicle recycling, learning and memory

    PubMed Central

    Glyvuk, Nataliya; Tsytsyura, Yaroslav; Geumann, Constanze; D'Hooge, Rudi; Hüve, Jana; Kratzke, Manuel; Baltes, Jennifer; Böning, Daniel; Klingauf, Jürgen; Schu, Peter

    2010-01-01

    Synaptic vesicle recycling involves AP-2/clathrin-mediated endocytosis, but it is not known whether the endosomal pathway is also required. Mice deficient in the tissue-specific AP-1–σ1B complex have impaired synaptic vesicle recycling in hippocampal synapses. The ubiquitously expressed AP-1–σ1A complex mediates protein sorting between the trans-Golgi network and early endosomes. Vertebrates express three σ1 subunit isoforms: A, B and C. The expressions of σ1A and σ1B are highest in the brain. Synaptic vesicle reformation in cultured neurons from σ1B-deficient mice is reduced upon stimulation, and large endosomal intermediates accumulate. The σ1B-deficient mice have reduced motor coordination and severely impaired long-term spatial memory. These data reveal a molecular mechanism for a severe human X-chromosome-linked mental retardation. PMID:20203623

  5. Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.

    PubMed

    Pei, Qi; Liu, Jun-Yan; Yin, Ji-Ye; Yang, Guo-Ping; Liu, Shi-Kun; Zheng, Yi; Xie, Pan; Guo, Cheng-Xian; Luo, Mi; Zhou, Hong-Hao; Li, Xi; Liu, Zhao-Qian

    2018-05-11

    On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed. IC 50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [C max ] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0-8 h [AUC 0-8 ] increased 34% (P = 0.004), while the minimum blood glucose concentration [C min ] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan. SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

  6. SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

    PubMed

    Li, Xinwei; Huang, Weikun; Gu, Jingmin; Du, Xiliang; Lei, Lin; Yuan, Xue; Sun, Guoquan; Wang, Zhe; Li, Xiaobing; Liu, Guowen

    2015-10-01

    Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver. Copyright © 2015. Published by Elsevier Inc.

  7. Isobaric heat capacity for liquid 1-chloro-1,1-difluoroethane and 1,1-difluoroethane

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

    Nakagawa, Shinsuke; Hori, Tatsuhi; Sato, Haruki

    1993-01-01

    The isobaric heat capacities (C[sub P]) for liquid 1-chloro-1,1-difluoroethane (HCFC-142b) and 1,1-difluoroethane (HFC-152a) have been measured by means of flow calorimetry. For HCFC-142b, 31 C[sub P] values have been measured at temperatures from 276 to 350 K and pressures from 1.0 to 3.0 MPa. For HFC-152a, 36 C[sub P] have been measured at temperature from 276 to 360 K and pressures from 1.0 to 3.2 MPa. The uncertainties are estimated as [plus minus] 13 mK in temperature, [plus minus]3 kPa in pressure, and [plus minus] kPa in pressure, and [plus minus]0.4% for most of the C[sub P] measurements. The puritymore » of samples used for both HCFC-142b and HFC-152a measurements was 99.95 mol%. Correlations of liquid C[sub P] as a function of temperature and pressure have been developed for both refrigerants on the basis of the measurements.« less

  8. Association between SLCO1B1 -521T>C and -388A>G polymorphisms and risk of statin-induced adverse drug reactions: A meta-analysis.

    PubMed

    Jiang, Jiajia; Tang, Qing; Feng, Jing; Dai, Rong; Wang, Yang; Yang, Yuan; Tang, Xiaojun; Deng, Changkai; Zeng, Huan; Zhao, Yong; Zhang, Fan

    2016-01-01

    An increasing number of studies have investigated the association between SLCO1B1 -521T>C and -388A>G polymorphisms and the risk of statin-induced adverse drug reactions (ADRs), but the results have been inconsistent. This meta-analysis was performed to gain more insight into the relationship. PubMed, Embase, Cochrane Library and Web of Science were searched for relevant articles published before March 5th, 2015. The quality of included studies was evaluated by the Newcastle-Ottawa Quality scale. Pooled effect estimates (odds ratios [ORs] or hazard ratios [HRs) and corresponding 95 % confidence intervals (CIs) were calculated to assess the association in overall and subgroup analyses for various genetic models. Begg's rank correlation test and Egger's linear regression test were used to examine the publication bias. A total of nine cohort and four case-control studies involving 11, 246 statin users, of whom 2, 355 developing ADRs were included in the analysis. Combined analysis revealed a significant association between the SLCO1B1-521T>C polymorphism and increased risk for ADRs caused by various statins, but the synthesis heterogeneity was generally large (dominant model: pooled effect estimate = 1.85, 95 % CI 1.20-2.85, P = 0.005; I (2) = 80.70 %, Pheterogeneity < 0.001). Subgroup analysis by statin type showed that the ADRs risk was significantly elevated among simvastatin users (dominant model: pooled effect estimate = 3.43, 95 % CI 1.80-6.52, P = 0.001; I (2) = 59.60 %, Pheterogeneity = 0.060), but not among atorvastatin users. No significant relationship was found between the -388A>G polymorphism and ADRs caused by various statins (dominant model: pooled effect estimate = 0.94, 95 % CI 0.79-1.13, P = 0.526; I (2) = 40.10 %, Pheterogeneity = 0.196). The meta-analysis suggests that SLCO1B1 -521T>C polymorphism may be a risk factor for statin-induced ADRs, especially in simvastatin therapy. Conversely, there may be no significant

  9. Inducible overexpression of RUNX1b/c in human embryonic stem cells blocks early hematopoiesis from mesoderm.

    PubMed

    Chen, B; Teng, Jiawen; Liu, Hongwei; Pan, X; Zhou, Y; Huang, Shu; Lai, Mowen; Bian, Guohui; Mao, Bin; Sun, Wencui; Zhou, Qiongxiu; Yang, Shengyong; Nakahata, Tatsutoshi; Ma, Feng

    2017-08-01

    RUNX1 is absolutely required for definitive hematopoiesis, but the function of RUNX1b/c, two isoforms of human RUNX1, is unclear. We established inducible RUNX1b/c-overexpressing human embryonic stem cell (hESC) lines, in which RUNX1b/c overexpression prevented the emergence of CD34+ cells from early stage, thereby drastically reducing the production of hematopoietic stem/progenitor cells. Simultaneously, the expression of hematopoiesis-related factors was downregulated. However, such blockage effect disappeared from day 6 in hESC/AGM-S3 cell co-cultures, proving that the blockage occurred before the generation of hemogenic endothelial cells. This blockage was partially rescued by RepSox, an inhibitor of the transforming growth factor (TGF)-β signaling pathway, indicating a close relationship between RUNX1b/c and TGF-β pathway. Our results suggest a unique inhibitory function of RUNX1b/c in the development of early hematopoiesis and may aid further understanding of its biological function in normal and diseased models. © The Author (2017). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  10. The p65 Subunit of NF-κB Inhibits COL1A1 Gene Transcription in Human Dermal and Scleroderma Fibroblasts through Its Recruitment on Promoter by Protein Interaction with Transcriptional Activators (c-Krox, Sp1, and Sp3)*

    PubMed Central

    Beauchef, Gallic; Bigot, Nicolas; Kypriotou, Magdalini; Renard, Emmanuelle; Porée, Benoît; Widom, Russell; Dompmartin-Blanchere, Anne; Oddos, Thierry; Maquart, François-Xavier; Demoor, Magali; Boumediene, Karim; Galera, Philippe

    2012-01-01

    Transcriptional mechanisms regulating type I collagen genes expression in physiopathological situations are not completely known. In this study, we have investigated the role of nuclear factor-κB (NF-κB) transcription factor on type I collagen expression in adult normal human (ANF) and scleroderma (SF) fibroblasts. We demonstrated that NF-κB, a master transcription factor playing a major role in immune response/apoptosis, down-regulates COL1A1 expression by a transcriptional control involving the −112/−61 bp sequence. This 51-bp region mediates the action of two zinc fingers, Sp1 (specific protein-1) and Sp3, acting as trans-activators of type I collagen expression in ANF and SF. Knockdown of each one of these trans factors by siRNA confirmed the trans-activating effect of Sp1/Sp3 and the p65 subunit of NF-κB trans-inhibiting effect on COL1A1 expression. Despite no existing κB consensus sequence in the COL1A1 promoter, we found that Sp1/Sp3/c-Krox and NF-κB bind and/or are recruited on the proximal promoter in chromatin immunoprecipitation (ChIP) assays. Attempts to elucidate whether interactions between Sp1/Sp3/c-Krox and p65 are necessary to mediate the NF-κB inhibitory effect on COL1A1 in ANF and SF were carried out; in this regard, immunoprecipitation assays revealed that they interact, and this was validated by re-ChIP. Finally, the knockdown of Sp1/Sp3/c-Krox prevents the p65 inhibitory effect on COL1A1 transcription in ANF, whereas only the siRNAs targeting Sp3 and c-Krox provoked the same effect in SF, suggesting that particular interactions are characteristic of the scleroderma phenotype. In conclusion, our findings highlight a new mechanism for COL1A1 transcriptional regulation by NF-κB, and these data could allow the development of new antifibrotic strategies. PMID:22139845

  11. 48 CFR 215.403-1 - Prohibition on obtaining cost or pricing data (10 U.S.C. 2306a and 41 U.S.C. 254b).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... cost or pricing data (10 U.S.C. 2306a and 41 U.S.C. 254b). 215.403-1 Section 215.403-1 Federal... METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Contract Pricing 215.403-1 Prohibition on obtaining cost or pricing data (10 U.S.C. 2306a and 41 U.S.C. 254b). (b) Exceptions to cost or pricing data...

  12. Method 446.0: In Vitro Determination of Chlorophylls a, b, c + c and Pheopigments in 1 2Marine And Freshwater Algae by Visible Spectrophotometry

    EPA Science Inventory

    This method provides a procedure for determination of chlorophylls a (chl a), b (chl b), c + c 1 2 (chl c + c ) and pheopigments of chlorophyll a (pheo a) 1 2 found in marine and freshwater phytoplankton. Chlorophyllide a is determined as chl a. Visible wavelength spectrophotomet...

  13. Chronic stress targets posttranscriptional mechanisms to rapidly upregulate α1C-subunit of Cav1.2b calcium channels in colonic smooth muscle cells.

    PubMed

    Li, Qingjie; Sarna, Sushil K

    2011-01-01

    Chronic stress elevates plasma norepinephrine, which enhances expression of the α(1C)-subunit of Ca(v)1.2b channels in colonic smooth muscle cells within 1 h. Transcriptional upregulation usually does not explain such rapid protein synthesis. We investigated whether chronic stress-induced release of norepinephrine utilizes posttranscriptional mechanisms to enhance the α(1C)-subunit. We performed experiments on colonic circular smooth muscle strips and in conscious rats, using a 9-day chronic intermittent stress protocol. Incubation of rat colonic muscularis externa with norepinephrine enhanced α(1C)-protein expression within 45 min, without a concomitant increase in α(1C) mRNA, indicating posttranscriptional regulation of α(1C)-protein by norepinephrine. We found that norepinephrine activates the PI3K/Akt/GSK-3β pathway to concurrently enhance α(1C)-protein translation and block its polyubiquitination and proteasomal degradation. Incubation of colonic muscularis externa with norepinephrine or LiCl, which inhibits GSK-3β, enhanced p-GSK-3β and α(1C)-protein time dependently. Using enrichment of phosphoproteins and ubiquitinated proteins, we found that both norepinephrine and LiCl decrease α(1C) phosphorylation and polyubiquitination. Concurrently, they suppress eIF2α (Ser51) phosphorylation and 4E-BP1 expression, which stimulates gene-specific translation. The antagonism of two upstream kinases, PI3K and Akt, inhibits the induction of α(1C)-protein by norepinephrine. Cyanopindolol (β(3)-AR-antagonist) almost completely suppresses and propranolol (β(1/2)-AR antagonist) partially suppresses norepinephrine-induced α(1C)-protein expression, whereas phentolamine and prazosin (α-AR and α(1)-AR antagonist, respectively) have no significant effect. Experiments in conscious animals showed that chronic stress activates the PI3K/Akt/GSK-3β signaling. We conclude that norepinephrine released by chronic stress rapidly enhances the protein expression of α(1C

  14. Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons.

    PubMed

    Compan, V; Segu, L; Buhot, M C; Daszuta, A

    1998-05-18

    Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after

  15. Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin.

    PubMed

    Surichan, Somchaiya; Arroo, Randolph R; Tsatsakis, Aristidis M; Androutsopoulos, Vasilis P

    2018-04-04

    Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line MCF10A. Tangeretin was converted to 4' OH tangeretin by recombinant CYP1 enzymes and by CYP1 enzymes expressed in MCF7 and MDA-MB-468 cells. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Tangeretin exhibited submicromolar IC50 (0.25 ± 0.15 μM) in MDA-MB-468 cells, whereas it was less active in MCF7 cells (39.3 ± 1.5 μM) and completely inactive in MCF10A cells (>100 μM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18 ± 1.6 μM) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4' OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55 ± 0.19 μM vs. 6.33 ± 0.12 μM). The mechanism of antiproliferative action involved cell cycle arrest at the G1 phase for MCF7 and MDA-MB-468 cells. Tangeretin was further shown to induce CYP1 enzyme activity and CYP1A1/CYP1B1 protein expression in MCF7 and MDA-MB-468 cells. These results suggest that tangeretin inhibits the proliferation of breast cancer cells via CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1.

    PubMed

    Liu, Jiawang; Taylor, Shannon F; Dupart, Patrick S; Arnold, Corey L; Sridhar, Jayalakshmi; Jiang, Quan; Wang, Yuji; Skripnikova, Elena V; Zhao, Ming; Foroozesh, Maryam

    2013-05-23

    Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor 5-hydroxy-4'-propargyloxyflavone (5H4'FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while β-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively.

  17. Enhanced susceptibility to acute pneumococcal otitis media in mice deficient in complement C1qa, factor B, and factor B/C2.

    PubMed

    Tong, Hua Hua; Li, Yong Xing; Stahl, Gregory L; Thurman, Joshua M

    2010-03-01

    To define the roles of specific complement activation pathways in host defense against Streptococcus pneumoniae in acute otitis media (AOM), we investigated the susceptibility to AOM in mice deficient in complement factor B and C2 (Bf/C2(-/)(-)), C1qa (C1qa(-/)(-)), and factor B (Bf(-)(/)(-)). Bacterial titers of both S. pneumoniae serotype 6A and 14 in the middle ear lavage fluid samples from Bf/C2(-/)(-), Bf(-)(/)(-), and C1qa(-/)(-) mice were significantly higher than in samples from wild-type mice 24 h after transtympanical infection (P < 0.05) and remained persistently higher in samples from Bf/C2(-/)(-) mice than in samples from wild-type mice. Bacteremia occurred in Bf/C2(-/)(-), Bf(-)(/)(-), and C1qa(-/)(-) mice infected with both strains, but not in wild-type mice. Recruitment of inflammatory cells was paralleled by enhanced production of inflammatory mediators in the middle ear lavage samples from Bf/C2(-/)(-) mice. C3b deposition on both strains was greatest for sera obtained from wild-type mice, followed by C1qa(-)(/)(-) and Bf(-)(/)(-) mice, and least for Bf/C2(-)(/)(-) mice. Opsonophagocytosis and whole-blood killing capacity of both strains were significantly decreased in the presence of sera or whole blood from complement-deficient mice compared to wild-type mice. These findings indicate that both the classical and alternative complement pathways are critical for middle ear immune defense against S. pneumoniae. The reduced capacity of complement-mediated opsonization and phagocytosis in the complement-deficient mice appears to be responsible for the impaired clearance of S. pneumoniae from the middle ear and dissemination to the bloodstream during AOM.

  18. The frequency of SLCO1B1*5 polymorphism genotypes among Russian and Sakha (Yakutia) patients with hypercholesterolemia.

    PubMed

    Sychev, Dmitrij Alekseevitch; Shuev, Grigorij Nikolaevich; Chertovskih, Jana Valer'evna; Maksimova, Nadezhda Romanovna; Grachev, Andrej Vladimirovich; Syrkova, Ol'ga Aleksandrovna

    2016-01-01

    Statins are the most commonly prescribed medicines for treatment of hypercholesterolemia. At the same time, up to 25% of patients cannot tolerate or have to discontinue the statin therapy due to statin-induced myopathy. In a majority of cases, statin-induced myopathy is attributed to SLCO1B1 gene polymorphism. The strongest association between statin-induced myopathy and SLCO1B1 gene polymorphism was described for simvastatin. Our research was focused on the frequency of SLCO1B1*5 genetic variant in the Russian population and in the native population of Sakha (Yakutia). A total of 1,071 hyperlipidemic Russian and 76 hyperlipidemic Sakha (Yakutian) patients were included in the study. Genotypes of SLCO1B1*5 (c.521T>C, rs4149056) were determined with polymerase chain reaction amplification. The results of our study were compared with data about hyperlipidemic patients in available publications. In the Russian population 665 (62%) patients had TT genotype of SLCO1B1*5, 346 (32%) patients had TC genotype, and in 60 patients (6%) CC variant was found (Hardy-Weinberg's chi-square test was 3.1 P=0.21). In comparison with Brazil, France, the People's Republic of China, Japan, and the native population of Sakha (Yakutia), C-allele, which causes an increased risk of statin-induced myopathy, was found significantly more often in the Russian population. In the native population of Sakha (Yakutia) SLCO1B1 polymorphism was TT - 62 (82%), TC - 11 (14%), CC - 3 (4%) (Hardy-Weinberg's chi-square test was 5.13 P=0.077). In comparison with data from Brazil, France, the People's Republic of China, and Japan, C-allele frequency in the Sakha (Yakutian) population was not significantly different. Thus, we have studied the incidence of pathologic SLCO1B1 c.521C-allele in Russian and Sakha hyperlipidemic patients. The presence of SLCO1B1 C-allele in patients with hyperlipidemia forces us to be more careful in hypolipidemic drug prescription, especially statins, according to a higher risk

  19. Genotype X/C recombinant (putative genotype I) of hepatitis B virus is rare in Hanoi, Vietnam--genotypes B4 and C1 predominate.

    PubMed

    Phung, Thi Bich Thuy; Alestig, Erik; Nguyen, Thanh Liem; Hannoun, Charles; Lindh, Magnus

    2010-08-01

    There are eight known genotypes of hepatitis B virus, A-H, and several subgenotypes, with rather well-defined geographic distributions. HBV genotypes were evaluated in 153 serum samples from Hanoi, Vietnam. Of the 87 samples that could be genotyped, genotype B was found in 67 (77%) and genotype C in 19 (22%). All genotype C strains were of subgenotype C1, and the majority of genotype B strains were B4, while a few were B2. The genotype X/C recombinant strain, identified previously in Swedish patients of indigenous Vietnamese origin, was found in one sample. This variant, proposed to be classified as genotype I, has been found recently also by others in Vietnam and Laos. The current study indicates that the genotype X/C recombinant may represent approximately 1% of the HBV strains circulating in Vietnam. (c) 2010 Wiley-Liss, Inc.

  20. Effect of SLCO1B1 gene polymorphisms and vitamin D on statin-induced myopathy.

    PubMed

    Alghalyini, Baraa; El Shamieh, Said; Salami, Ali; Visvikis Siest, Sophie; Fakhoury, Hana M; Fakhoury, Rajaa

    2018-03-28

    Background Statin therapy used to lower cholesterol levels results in a substantial reduction in cardiovascular complications. Previous observations in different ethnic populations showed that rs2306283A>G, p.Asn130Asp and rs4149056T>C, p.Val174Ala in solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the organic transporter protein may be responsible for statin uptake, thus explaining the majority of statin-associated symptoms. In addition to the genetic component, vitamin D (vit D) deficiency is common in Saudi Arabia and worldwide and may cause muscle dysfunction and ache. The aim of the present study was first to reveal an effect of vit D, rs2306283A>G, and rs4149056T>C and related haplotypes on statin-associated myopathy (SAM) and then to investigate a possible interaction between low vit D levels and the above-mentioned variants. Methods The genomic DNA obtained from 50 individuals diagnosed with hypercholesterolemia was genotyped using light SNiP hybridization probes. Results Low vit D levels were associated with SAM (OR=3.6, p=0.03); however, CK levels, rs2306283A>G, and rs4149056T>C did not show any association. Interestingly, rs4149056T>C was interacting with vit D to influence SAM (p=0.02). Haplotype analysis showed that SLCO1B1 *1B and *15 were more prevalent in individuals with SAM (p=0.05). When stratified according to vit D levels, rs2306283A allele showed an increase in individuals having SAM along with low vit D (p=0.03). Conclusions Although preliminary, our results show an involvement of vit D and rs4149056T>C of SLCO1B1 in SAM.

  1. Induction of CYP1A1 and CYP1B1 by benzo(k)fluoranthene and benzo(a)pyrene in T-47D human breast cancer cells: Roles of PAH interactions and PAH metabolites

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

    Spink, David C.; Wu, Susan J.; Spink, Barbara C.

    2008-02-01

    The interactions of polycyclic aromatic hydrocarbons (PAH) and cytochromes P450 (CYP) are complex; PAHs are enzyme inducers, substrates, and inhibitors. In T-47D breast cancer cells, exposure to 0.1 to 1 {mu}M benzo(k)fluoranthene (BKF) induced CYP1A1/1B1-catalyzed 17{beta}-estradiol (E{sub 2}) metabolism, whereas BKF levels greater than 1 {mu}M inhibited E{sub 2} metabolism. Time course studies showed that induction of CYP1-catalyzed E{sub 2} metabolism persisted after the disappearance of BKF or co-exposed benzo(a)pyrene, suggesting that BKF metabolites retaining Ah receptor agonist activity were responsible for prolonged CYP1 induction. BKF metabolites were shown, through the use of ethoxyresorufin O-deethylase and CYP1A1-promoter-luciferase reporter assays tomore » induce CYP1A1/1B1 in T-47D cells. Metabolites formed by oxidation at the C-2/C-3 region of BKF had potencies for CYP1 induction exceeding those of BKF, whereas C-8/C-9 oxidative metabolites were somewhat less potent than BKF. The activities of expressed human CYP1A1 and 1B1 with BKF as substrate were investigated by use of HPLC with fluorescence detection, and by GC/MS. The results showed that both enzymes efficiently catalyzed the formation of 3-, 8-, and 9-OHBKF from BKF. These studies indicate that the inductive effects of PAH metabolites as potent CYP1 inducers are likely to be additional important factors in PAH-CYP interactions that affect metabolism and bioactivation of other PAHs, ultimately modulating PAH toxicity and carcinogenicity.« less

  2. 26 CFR 1.280B-1 - Demolition of structures.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Demolition of structures. 1.280B-1 Section 1... (CONTINUED) INCOME TAXES Items Not Deductible § 1.280B-1 Demolition of structures. (a) In general. Section 280B provides that, in the case of the demolition of any structure, no deduction otherwise allowable...

  3. Knockdown of synaptic scaffolding protein Homer 1b/c attenuates secondary hyperalgesia induced by complete Freund's adjuvant in rats.

    PubMed

    Yao, Yong-Xing; Jiang, Zhen; Zhao, Zhi-Qi

    2011-12-01

    Previous studies have demonstrated that Homer 1b/c, a postsynaptic molecular scaffolding protein that binds and clusters metabotropic glutamate receptors at neuronal synapses, has an important role in the metabotropic glutamate receptor signaling process. In the current study, we investigated the possible involvement of Homer 1b/c in secondary hyperalgesia induced by complete Freund's adjuvant (CFA). Chronic inflammation was induced by injecting CFA into the left hind ankle of Wistar rats. Homer 1b/c antisense or missense oligonucleotides were intrathecally administrated (antisense, 10 μg/10 μL, 5 μg/10 μL, or 2.5 μg/10 μL, once a day; missense, 10 μg/10 μL) from 5 to 8 days after the onset of inflammation. The withdrawal threshold and withdrawal latency to mechanical or thermal stimuli were determined before and after the intrathecal administration. The expression and distribution of Homer 1b/c were examined in the spinal cord using immunological techniques. Mechanical allodynia and thermal hyperalgesia were induced within 24 hours and maintained for >2 weeks after the CFA injection. The expression of Homer 1b/c reached the highest level 7 days after inflammation and returned to baseline at day 28. Intrathecal administration of Homer 1b/c antisense oligonucleotides markedly reduced the expression of Homer 1b/c protein in the spinal cord. Additionally, administration of Homer 1b/c antisense oligonucleotides attenuated secondary mechanical hypersensitization on days 2 to 5 and reduced thermal hypersensitization on days 3 to 4. There were no effects of missense oligonucleotides on hypersensitization and the expression of Homer 1b/c. In the naïve rats, Homer 1b/c antisense oligonucleotides did not affect the mechanical and thermal responses or locomotor activity. These novel results demonstrate that Homer 1b/c in the spinal cord contributes to the maintenance of secondary hyperalgesia induced by CFA and suggest that Homer 1b/c may be a novel target for pain

  4. Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B.

    PubMed

    Wiese, Jutta; Aldemir, Hülya; Schmaljohann, Rolf; Gulder, Tobias A M; Imhoff, Johannes F

    2017-06-21

    In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillus sydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B ( 1 ) contains an additional phenolic hydroxy function at C-6 and exhibits an IC 50 value against PTP1B of 2 μM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin ( 2 ) did not show any inhibition of this enzymatic activity. Asperentin B ( 1 ) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness.

  5. Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B

    PubMed Central

    Wiese, Jutta; Aldemir, Hülya; Schmaljohann, Rolf; Gulder, Tobias A. M.; Imhoff, Johannes F.

    2017-01-01

    In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillus sydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B (1) contains an additional phenolic hydroxy function at C-6 and exhibits an IC50 value against PTP1B of 2 μM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin (2) did not show any inhibition of this enzymatic activity. Asperentin B (1) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness. PMID:28635658

  6. Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3.

    PubMed

    Gozalpour, Elnaz; Greupink, Rick; Wortelboer, Heleen M; Bilos, Albert; Schreurs, Marieke; Russel, Frans G M; Koenderink, Jan B

    2014-06-02

    Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO-NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK-OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of β-estradiol 17-β-d-glucuronide (E217βG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 μM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 μM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12

  7. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase.

    PubMed

    Stein, E; Huynh-Do, U; Lane, A A; Cerretti, D P; Daniel, T O

    1998-01-16

    Eph family receptor tyrosine kinases signal axonal guidance, neuronal bundling, and angiogenesis; yet the signaling systems that couple these receptors to targeting and cell-cell assembly responses are incompletely defined. Functional links to regulators of cytoskeletal structure are anticipated based on receptor mediated cell-cell aggregation and migratory responses. We used two-hybrid interaction cloning to identify EphB1-interactive proteins. Six independent cDNAs encoding the SH2 domain of the adapter protein, Nck, were recovered in a screen of a murine embryonic library. We mapped the EphB1 subdomain that binds Nck and its Drosophila homologue, DOCK, to the juxtamembrane region. Within this subdomain, Tyr594 was required for Nck binding. In P19 embryonal carcinoma cells, activation of EphB1 (ELK) by its ligand, ephrin-B1/Fc, recruited Nck to native receptor complexes and activated c-Jun kinase (JNK/SAPK). Transient overexpression of mutant EphB1 receptors (Y594F) blocked Nck recruitment to EphB1, attenuated downstream JNK activation, and blocked cell attachment responses. These findings identify Nck as an important intermediary linking EphB1 signaling to JNK.

  8. Different patterns of supramolecular assembly in constitutionally similar 6-arylimidazo[2,1-b][1,3,4]thiadiazoles.

    PubMed

    Praveen, Aletti S; Yathirajan, Hemmige S; Kaur, Manpreet; Narayana, Badiadka; Hosten, Eric C; Betz, Richard; Glidewell, Christopher

    2014-09-01

    Four imidazo[2,1-b][1,3,4]thiadiazoles containing a simply-substituted 6-aryl group have been synthesized by reaction of 2-amino-1,3,4-thiadiazoles with bromoacetylarenes using microwave irradiation and brief reaction times. 6-(2-Chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole, C(10)H(6)ClN(3)S, (I), 6-(2-chlorophenyl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole, C(11)H(8)ClN(3)S, (II), 6-(3,4-dichlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole, C(10)H(5)Cl(2)N(3)S, (III), and 6-(4-fluoro-3-methoxyphenyl)-2-methylimidazo[2,1-b][1,3,4]thiadiazole, C(12)H(10)FN(3)OS, (IV), crystallize with Z' values of 2, 1, 1 and 2 respectively. The molecular skeletons are all nearly planar and the dihedral angles between the imidazole and aryl rings are 1.51 (8) and 7.28 (8)° in (I), 9.65 (7)° in (II), 10.44 (8)° in (III), and 1.05 (8) and 7.21 (8)° in (IV). The molecules in (I) are linked by three independent C-H...N hydrogen bonds to form ribbons containing alternating R2(2)(8) and R4(4)(18) rings, and these ribbons are linked into a three-dimensional array by three independent π-stacking interactions. Both (II) and (III) contain centrosymmetric dimers formed by π-stacking interactions but hydrogen bonds are absent, and the molecules of (IV) are linked into centrosymmetric R2(2)(8) dimers by C-H...N hydrogen bonds. Comparisons are made with a number of related compounds.

  9. Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB.

    PubMed

    Hutchinson, Catherine L; Lowe, Peter N; McLaughlin, Stephen H; Mott, Helen R; Owen, Darerca

    2013-11-12

    Protein kinase C-related kinases (PRKs) are members of the protein kinase C superfamily of serine-threonine kinases and can be activated by binding to members of the Rho family of GTPases via a Rho-binding motif known as an HR1 domain. Three tandem HR1 domains reside at the N-terminus of the PRKs. We have assessed the ability of the HR1a and HR1b domains from the three PRK isoforms (PRK1, PRK2, and PRK3) to interact with the three Rho isoforms (RhoA, RhoB, and RhoC). The affinities of RhoA and RhoC for a construct encompassing both PRK1 HR1 domains were similar to those for the HR1a domain alone, suggesting that these interactions are mediated solely by the HR1a domain. The affinities of RhoB for both the PRK1 HR1a domain and the HR1ab didomain were higher than those of RhoA or RhoC. RhoB also bound more tightly to the didomain than to the HR1a domain alone, implicating the HR1b domain in the interaction. As compared with PRK1 HR1 domains, PRK2 and PRK3 domains bind less well to all Rho isoforms. Uniquely, however, the PRK3 domains display a specificity for RhoB that requires both the C-terminus of RhoB and the PRK3 HR1b domain. The thermal stability of the HR1a and HR1b domains was also investigated. The PRK2 HR1a domain was found to be the most thermally stable, while PRK2 HR1b, PRK3 HR1a, and PRK3 HR1b domains all exhibited lower melting temperatures, similar to that of the PRK1 HR1a domain. The lower thermal stability of the PRK2 and PRK3 HR1b domains may impart greater flexibility, driving their ability to interact with Rho isoforms.

  10. EXAFS spectrum peculiarities of Y 1- xYb xNi 2B 2C

    NASA Astrophysics Data System (ADS)

    Cortes, R.; Fomicheva, L. N.; Menushenkov, A. P.; Meyer-Klaucke, W.; Konarev, P. V.; Tsvyashchenko, A. V.

    2001-09-01

    The results on the temperature dependent EXAFS studies of the local structure peculiarities of Y 1- xYb xNi 2B 2C series synthesized at a high pressure of 8 GPa are presented. The interrelation between the local structure of Y 1- xYb xNi 2B 2C and its superconducting and magnetic properties was observed supporting the model where the contributions from all type of the nearest atoms to the electron-phonon coupling are important and cannot be neglected.

  11. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

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

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 andmore » CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO

  12. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 3 2013-04-01 2013-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation...

  13. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 3 2011-04-01 2011-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation...

  14. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 3 2014-04-01 2014-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation...

  15. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 3 2012-04-01 2012-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES (CONTINUED) Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation...

  16. Low-energy hydrogen uptake by small-cage C n and C n-1B fullerenes

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

    Dominguez-Gutierrez, F. Javier; Krstic, Predrag S.; Irle, Stephan

    We present a theoretical study of the hydrogen uptake capability of carbon fullerene cages Cn and their boron-doped heterofullerene equivalents C n-1B, with n = 20, 40, and 60, irradiated by hydrogen atoms in an impact energy range of 0.1–100 eV. In order to predict exohedral and endohedral hydrogen captures as well as the scattering probability of hydrogen for various cage types and sizes, we perform quantum-classical molecular dynamics (QCMD) calculations using the self-consistent-charge density-functional tight-binding (SCC-DFTB) method. Maximum endohedral hydrogen capture probabilities of 20% for n = 60 and 14% for n = 40 are found at impact energiesmore » close to 15 eV for both C n and C n-1B systems. For n = 20, however, endohedral capture is observed at a maximum of 2%, while the exohedral capture reaches a maximum of 5% both at 15 eV. Similar results for the hydrogen capture are obtained by classical molecular dynamics based on the ReaxFF potential. Lastly, the stopping cross section per carbon atom from the QCMD simulations for all cage sizes displays a linear dependence on the projectile velocity with a threshold at 0.8 eV, and extrapolates well to the available theoretical data.« less

  17. Low-energy hydrogen uptake by small-cage C n and C n-1B fullerenes

    DOE PAGES

    Dominguez-Gutierrez, F. Javier; Krstic, Predrag S.; Irle, Stephan; ...

    2018-08-29

    We present a theoretical study of the hydrogen uptake capability of carbon fullerene cages Cn and their boron-doped heterofullerene equivalents C n-1B, with n = 20, 40, and 60, irradiated by hydrogen atoms in an impact energy range of 0.1–100 eV. In order to predict exohedral and endohedral hydrogen captures as well as the scattering probability of hydrogen for various cage types and sizes, we perform quantum-classical molecular dynamics (QCMD) calculations using the self-consistent-charge density-functional tight-binding (SCC-DFTB) method. Maximum endohedral hydrogen capture probabilities of 20% for n = 60 and 14% for n = 40 are found at impact energiesmore » close to 15 eV for both C n and C n-1B systems. For n = 20, however, endohedral capture is observed at a maximum of 2%, while the exohedral capture reaches a maximum of 5% both at 15 eV. Similar results for the hydrogen capture are obtained by classical molecular dynamics based on the ReaxFF potential. Lastly, the stopping cross section per carbon atom from the QCMD simulations for all cage sizes displays a linear dependence on the projectile velocity with a threshold at 0.8 eV, and extrapolates well to the available theoretical data.« less

  18. 26 CFR 1.7702B-1 - Consumer protection provisions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 13 2011-04-01 2011-04-01 false Consumer protection provisions. 1.7702B-1 Section 1.7702B-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) General Actuarial Valuations § 1.7702B-1 Consumer protection...

  19. Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin

    PubMed Central

    Rose, R H; Neuhoff, S; Abduljalil, K; Chetty, M; Rostami-Hodjegan, A; Jamei, M

    2014-01-01

    Typically, pharmacokinetic–pharmacodynamic (PK/PD) models use plasma concentration as the input that drives the PD model. However, interindividual variability in uptake transporter activity can lead to variable drug concentrations in plasma without discernible impact on the effect site organ concentration. A physiologically based PK/PD model for rosuvastatin was developed that linked the predicted liver concentration to the PD response model. The model was then applied to predict the effect of genotype-dependent uptake by the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter on the pharmacological response. The area under the plasma concentration–time curve (AUC0–∞) was increased by 63 and 111% for the c.521TC and c.521CC genotypes vs. the c.521TT genotype, while the PD response remained relatively unchanged (3.1 and 5.8% reduction). Using local concentration at the effect site to drive the PD response enabled us to explain the observed disconnect between the effect of the OATP1B1 c521T>C polymorphism on rosuvastatin plasma concentration and the cholesterol synthesis response. PMID:25006781

  20. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation is a stapled...

  1. Superstructures with diverse morphologies and highly ordered fullerene C60 arrays from 1 : 1 and 2 : 1 adamantane-C60 hybrid molecules.

    PubMed

    Zhou, Shengju; Wang, Lin; Chen, Mengjun; Liu, Baoyong; Sun, Xiaofeng; Cai, Meirong; Li, Hongguang

    2017-11-02

    Superstructures from fullerene C 60 -containing compounds, especially those tethered to rigid functional groups with defined shapes, remain largely unexplored. Being the smallest diamondoid, adamantane (Ad) can be viewed as a promising building block for the construction of well-defined superstructures. Here, we report the syntheses of 1 : 1 (4a) and 2 : 1 (4b) Ad-C 60 hybrid molecules, which were then used to construct superstructures in binary solvent mixtures via a modified liquid/liquid interfacial precipitation (LLIP) method using CHCl 3 as a good solvent. Typically in the combination of DMSO/CHCl 3 with a final concentration (c f ) of 1.0 mmol L -1 , 4a successively forms spheres, plates, nanoflowers and plicated particles with increasing content of DMSO while 4b forms cuboid blocks and microparticles with hierarchically organized surfaces. Changing from DMSO to other poor solvents including acetone, MeOH and EtOAc leads to variations of the morphology of the superstructures for both 4a and 4b. At the nanometer length scale, 4a and 4b adopt different organizations within the superstructures. While 4a tends to self-organize into lamellae with highly ordered C 60 layers, the hexagonal phase is dominant in the superstructures formed by 4b. Wettability tests indicate that films formed by the superstructures of 4a and 4b show anti-wetting properties. Besides the solvent effect, the morphology of the superstructures can be also tuned by concentration. For example, when c f is lowered to 0.5 mmol L -1 , a new form of superstructure, i.e., fibers, was detected for 4a. Our results also indicate that besides the solvent-induced aggregate transition, gravity-induced sedimentation and subsequent structure ripening can have a significant influence on the final morphology of the superstructures and the aggregate transition pathways.

  2. HTR1B and HTR2C in autism spectrum disorders in Brazilian families.

    PubMed

    Orabona, G M; Griesi-Oliveira, K; Vadasz, E; Bulcão, V L S; Takahashi, V N V O; Moreira, E S; Furia-Silva, M; Ros-Melo, A M S; Dourado, F; Matioli, S R; Matioli, R; Otto, P; Passos-Bueno, M R

    2009-01-23

    Autism spectrum disorders (ASD) is a group of behaviorally defined neurodevelopmental disabilities characterized by multiple genetic etiologies and a complex presentation. Several studies suggest the involvement of the serotonin system in the development of ASD, but only few have investigated serotonin receptors. We have performed a case-control and a family-based study with 9 polymorphisms mapped to two serotonin receptor genes (HTR1B and HTR2C) in 252 Brazilian male ASD patients of European ancestry. These analyses showed evidence of undertransmission of the HTR1B haplotypes containing alleles -161G and -261A at HTR1B gene to ASD (P=0.003), but no involvement of HTR2C to the predisposition to this disease. Considering the relatively low level of statistical significance and the power of our sample, further studies are required to confirm the association of these serotonin-related genes and ASD.

  3. Structure of a BMI-1-Ring1B Polycomb Group Ubiquitin Ligase Complex

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

    Li,Z.; Cao, R.; Wang, M.

    2006-01-01

    Polycomb group (PcG) proteins Bmi-1 and Ring1B are core subunits of the PRC1 complex which plays important roles in the regulation of Hox gene expression, X-chromosome inactivation, tumorigenesis and stem cell self-renewal. The RING finger protein Ring1B is an E3 ligase that participates in the ubiquitination of lysine 119 of histone H2A, and the binding of Bmi-1 stimulates the E3 ligase activity. We have mapped the regions of Bmi-1 and Ring1B required for efficient ubiquitin transfer and determined a 2.5 Angstroms structure of the Bmi-1-Ring1B core domain complex. The structure reveals that Ring1B 'hugs' Bmi-1 through extensive RING domain contactsmore » and its N-terminal tail wraps around Bmi-1. The two regions of interaction have a synergistic effect on the E3 ligase activity. Our analyses suggest a model where the Bmi-1-Ring1B complex stabilizes the interaction between the E2 enzyme and the nucleosomal substrate to allow efficient ubiquitin transfer.« less

  4. Asymmetric Dual-Band Tracking Technique for Optimal Joint Processing of BDS B1I and B1C Signals.

    PubMed

    Wang, Chuhan; Cui, Xiaowei; Ma, Tianyi; Zhao, Sihao; Lu, Mingquan

    2017-10-16

    Along with the rapid development of the Global Navigation Satellite System (GNSS), satellite navigation signals have become more diversified, complex, and agile in adapting to increasing market demands. Various techniques have been developed for processing multiple navigation signals to achieve better performance in terms of accuracy, sensitivity, and robustness. This paper focuses on a technique for processing two signals with separate but adjacent center frequencies, such as B1I and B1C signals in the BeiDou global system. The two signals may differ in modulation scheme, power, and initial phase relation and can be processed independently by user receivers; however, the propagation delays of the two signals from a satellite are nearly identical as they are modulated on adjacent frequencies, share the same reference clock, and undergo nearly identical propagation paths to the receiver, resulting in strong coherence between the two signals. Joint processing of these signals can achieve optimal measurement performance due to the increased Gabor bandwidth and power. In this paper, we propose a universal scheme of asymmetric dual-band tracking (ASYM-DBT) to take advantage of the strong coherence, the increased Gabor bandwidth, and power of the two signals in achieving much-reduced thermal noise and more accurate ranging results when compared with the traditional single-band algorithm.

  5. Stack Characterization in CryoSat Level1b SAR/SARin Baseline C

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

    CryoSat was launched on the 8th April 2010 and is the first European ice mission dedicated to the monitoring of precise changes in the thickness of polar ice sheets and floating sea ice. CryoSat is the first altimetry mission operating in SAR mode and it carries an innovative radar altimeter called the Synthetic Aperture Interferometric Altimeter (SIRAL), that transmits pulses at a high pulse repetition frequency thus making the received echoes phase coherent and suitable for azimuth processing. The current CryoSat IPF (Instrument Processing Facility), Baseline B, was released in operation in February 2012. After more than 2 years of development, the release in operations of the Baseline C is expected in the first half of 2015. It is worth recalling here that the CryoSat SAR/SARin IPF1 generates 20Hz waveforms in correspondence of an approximately equally spaced set of ground locations on the Earth surface, i.e. surface samples, and that a surface sample gathers a collection of single-look echoes coming from the processed bursts during the time of visibility. Thus, for a given surface sample, the stack can be defined as the collection of all the single-look echoes pointing to the current surface sample, after applying all the necessary range corrections. The L1B product contains the power average of all the single-look echoes in the stack: the multi-looked L1B waveform. This reduces the data volume, while removing some information contained in the single looks, useful for characterizing the surface and modelling the L1B waveform. To recover such information, a set of parameters has been added to the L1B product: the stack characterization or beam behaviour parameters. The stack characterization, already included in previous Baselines, has been reviewed and expanded in Baseline C. This poster describes all the stack characterization parameters, detailing what they represent and how they have been computed. In details, such parameters can be summarized in: - Stack

  6. 16 CFR Figure 1 to Part 1513 - Wedge Block for Tests in § 1513.4 (a), (b), and (c)

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Wedge Block for Tests in § 1513.4 (a), (b), and (c) 1 Figure 1 to Part 1513 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FEDERAL... Block for Tests in § 1513.4 (a), (b), and (c) ER22DE99.002 ...

  7. Polycyclic phloroglucinols as PTP1B inhibitors from Hypericum longistylum: Structures, PTP1B inhibitory activities, and interactions with PTP1B.

    PubMed

    Cao, Xiangrong; Yang, Xueyuan; Wang, Peixia; Liang, Yue; Liu, Feng; Tuerhong, Muhetaer; Jin, Da-Qing; Xu, Jing; Lee, Dongho; Ohizumi, Yasushi; Guo, Yuanqiang

    2017-12-01

    Protein tyrosine phosphatase 1B (PTP1B) has been regarded asa target for the research and development of new drugs to treat type II diabetes and PTP1B inhibitors are potential lead compounds for this type of new drugs. A phytochemical investigation to obtain new PTP1B inhibitors resulted in the isolation of four new phloroglucinols, longistyliones A-D (1-4) from the aerial parts of Hypericum longistylum. The structures of 1-4 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by comparing their experimental electronic circular dichroism (ECD) spectra with those calculated by the time-dependent density functional theory method. Compounds 1-4 possess a rare polycyclic phloroglucinol skeleton. The following biological evaluation revealed that all of the compounds showed PTP1B inhibitory effects. The further molecular docking studies indicated the strong interactions between these bioactive compounds with the PTP1B protein, which revealed the possible mechanism of PTP1B inhibition of bioactive compounds. All of the results implied that these compounds are potentially useful for the treatment of type II diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Photometric Analysis and Transit Times of TRAPPIST-1 B and C

    NASA Astrophysics Data System (ADS)

    Morris, Brett M.; Agol, Eric; Hawley, Suzanne L.

    2018-01-01

    TRAPPIST-1 hosts seven Earth-sized planets transiting an M8 star. We observed mid-transit times of each of the inner two planets with the Astrophysical Research Consortium (ARC) 3.5 m Telescope at Apache Point Observatory (APO) to help constrain the planet masses with transit timing variations, and we outline a procedure for analyzing transit observations of late-M stars with APO. The transit times of TRAPPIST-1 b and c are $\\mathrm{BJD}_{\\mathrm{TDB}} = 2457580.87634^{+0.00034}_{-0.00034}$ and $2457558.89477^{+0.00080}_{-0.00085}$, respectively, which will help constrain the planet masses.

  9. 26 CFR 1.468B-1 - Qualified settlement funds.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 6 2010-04-01 2010-04-01 false Qualified settlement funds. 1.468B-1 Section 1... (CONTINUED) INCOME TAXES Taxable Year for Which Deductions Taken § 1.468B-1 Qualified settlement funds. (a) In general. A qualified settlement fund is a fund, account, or trust that satisfies the requirements...

  10. Effects of cumin extract on oxLDL, paraoxanase 1 activity, FBS, total cholesterol, triglycerides, HDL-C, LDL-C, Apo A1, and Apo B in in the patients with hypercholesterolemia

    PubMed Central

    Samani, Keihan Ghatreh; Farrokhi, Effat

    2014-01-01

    Objectives Paraoxanase 1 (PON1) plays a protective role against the oxidative modification of plasma lipoproteins and hydrolyzes lipid peroxides in human atherosclerotic lesions. Cumin is the dried seed of the herb Cuminumcyminum that is known as Zeera in Iran. Cumin seeds contain flavonoids which are now generally recognized to have antioxidant activity and improve the antioxidant system. So, they possibly modify PON1 activity and oxidized low density lipoprotein (oxLDL) level. The present study was aimed to evaluate the effects of cumin extract supplementation on oxLDL, paraoxanase 1 activity, FBS, total cholesterol, triglycerides, High density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (Apo A1), and apolipoprotein B (Apo B)in the patients with hypercholesterolemia. Methodology A fasting venous blood sample was obtained from the voluntary persons before and 45±3 days after taking cumin. Glucose, total cholesterol, and triglycerides were assayed using standard enzymatic procedures. HDL-Cand LDL-C were measured by direct method and ApoA1 and ApoB levels by immunoturbidimeteric methods. The levels of arylesterase and paraoxanase activities in the samples were measured by photometry methods and oxLDL by enzyme-linked immunosorbent assay (ELISA) method. 3 to 5 drops of cumin extract were added to the patient’s diet three times a day based on manufacturer’s instruction for 45±3 days. The biochemical parameters were compared before and after taking cumin. Data were analyzed using paired Student’s t-test in SPSS statistical software (version 11.5). Results The results demonstrated that there was a significant decrease in the level of oxLDL after receiving cumin. Paraoxonase and arylesterase activities increased in serum after taking cumin extract. Conclusion Based on the results, cumin reduces oxLDL level and increases both paraoxonase and arylesterase activity. PMID:24899878

  11. Phosphatidylserine Stimulates Ceramide 1-Phosphate (C1P) Intermembrane Transfer by C1P Transfer Proteins.

    PubMed

    Zhai, Xiuhong; Gao, Yong-Guang; Mishra, Shrawan K; Simanshu, Dhirendra K; Boldyrev, Ivan A; Benson, Linda M; Bergen, H Robert; Malinina, Lucy; Mundy, John; Molotkovsky, Julian G; Patel, Dinshaw J; Brown, Rhoderick E

    2017-02-10

    Genetic models for studying localized cell suicide that halt the spread of pathogen infection and immune response activation in plants include Arabidopsis accelerated-cell-death 11 mutant ( acd11 ). In this mutant, sphingolipid homeostasis is disrupted via depletion of ACD11, a lipid transfer protein that is specific for ceramide 1-phosphate (C1P) and phyto-C1P. The C1P binding site in ACD11 and in human ceramide-1-phosphate transfer protein (CPTP) is surrounded by cationic residues. Here, we investigated the functional regulation of ACD11 and CPTP by anionic phosphoglycerides and found that 1-palmitoyl-2-oleoyl-phosphatidic acid or 1-palmitoyl-2-oleoyl-phosphatidylglycerol (≤15 mol %) in C1P source vesicles depressed C1P intermembrane transfer. By contrast, replacement with 1-palmitoyl-2-oleoyl-phosphatidylserine stimulated C1P transfer by ACD11 and CPTP. Notably, "soluble" phosphatidylserine (dihexanoyl-phosphatidylserine) failed to stimulate C1P transfer. Also, none of the anionic phosphoglycerides affected transfer action by human glycolipid lipid transfer protein (GLTP), which is glycolipid-specific and has few cationic residues near its glycolipid binding site. These findings provide the first evidence for a potential phosphoglyceride headgroup-specific regulatory interaction site(s) existing on the surface of any GLTP-fold and delineate new differences between GLTP superfamily members that are specific for C1P versus glycolipid. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Hadronic production of the P-wave excited B{sub c} states (B{sub cJ,L=1}*)

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

    Chang, C.-H.; Institute of Theoretical Physics, Chinese Academy of Sciences, P.O. Box 2735, Beijing 100080; Wang, J.-X.

    2004-12-01

    Adopting the complete {alpha}{sub s}{sup 4} approach of the perturbative QCD and the updated parton distribution functions, we have estimated the hadronic production of the P-wave excited B{sub c} states (B{sub cJ,L=1}*). In the estimate, special care has been paid to the dependence of the production amplitude on the derivative of the wave function at origin which is obtained by the potential model. For experimental references, main theoretical uncertainties are discussed, and the total cross section as well as the distributions of the production with reasonable cuts at the energies of Tevatron and CERN LHC are computed and presented properly.more » The results show that the P-wave production may contribute to the B{sub c}-meson production indirectly by a factor of about 0.5 of the direct production, and according to the estimated cross section, it is further worthwhile to study the possibility of observing the P-wave production itself experimentally.« less

  13. ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-κB signaling activity

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

    Liu, Xin-Hua; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Bauman, William A.

    2015-08-14

    Transcription factors of the nuclear factor-kappa B (NF-κB) family play a pivotal role in inflammation, immunity and cell survival responses. Recent studies revealed that NF-κB also regulates the processes of muscle atrophy. NF-κB activity is regulated by various factors, including ankyrin repeat domain 2 (AnkrD2), which belongs to the muscle ankyrin repeat protein family. Another member of this family, AnkrD1 is also a transcriptional effector. The expression levels of AnkrD1 are highly upregulated in denervated skeletal muscle, suggesting an involvement of AnkrD1 in NF-κB mediated cellular responses to paralysis. However, the molecular mechanism underlying the interactive role of AnkrD1 inmore » NF-κB mediated cellular responses is not well understood. In the current study, we examined the effect of AnkrD1 on NF-κB activity and determined the interactions between AnkrD1 expression and NF-κB signaling induced by TNFα in differentiating C2C12 myoblasts. TNFα upregulated AnkrD1 mRNA and protein levels. AnkrD1-siRNA significantly increased TNFα-induced transcriptional activation of NF-κB, whereas overexpression of AnkrD1 inhibited TNFα-induced NF-κB activity. Co-immunoprecipitation studies demonstrated that AnkrD1 was able to bind p50 subunit of NF-κB and vice versa. Finally, CHIP assays revealed that AnkrD1 bound chromatin at a NF-κB binding site in the AnrkD2 promoter and required NF-κB to do so. These results provide evidence of signaling integration between AnkrD1 and NF-κB pathways, and suggest a novel anti-inflammatory role of AnkrD1 through feedback inhibition of NF-κB transcriptional activity by which AnkrD1 modulates the balance between physiological and pathological inflammatory responses in skeletal muscle. - Highlights: • AnkrD1 is upregulated by TNFα and represses NF-κB-induced transcriptional activity. • AnkrD1 binds to p50 subunit of NF-κB and is recruited to NF-κB bound to chromatin. • AnkrD1 mediates a feed

  14. Electronic Warfare Systems Career Ladder, AFSC 456X1A/B.

    DTIC Science & Technology

    1991-04-01

    En .. 𔃾- (AS L o t.. 4 - 0 L. 0 IXtC SL U41 .004- -C . W a 3 2 ) P- C XL x1. C4’ X O b .4 -J L. 0...2 Im 1m 1 AL/HRD/ID 1 1M lm/lh1 ARMY OCCUPATIONAL SURVEY BRANCH 1 CCAF/AYX 1 DEFENSE TECHNICAL INFORMATION CENTER 2 DE1 3 , USAFOMS (KEESLER AFB MS) 1...1 i HQ AFISC/DAP 2 HQ AFLC/DPMAE 3 HQ AFSC/DPAL 3 3 HQ AFSC/TTA 1 1 HQ ATC/DPAE 3 3 HQ ATC/TTOA 2 1 HQ ESC/DPTE 3 3 HQ ESC/TTA 1 1 HQ MAC/DPAT 3 3

  15. Isolation and properties of the subunit form EF-1C of elongation factor 1 from Guerin epithelioma cells.

    PubMed

    Marcinkiewicz, C; Gałasiński, W

    1993-01-01

    EF-1C is a component of the aggregate EF-1B, consisting of the subunit forms EF-1A.EF-1C; it was isolated by dissociation of this aggregate in the presence of GTP. The subunit form EF-1C stimulates binding of aminoacyl-tRNA to ribosomes, catalysed by EF-1A, similarly as EF-1 beta gamma which stimulates the activity of EF-1 in other eukaryotic cells. EF-1C in the presence of 6 M urea was separated into two polypeptides. Polypeptide of molecular mass 32,000 Da is responsible for regeneration of the EF-1A.GTP active complex. Thermal sensitivity of EF-1A was much higher than that of EF-1B, thus a protective role of EF-1C in the EF-1A.EF-1C complex is suggested.

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  17. Preference of Conjugated Bile Acids over Unconjugated Bile Acids as Substrates for OATP1B1 and OATP1B3

    PubMed Central

    Suga, Takahiro; Sato, Toshihiro; Maekawa, Masamitsu; Goto, Junichi; Mano, Nariyasu

    2017-01-01

    Bile acids, the metabolites of cholesterol, are signaling molecules that play critical role in many physiological functions. They undergo enterohepatic circulation through various transporters expressed in intestine and liver. Human organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of bile acids such as taurocholic acid. However, the transport properties of individual bile acids are not well understood. Therefore, we selected HEK293 cells overexpressing OATP1B1 and OATP1B3 to evaluate the transport of five major human bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, lithocholic acid) together withtheir glycine and taurine conjugates via OATP1B1 and OATP1B3. The bile acids were quantified by liquid chromatography-tandem mass spectrometry. The present study revealed that cholic acid, chenodeoxyxcholic acid, and deoxycholic acid were transported by OATP1B1 and OATP1B3, while ursodeoxycholic acid and lithocholic acid were not significantly transported by OATPs. However, all the conjugated bile acids were taken up rapidly by OATP1B1 and OATP1B3. Kinetic analyses revealed the involvement of saturable OATP1B1- and OATP1B3-mediated transport of bile acids. The apparent Km values for OATP1B1 and OATP1B3 of the conjugated bile acids were similar (0.74–14.7 μM for OATP1B1 and 0.47–15.3 μM for OATP1B3). They exhibited higher affinity than cholic acid (47.1 μM for OATP1B1 and 42.2 μM for OATP1B3). Our results suggest that conjugated bile acids (glycine and taurine) are preferred to unconjugated bile acids as substrates for OATP1B1 and OATP1B3. PMID:28060902

  18. Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism.

    PubMed

    Kalliokoski, A; Backman, J T; Kurkinen, K J; Neuvonen, P J; Niemi, M

    2008-10-01

    In a randomized crossover study, 24 SLCO181-genotyped healthy volunteers were given daily doses of 1,200 mg gemfibrozil, 40 mg atorvastatin, or placebo, followed by 0.25 mg of repaglinide on day 3. The mean increase in the repaglinide area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) produced by gemfibrozil was larger in individuals with the SLCO1B1 c.521CC genotype (n = 6) than in those with the c.521TC (n = 6) and c.521TT (n = 12) genotypes, by factors of 1.56 (P = 0.004) and 1.54 (P = 0.002), respectively. Gemfibrozil prolonged the repaglinide elimination half-life 1.43 times more in the c.521 CC group than in the c.521TT group (P = 0.047), but no differences were seen in the effects on peak plasma concentration (C(max)). While on gemfibrozil, the minimum blood glucose concentration after repaglinide intake was 19% lower in the c.521CC participants than in the c.521TT participants (P = 0.009). In the c.521TT group, atorvastatin intake had the effect of increasing repaglinide Cmax and AUC(0-infinity) by41% (P = 0.001) and 18% (P = 0.033), respectively. In conclusion, the extent of gemfibrozil-repaglinide interaction depends on SLCO1B1 genotype. Atorvastatin raises plasma repaglinide concentrations, probably by inhibiting organic anion transporting polypeptide 1B1 (OATP1B1).

  19. Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers.

    PubMed

    He, Jiake; Qiu, Zhixia; Li, Ning; Yu, Yang; Lu, Yang; Han, Deen; Li, Tingting; Zhao, Di; Sun, Wei; Fang, Fang; Zheng, Jianheng; Fan, Hongwei; Chen, Xijing

    2011-07-01

    Repaglinide is commonly used in the treatment of patients with type 2 diabetes mellitus to reduce postprandial hyperglycemia. The objective of this research was to study the effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. A total of 22 healthy young male participants were recruited from a pool of pharmacogenetically characterized participants genotyped for SLCO1B1, CYP3A4, and CYP2C8 SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Volunteers with CYP2C8*3 and CYP3A4*4 alleles were excluded from the clinical study. Then selected volunteers took part in the clinical pharmacokinetic study, receiving 2 mg repaglinide. Healthy participants with SLCO1B1*1A/*1B or *1A/*1A genotype and SLCO1B1 *15/*1A or *5/*1A genotype had significantly higher AUC(0-∞) than participants with SLCO1B1*1B/*1B genotype, with the former showing an increase over the latter of 39.81 and 42.09%, respectively (P = 0.028, 0.032). The clearance in the former two genotype groups was significantly attenuated (by 27.39 and 28.55%, respectively) compared with individuals with SLCO1B1*1B/*1B genotype (P = 0.015, 0.019). No significant differences in blood glucose-lowering effect were observed among three genotype groups. SLCO1B1*1B/*1B genotype is associated with reduced pharmacokinetic exposure after a single dose oral administration of 2 mg repaglinide, including decreased AUC(0-∞) and increased clearance of repaglinide. Moreover, this polymorphism of SLCO1B1 has significant influence on the pharmacokinetics of repaglinide, but no effects on its pharmacodynamics.

  20. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Quarantine policy. 73.1b Section 73.1b... Quarantine policy. Under the Animal Health Protection Act (7 U.S.C. 8301 et seq.), the Secretary may... interstate movement of cattle from such areas. It is the policy of the Department to quarantine those...

  1. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Quarantine policy. 73.1b Section 73.1b... Quarantine policy. Under the Animal Health Protection Act (7 U.S.C. 8301 et seq.), the Secretary may... interstate movement of cattle from such areas. It is the policy of the Department to quarantine those...

  2. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Quarantine policy. 73.1b Section 73.1b... Quarantine policy. Under the Animal Health Protection Act (7 U.S.C. 8301 et seq.), the Secretary may... interstate movement of cattle from such areas. It is the policy of the Department to quarantine those...

  3. 9 CFR 73.1b - Quarantine policy.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Quarantine policy. 73.1b Section 73.1b... Quarantine policy. Under the Animal Health Protection Act (7 U.S.C. 8301 et seq.), the Secretary may... interstate movement of cattle from such areas. It is the policy of the Department to quarantine those...

  4. Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1

    PubMed Central

    Xu, Zhiwei; Potula, Hari-Hara SK; Vallurupalli, Anusha; Perry, Daniel; Baker, Henry; Croker, Byron P.; Dozmorov, Igor; Morel, Laurence

    2013-01-01

    Sle2c1 is an NZM2410 and NZB-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18INK4c (p18), as the top candidate gene for inducing the Slec2c1 associated expansion of B1a cells. A novel SNP in the NZB allele of the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and Pc B1a cells from Sle2c1-carrying mice, which leads to a defective G1 cell cycle arrest in splenic B cells and increased proliferation of Pc B1a cells. As cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c plays a critical role in B1a cell self-renewal, and that its impaired expression leads to an accumulation of these cells with high autoreactive potential. PMID:21543644

  5. Overexpression and enhanced specific activity of aldoketo reductases (AKR1B1 & AKR1B10) in human breast cancers.

    PubMed

    Reddy, K Ashok; Kumar, P Uday; Srinivasulu, M; Triveni, B; Sharada, K; Ismail, Ayesha; Reddy, G Bhanuprakash

    2017-02-01

    The incidence of breast cancer in India is on the rise and is rapidly becoming the primary cancer in Indian women. The aldoketo reductase (AKR) family has more than 190 proteins including aldose reductase (AKR1B1) and aldose reductase like protein (AKR1B10). Apart from liver cancer, the status of AKR1B1 and AKR1B10 with respect to their expression and activity has not been reported in other human cancers. We studied the specific activity and expression of AKR1B1 and AKR1B10 in breast non tumor and tumor tissues and in the blood. Fresh post-surgical breast cancer and non-cancer tissues and blood were collected from the subjects who were admitted for surgical therapy. Malignant, benign and pre-surgical chemotherapy samples were evaluated by histopathology scoring. Expression of AKR1B1 and AKR1B10 was carried out by immunoblotting and immunohistochemistry (IHC) while specific activity was determined spectrophotometrically. The specific activity of AKR1B1 was significantly higher in red blood cells (RBC) in all three grades of primary surgical and post-chemotherapy samples. Specific activity of both AKR1B1 and AKR1B10 increased in tumor samples compared to their corresponding non tumor samples (primary surgical and post-chemotherapy). Immunoblotting and IHC data also indicated overexpression of AKR1B1 in all grades of tumors compared to their corresponding non tumor samples. There was no change in the specific activity of AKR1B1 in benign samples compared to all grades of tumor and non-tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.

    PubMed

    Zinker, Bradley A; Rondinone, Cristina M; Trevillyan, James M; Gum, Rebecca J; Clampit, Jill E; Waring, Jeffrey F; Xie, Nancy; Wilcox, Denise; Jacobson, Peer; Frost, Leigh; Kroeger, Paul E; Reilly, Regina M; Koterski, Sandra; Opgenorth, Terry J; Ulrich, Roger G; Crosby, Seth; Butler, Madeline; Murray, Susan F; McKay, Robert A; Bhanot, Sanjay; Monia, Brett P; Jirousek, Michael R

    2002-08-20

    The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes.

  7. 26 CFR 1.50B-1 - Definitions of WIN expenses and WIN employees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... employee. (c) Trade or business expenses. The term “WIN expenses” includes only salaries and wages which... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Definitions of WIN expenses and WIN employees. 1... INCOME TAXES Rules for Computing Credit for Expenses of Work Incentive Programs § 1.50B-1 Definitions of...

  8. Cyp1b1 Regulates Ocular Fissure Closure Through a Retinoic Acid–Independent Pathway

    PubMed Central

    Williams, Antionette L.; Eason, Jessica; Chawla, Bahaar; Bohnsack, Brenda L.

    2017-01-01

    Purpose Mutations in the CYP1B1 gene are the most commonly identified genetic causes of primary infantile-onset glaucoma. Despite this disease association, the role of CYP1B1 in eye development and its in vivo substrate remain unknown. In the present study, we used zebrafish to elucidate the mechanism by which cyp1b1 regulates eye development. Methods Zebrafish eye and neural crest development were analyzed using live imaging of transgenic zebrafish embryos, in situ hybridization, immunostaining, TUNEL assay, and methylacrylate sections. Cyp1b1 and retinoic acid (RA) levels were genetically (morpholino oligonucleotide antisense and mRNA) and pharmacologically manipulated to examine gene function. Results Using zebrafish, we observed that cyp1b1 was expressed in a specific spatiotemporal pattern in the ocular fissures of the developing zebrafish retina and regulated fissure patency. Decreased Cyp1b1 resulted in the premature breakdown of laminin in the ventral fissure and altered subsequent neural crest migration into the anterior segment. In contrast, cyp1b1 overexpression inhibited cell survival in the ventral ocular fissure and prevented fissure closure via an RA-independent pathway. Cyp1b1 overexpression also inhibited the ocular expression of vsx2, pax6a, and pax6b and increased the extraocular expression of shha. Importantly, embryos injected with human wild-type but not mutant CYP1B1 mRNA also showed colobomas, demonstrating the evolutionary and functional conservation of gene function between species. Conclusions Cyp1b1 regulation of ocular fissure closure indirectly affects neural crest migration and development through an RA-independent pathway. These studies provide insight into the role of Cyp1b1 in eye development and further elucidate the pathogenesis of primary infantile-onset glaucoma. PMID:28192799

  9. The Metastasis Efficiency Modifier Ribosomal RNA Processing 1 Homolog B (RRP1B) Is a Chromatin-associated Factor*

    PubMed Central

    Crawford, Nigel P. S.; Yang, Hailiu; Mattaini, Katherine R.; Hunter, Kent W.

    2009-01-01

    There is accumulating evidence for a role of germ line variation in breast cancer metastasis. We have recently identified a novel metastasis susceptibility gene, Rrp1b (ribosomal RNA processing 1 homolog B). Overexpression of Rrp1b in a mouse mammary tumor cell line induces a gene expression signature that predicts survival in breast cancer. Here we extend the analysis of RRP1B function by demonstrating that the Rrp1b activation gene expression signature accurately predicted the outcome in three of four publicly available breast carcinoma gene expression data sets. In addition, we provide insights into the mechanism of RRP1B. Tandem affinity purification demonstrated that RRP1B physically interacts with many nucleosome binding factors, including histone H1X, poly(ADP-ribose) polymerase 1, TRIM28 (tripartite motif-containing 28), and CSDA (cold shock domain protein A). Co-immunofluorescence and co-immunoprecipitation confirmed these interactions and also interactions with heterochromatin protein-1α and acetyl-histone H4 lysine 5. Finally, we investigated the effects of ectopic expression of an RRP1B allelic variant previously associated with improved survival in breast cancer. Gene expression analyses demonstrate that, compared with ectopic expression of wild type RRP1B in HeLa cells, the variant RRP1B differentially modulates various transcription factors controlled by TRIM28 and CSDA. These data suggest that RRP1B, a tumor progression and metastasis susceptibility candidate gene, is potentially a dynamic modulator of transcription and chromatin structure. PMID:19710015

  10. Interleukin 1B variant -1473G/C (rs1143623) influences triglyceride and interleukin 6 metabolism.

    PubMed

    Delgado-Lista, Javier; Garcia-Rios, Antonio; Perez-Martinez, Pablo; Solivera, Juan; Yubero-Serrano, Elena M; Fuentes, Francisco; Parnell, Laurence D; Shen, Jian; Gomez, Purificacion; Jimenez-Gomez, Yolanda; Gomez-Luna, Maria J; Marin, Carmen; Belisle, Sarah E; Rodriguez-Cantalejo, Fernando; Meydani, Simin N; Ordovas, Jose M; Perez-Jimenez, Francisco; Lopez-Miranda, Jose

    2011-05-01

    IL1b (IL1B or IL1β), a key modulator of the immune response, exerts its functions mainly via IL6 regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susceptibility. We evaluated the influence of a genetic variant located in the promoter region of IL1B (-1473G/C) on fasting and postprandial lipids and IL6. A total of 477 people over age 65 yr were genotyped for IL1B -1473G/C, and we evaluated fasting lipids depending on genotype. Then, 88 healthy young men were also genotyped and were fed a saturated fatty acid-rich meal. Serial blood samples were drawn for 11 h after the meal, and lipid fractions and IL6 were assayed. MAIN OUTCOME AND INTERVENTIONS: Fasting lipids were studied in the aged persons. Fasting and postprandial measurements of lipids and IL6 were performed in the healthy young men. In the aged persons, CC subjects (minor allele homozygotes) showed higher triglyceride (P = 0.002) and cholesterol (P = 0.011) levels. Healthy young male carriers of the minor C allele showed higher postprandial triglycerides (P = 0.037), and those carried into large triglyceride-rich lipoproteins (P = 0.004). In addition, they showed higher postprandial IL6 concentrations (P = 0.008). Our work shows that inflammatory genes may regulate fasting and postprandial lipids because the carriers of the minor allele of an IL gene variant have altered lipid metabolism. To reinforce these gene-phenotype findings, IL6 (the natural effector of IL1B) was increased in these persons.

  11. Regulatory single nucleotide polymorphisms (rSNPs) at the promoters 1A and 1B of the human APC gene.

    PubMed

    Matveeva, Marina Yu; Kashina, Elena V; Reshetnikov, Vasily V; Bryzgalov, Leonid O; Antontseva, Elena V; Bondar, Natalia P; Merkulova, Tatiana I

    2016-12-22

    Germline mutations in the coding sequence of the tumour suppressor APC gene give rise to familial adenomatous polyposis (which leads to colorectal cancer) and are associated with many other oncopathologies. The loss of APC function because of deletion of putative promoter 1A or 1B also results in the development of colorectal cancer. Since the regions of promoters 1A and 1B contain many single nucleotide polymorphisms (SNPs), the aim of this study was to perform functional analysis of some of these SNPs by means of an electrophoretic mobility shift assay (EMSA) and a luciferase reporter assay. First, it was shown that both putative promoters of APC (1A and 1B) drive transcription in an in vitro reporter experiment. From eleven randomly selected SNPs of promoter 1A and four SNPs of promoter 1B, nine and two respectively showed differential patterns of binding of nuclear proteins to oligonucleotide probes corresponding to alternative alleles. The luciferase reporter assay showed that among the six SNPs tested, the rs75612255 C allele and rs113017087 C allele in promoter 1A as well as the rs138386816 T allele and rs115658307 T allele in promoter 1B significantly increased luciferase activity in the human erythromyeloblastoid leukaemia cell line K562. In human colorectal cancer HCT-116 cells, none of the substitutions under study had any effect, with the exception of minor allele G of rs79896135 in promoter 1B. This allele significantly decreased the luciferase reporter's activity CONCLUSION: Our results indicate that many SNPs in APC promoters 1A and 1B are functionally relevant and that allele G of rs79896135 may be associated with the predisposition to colorectal cancer.

  12. Trailblazer 1B Flight Preparations

    NASA Image and Video Library

    1959-06-04

    L59-3896 Engineers W. N. Gardner and C.A. Brown, Jr., check operations as Trailblazer 1b is readied for Flight, June 4, 1959. Photograph published in A New Dimension Wallops Island Flight Test Range: The First Fifteen Years by Joseph Shortal. A NASA publication, page 675. D58-3001 Model. Engineers W. N. Gardner and C.A. Brown

  13. Asymmetric Dual-Band Tracking Technique for Optimal Joint Processing of BDS B1I and B1C Signals

    PubMed Central

    Wang, Chuhan; Cui, Xiaowei; Ma, Tianyi; Lu, Mingquan

    2017-01-01

    Along with the rapid development of the Global Navigation Satellite System (GNSS), satellite navigation signals have become more diversified, complex, and agile in adapting to increasing market demands. Various techniques have been developed for processing multiple navigation signals to achieve better performance in terms of accuracy, sensitivity, and robustness. This paper focuses on a technique for processing two signals with separate but adjacent center frequencies, such as B1I and B1C signals in the BeiDou global system. The two signals may differ in modulation scheme, power, and initial phase relation and can be processed independently by user receivers; however, the propagation delays of the two signals from a satellite are nearly identical as they are modulated on adjacent frequencies, share the same reference clock, and undergo nearly identical propagation paths to the receiver, resulting in strong coherence between the two signals. Joint processing of these signals can achieve optimal measurement performance due to the increased Gabor bandwidth and power. In this paper, we propose a universal scheme of asymmetric dual-band tracking (ASYM-DBT) to take advantage of the strong coherence, the increased Gabor bandwidth, and power of the two signals in achieving much-reduced thermal noise and more accurate ranging results when compared with the traditional single-band algorithm. PMID:29035350

  14. Optimised purification and characterisation of lipid transfer protein 1 (LTP1) and its lipid-bound isoform LTP1b from barley malt.

    PubMed

    Nieuwoudt, Melanie; Lombard, Nicolaas; Rautenbach, Marina

    2014-08-15

    In beer brewing, brewers worldwide strive to obtain product consistency in terms of flavour, colour and foam. Important proteins contributing to beer foam are lipid transfer proteins (LTPs), in particular LTP1 and its lipid-bound isoform LTP1b, which are known to transport lipids in vivo and prevent lipids from destabilising the beer foam. LTP1 and LTP1b were successfully purified using only five purification steps with a high purified protein yield (160 mg LTP1 and LTP1b from 200 g barley). Circular dichroism of LTP1 and LTP1b confirmed that both proteins are highly tolerant to high temperatures (>90 °C) and are pH stable, particularly at a neutral to a more basic pH. Only LTP1 exhibited antiyeast and thermo-stable lytic activity, while LTP1b was inactive, indicating that the fatty acid moiety compromised the antimicrobial activity of LTP1. This lack in antiyeast activity and the positive foam properties of LTP1b would benefit beer fermentation and quality. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. NS3 genomic sequencing and phylogenetic analysis as alternative to a commercially available assay to reliably determine hepatitis C virus subtypes 1a and 1b

    PubMed Central

    Neukam, Karin; Martínez, Alfredo P.; Culasso, Andrés C. A.; Ridruejo, Ezequiel; García, Gabriel

    2017-01-01

    Objective To evaluate the use of hepatitis C virus (HCV) NS3 sequencing as alternative to the comercially available Versant HCV 2.0 reverse hybridization line-probe assay (LiPA 2.0) to determine HCV genotype 1 (HCV-1) subtypes. Patients and methods A cohort of 104 patients infected by HCV-1 according to LiPA 2.0 was analyzed in a cross-sectional study conducted in patients seen from January 2012 to June 2016 at an outpatient clinic in Buenos Aires, Argentina. Results The samples were included within well supported subtype clades: 64 with HCV-1b and 39 with HCV-1a infection. Twenty of the HCV-1a infected patientes were included in a supported sub-clade “1” and 19 individuals were among the basal sub-clade “2”. LiPA 2.0 failed to subtype HCV-1 in 20 (19.2%) individuals. Subtype classification determined by NS3 direct sequencing showed that 2/18 (11.1%) of the HCV-1a-infected patients as determined by LiPA 2.0 were in fact infected by HCV-1b. Of the HCV-1b-infected according to LiPA 2.0, 10/66 (15.2%) patients showed HCV-1a infection according to NS3 sequencing. Overall misclassification was 14.3% (κ-index for the concordance with NS3 sequencing = 0.635). One (1%) patient was erroneously genotyped as HCV-1 and was revealed as HCV genotype 4 infection. Conclusions Genomic sequencing of the HCV NS3 region represents an adequate alternative since it provides reliable genetic information. It even distinguishes between HCV-1a clades related to resistance-associated substitutions to HCV protease inhibitors, it provides reliable genetic information for genotyping/subgenotyping and simultaneously allows to determine the presence of resistance-associated substitutions to currently recommended DAAs. PMID:28753662

  16. Shikonin regulates C-MYC and GLUT1 expression through the MST1-YAP1-TEAD1 axis

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

    Vališ, Karel, E-mail: karel.valis@biomed.cas.cz; Faculty of Science, Charles University, Prague; Talacko, Pavel

    The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. We have found that two key regulators of glycolysis, C-MYC and GLUT1, are targets of the Hippo signaling pathway in human leukemia cells. Our results revealed that activation of MST1 by the natural compound shikonin inhibited the expression of GLUT1 and C-MYC. Furthermore, RNAi experiments confirmed the regulation of GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis. Surprisingly, YAP1 was found to positively regulate C-MYC mRNA levels in complexmore » with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Hence, YAP1 serves as a rheostat for C-MYC, which is regulated by MST1. In addition, depletion of MST1 stimulates lactate production, whereas the specific depletion of TEAD1 has an opposite effect. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. Finally, a bioinformatic analysis revealed conserved TEAD-binding motifs in the C-MYC and GLUT1 promoters providing another molecular data supporting our observations. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway. - Highlights: • Shikonin inhibits C-MYC and GLUT1 expression in MST1 and YAP1 dependent manner. • YAP1-TEAD1 interaction activates C-MYC and GLUT1 expression. • MST1 in cooperation with YAP1 inhibits C-MYC and GLUT1 expression. • MST1-YAP1-TEAD1 axis regulates lactate production by leukemic cells. • MST1 and YAP1 proteins block proliferation of leukemic cells.« less

  17. Structure determination of two structural analogs, named 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16F2N4S) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C23H16ClFN4S) by synchrotron X-ray powder diffraction

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

    Gündoğdu, Gülsüm; Aytaç, Sevim Peri; Müller, Melanie

    Two novel compounds, 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C 23H 16F 2N 4S) (1) and 3-[1-(2-fluoro-4-biphenyl)ethyl]-6-(4-chlorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (C 23H 16ClFN 4S) (2), have been designed and synthesized as cytotoxic agents. The compounds were characterized by infrared, proton nuclear magnetic resonance, mass spectral data, elemental analysis and X-ray powder diffraction. The present study comprises spectral data and crystal structures of these novel compounds determined from synchrotron X-ray powder diffraction data. The structure solutions were obtained by simulated annealing. The final structures were achieved by Rietveld refinement using soft restraints for all bond lengths, bond angles, and planar groups. Both compounds crystallize in space groupmore » $$P\\bar 1$$,Z= 2, with the unit-cell parametersa= 6.37433(9),b= 11.3641(2),c= 14.09115(19) Å,α= 80.1740(8)°,β= 85.1164(8)°,γ= 80.9831(10)°,V= 991.55(3) Å 3of compound (1) anda= 6.53736(6),b= 11.55725(15),c= 14.01373(13) Å,α= 80.3323(7)°,β= 84.8939(6)°,γ= 79.3954(8)°,V= 1024.08(2) Å 3of compound (2). Structural analyses reveal that the title compounds are isostructural.« less

  18. 26 CFR 1.1402(c)-3 - Employees.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... section 1402(c) and § 1.1402(c)-1. However, in six cases set forth in paragraphs (b) to (g), inclusive, of... Health, Education, and Welfare pursuant to section 218 of the Social Security Act at the time a fee is...

  19. Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer's Therapy?

    PubMed

    Vieira, Marcelo N N; Lyra E Silva, Natalia M; Ferreira, Sergio T; De Felice, Fernanda G

    2017-01-01

    Despite significant advances in current understanding of mechanisms of pathogenesis in Alzheimer's disease (AD), attempts at drug development based on those discoveries have failed to translate into effective, disease-modifying therapies. AD is a complex and multifactorial disease comprising a range of aberrant cellular/molecular processes taking part in different cell types and brain regions. As a consequence, therapeutics for AD should be able to block or compensate multiple abnormal pathological events. Here, we examine recent evidence that inhibition of protein tyrosine phosphatase 1B (PTP1B) may represent a promising strategy to combat a variety of AD-related detrimental processes. Besides its well described role as a negative regulator of insulin and leptin signaling, PTB1B recently emerged as a modulator of various other processes in the central nervous system (CNS) that are also implicated in AD. These include signaling pathways germane to learning and memory, regulation of synapse dynamics, endoplasmic reticulum (ER) stress and microglia-mediated neuroinflammation. We propose that PTP1B inhibition may represent an attractive and yet unexplored therapeutic approach to correct aberrant signaling pathways linked to AD.

  20. MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia.

    PubMed

    Tagde, Ashujit; Rajabi, Hasan; Stroopinsky, Dina; Gali, Reddy; Alam, Maroof; Bouillez, Audrey; Kharbanda, Surender; Stone, Richard; Avigan, David; Kufe, Donald

    2016-06-28

    Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression. In addition, MUC1 expression positively correlates with that of DNMT1 in primary AML cells, particularly the CD34+/CD38- population. The mechanistic basis for this relationship is supported by the demonstration that MUC1-C activates the NF-κB p65 pathway, promotes occupancy of the MUC1-C/NF-κB complex on the DNMT1 promoter and drives DNMT1 transcription. We also show that targeting MUC1-C substantially reduces gene promoter-specific DNA methylation, and derepresses expression of tumor suppressor genes, including CDH1, PTEN and BRCA1. In support of these results, we demonstrate that combining GO-203 with the DNMT1 inhibitor decitabine is highly effective in reducing DNMT1 levels and decreasing AML cell survival. These findings indicate that (i) MUC1-C is an attractive target for the epigentic reprogramming of AML cells, and (ii) targeting MUC1-C in combination with decitabine is a potentially effective clinical approach for the treatment of AML.

  1. 26 CFR 1.514(b)-1 - Definition of debt-financed property.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    .... Example 2. X, an exempt college, owns a four story office building which has been purchased with borrowed funds. In 1971, the lower two stories of the building are used to house computers which are used by X... in section 514(b)(1) (A), (B), (C), or (D). The gross income derived by X from the building is $6,000...

  2. 26 CFR 1.514(b)-1 - Definition of debt-financed property.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    .... Example 2. X, an exempt college, owns a four story office building which has been purchased with borrowed funds. In 1971, the lower two stories of the building are used to house computers which are used by X... in section 514(b)(1) (A), (B), (C), or (D). The gross income derived by X from the building is $6,000...

  3. 26 CFR 1.514(b)-1 - Definition of debt-financed property.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... Example 2. X, an exempt college, owns a four story office building which has been purchased with borrowed funds. In 1971, the lower two stories of the building are used to house computers which are used by X... in section 514(b)(1) (A), (B), (C), or (D). The gross income derived by X from the building is $6,000...

  4. 26 CFR 1.514(b)-1 - Definition of debt-financed property.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    .... Example 2. X, an exempt college, owns a four story office building which has been purchased with borrowed funds. In 1971, the lower two stories of the building are used to house computers which are used by X... in section 514(b)(1) (A), (B), (C), or (D). The gross income derived by X from the building is $6,000...

  5. 26 CFR 1.514(c)-1 - Acquisition indebtedness.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Acquisition indebtedness. 1.514(c)-1 Section 1.514(c)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Taxation of Business Income of Certain Exempt Organizations § 1.514(c)-1...

  6. Synthesis and Cytotoxic Evaluation of 1H-1,2,3-Triazol-1-ylmethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-diones.

    PubMed

    Chipoline, Ingrid C; Alves, Evelyne; Branco, Paola; Costa-Lotufo, Leticia V; Ferreira, Vitor F; Silva, Fernando C DA

    2018-01-01

    The 1,2-naphthoquinone compound was previously considered active against solid tumors. Moreover, glycosidase inhibitors such as 1,2,3-1H triazoles has been pointed out as efficient compounds in anticancer activity studies. Thus, a series of eleven 1,2-naphthoquinones tethered in C2 to 1,2,3-1H-triazoles 9a-k were designed, synthesized and their cytotoxic activity evaluated using HCT-116 (colon adenocarcinoma), MCF-7 (breast adenocarcinoma) and RPE (human nontumor cell line from retinal epithelium). The chemical synthesis was performed from C-3 allylation of lawsone followed by iodocyclization with subsequent nucleophilic displacement with sodium azide and, finally, the 1,3-dipolar cycloaddition catalyzed by Cu(I) with terminal alkynes led to the formation of 1H-1,2,3-Triazol-1-ylmethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-diones in good yields. Compounds containing aromatic group linked to 1,2,3-triazole ring (9c, 9d, 9e, 9i) presented superior cytotoxic activity against cancer cell lines with IC50 in the range of 0.74 to 4.4 µM indicating that the presence of aromatic rings substituents in the 1,2,3-1H-triazole moiety is probably responsible for the improved cytotoxic activity.

  7. Complementary DNA cloning and constitutive expression of cytochrome P450 1C1 in the gills of carp (Cyprinus carpio).

    PubMed

    Itakura, Takao; El-Kady, Mohamed; Mitsuo, Ryoichi; Kaminishi, Yoshio

    2005-01-01

    Cytochrome P450 (CYP) enzymes constitute a multigene family of many endogenous and xenobiotic substances. The CYP1 family is of particular interest in environmental toxicology because its members are dominant in the metabolism of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and aryl amines. A new complementary DNA of the CYP1C subfamily encoding CYP1C1 was isolated from carp liver after intraperitoneal injection of beta-napthoflavone (BNF). The full-length cDNA obtained contained a 5' noncoding region of 244 bp, an open reading frame of 1572 bp coding for 524 amino acids, a stop codon, and a 3' noncoding region of 965 bp. The predicted molecular weight of the protein was approximately 59.3 kDa. The deduced amino acid sequence of this cDNA was 82.1% and 80.2% similar to Japanese eel and scup CYP1C1 sequences, respectively, while it exhibited a similarity of 74.9% with the scup CYP1C2 sequence. The deduced amino acid sequence of carp CYP1C1 showed similarities with those of the reported CYP1B1s of teleosts and mammals of 48.4, 48.8, 48.2, 48.6, 45.3, and 45.5% for carp CYP1B1, carp CYP1B2, plaice CYP1B1, and human, rat, and mouse CYP1B1, respectively. The phylogenetic tree constructed using fish and mammalian CYP1 sequences suggested a closer relationship of the CYP1C subfamily to CYP1B than to CYP1A. The tree showed the possibility of the existence of CYP1C subfamily genes in mammalian species. Northern blot analysis for the liver, intestine, gills, and kidney showed no detectable induced expression but constitutive expression in the gill organs.

  8. DNA typing of HLA-A, -C, -B, AND -DRB1 in the children with autism in the Republic of Macedonia.

    PubMed

    Trajkovski, V; Spiroski, M

    2015-01-01

    In the present study, we report the first DNA analysis of HLA class I and class II alleles in Macedonian autistic subjects. We have analyzed the HLA-A, -C, -B, DRB1 genotypes of 35 autistic patients, and 98 healthy unrelated Macedonians (control group). HLA DNA typing of class I genes was performed using a Reverse Line Strip method (RLS), and the Sequencing Based Typing method (SBT) was used for typing of class II genes. In the autistic subjects for HLA-A locus 14 alleles have been identified with 2 being predominant *02 (25.7 %), and *24 (18.6 %). Among the 11 identified HLA-C alleles, 3 were predominant such as *12 (20.0 %), *07 (17.1 %), and *03 (12.9 %). Among the 18 identified HLA-B alleles, 2 were predominant: *51 (18.6 %), and *18 (11.4 %). For HLA-DRB1 locus, 10 alleles have been identified with 2 of them predominant such as: *11 (21.4 %), and *01 (14.3 %). The allele and haplotype frequencies in the patients group were compared to those of 98 control subjects. Our results showed significantly increased frequencies of HLA-C*03 (OR = 2.74*; χ2 = 4.68; p = 0.03), and HLA-DRB1*01 (OR = 3.10*; χ2 = 6.26; p = 0.012) alleles in autistic patients when compared to the controls. The most frequent haplotype frequencies in autistic sample were A*11-C*12-B*52-DRB1*15 (2.9 %), A*24-C*03-B*55-DRB1*16 (2.9 %), and A*24-C*03-B*55-DRB1*16 (2.9 %), but they were not statistically significant when compared to the control group. None of our patients carried allele or haplotype, which were protective in our population. Hardy-Weinberg equilibrium in autistic group showed that HLA-A (p < 0.03), HLA-C (p < 0.04), and HLA-DRB1 (p < 0.002) loci were in linkage disequilibria. In the control group, we found only for the HLA-DRB1 locus linkage disequilibrium (p < 0.002). Our results demonstrated the association of HLA-C*03 and HLA-DRB1*01 alleles with Macedonian autistic patients (Tab. 7, Ref. 37).

  9. Identification of O-methylsterigmatocystin as an aflatoxin B1 and G1 precursor in Aspergillus parasiticus.

    PubMed Central

    Bhatnagar, D; McCormick, S P; Lee, L S; Hill, R A

    1987-01-01

    An isolate of Aspergillus parasiticus CP461 (SRRC 2043) produced no detectable aflatoxins, but accumulated O-methylsterigmatocystin (OMST). When sterigmatocystin (ST) was fed to this isolate in a low-sugar medium, there was an increase in the accumulation of OMST, without aflatoxin synthesis. When radiolabeled [14C]OMST was fed to resting mycelia of a non-aflatoxin-, non-ST-, and non-OMST-producing mutant of A. parasiticus AVN-1 (SRRC 163), 14C-labeled aflatoxins B1 and G1 were produced; 10 nmol of OMST produced 7.8 nmol of B1 and 1.0 nmol of G1, while 10 nmol of ST produced 6.4 nmol of B1 and 0.6 nmol of G1. A time course study of aflatoxin synthesis in ST feeding experiments with AVN-1 revealed that OMST is synthesized by the mold during the onset of aflatoxin synthesis. The total amount of aflatoxins recovered from OMST feeding experiments was higher than from experiments in which ST was fed to the resting mycelia. These results suggest that OMST is a true metabolite in the aflatoxin biosynthetic pathway between sterigmatocystin and aflatoxins B1 and G1 and is not a shunt metabolite, as thought previously. PMID:3111363

  10. Comparison of genetic variations of the SLCO1B1, SLCO1B3, and SLCO2B1 genes among five ethnic groups.

    PubMed

    Namgoong, Suhg; Cheong, Hyun Sub; Kim, Ji On; Kim, Lyoung Hyo; Na, Han Sung; Koh, In Song; Chung, Myeon Woo; Shin, Hyoung Doo

    2015-11-01

    Organic anion-transporting polypeptide (OATP; gene symbol, SLCO) transporters are generally involved in the uptake of multiple drugs and their metabolites at most epithelial barriers. The pattern of single-nucleotide polymorphisms (SNPs) in these transporters may be determinants of interindividual variability in drug disposition and response. The objective of this study was to define the distribution of SNPs of three SLCO genes, SLCO1B1, SLCO1B3, and SLCO2B1, in a Korean population and other ethnic groups. The study was screened using the Illumina GoldenGate assay for genomic DNA from 450 interethnic subjects, including 11 pharmacogenetic core variants and 76 HapMap tagging SNPs. The genotype distribution of the Korean population was similar to East Asian populations, but significantly different from African American and European American cohorts. These interethnic differences will be useful information for prospective studies, including genetic association and pharmacogenetic studies of drug metabolism by SLCO families. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Peginterferon Lambda-1a/Ribavirin with Daclatasvir or Peginterferon Alfa-2a/Ribavirin with Telaprevir for Chronic Hepatitis C Genotype 1b.

    PubMed

    Flisiak, Robert; Kawazoe, Seiji; Znoyko, Olga; Assy, Nimer; Gadano, Adrian; Kao, Jia-Horng; Lee, Kwan-Sik; Zwirtes, Ricardo; Portsmouth, Simon; Dong, Yuping; Xu, Dong; Kumada, Hiromitsu; Srinivasan, Subasree

    2016-11-01

    The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P < 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

  12. Differential effects of Glycyrrhiza species on genotoxic estrogen metabolism: licochalcone A downregulates P450 1B1 whereas isoliquiritigenin stimulates

    PubMed Central

    Dunlap, Tareisha L.; Wang, Shuai; Simmler, Charlotte; Chen, Shao-Nong; Pauli, Guido F.; Dietz, Birgit M.; Bolton, Judy L.

    2015-01-01

    Estrogen chemical carcinogenesis involves 4-hydroxylation of estrone/estradiol (E1/E2) by P450 1B1, generating catechol and quinone genotoxic metabolites that cause DNA mutations and initiate/promote breast cancer. Inflammation enhances this effect by up-regulating P450 1B1. The present study tested the three authenticated medicinal species of licorice, [Glycyrrhiza glabra (GG), G. uralensis (GU), and G. inflata (GI)], used by women as dietary supplements, for their anti-inflammatory activities and their ability to modulate estrogen metabolism. The pure compounds, liquiritigenin (LigF), its chalcone isomer isoliquiritigenin (LigC), and the GI specific licochalcone A (LicA) were also tested. The licorice extracts and compounds were evaluated for anti-inflammatory activity by measuring inhibition of iNOS activity in macrophage cells: GI > GG > GU and LigC ≅ LicA > LigF. The Michael acceptor chalcone LicA, is likely responsible for the anti-inflammatory activity of GI. A sensitive LC-MS/MS assay was employed to quantify estrogen metabolism by measuring 2-MeOE1 as non-toxic and 4-MeOE1 as genotoxic biomarkers in the non-tumorigenic human mammary epithelial cell line, MCF-10A. GG, GU, and LigC increased 4-MeOE1, whereas GI and LicA inhibited 2- and 4-MeOE1 levels. GG, GU (5 μg/mL), and LigC (1 μM) also enhanced P450 1B1 expression and activities, which was further increased by inflammatory cytokines (TNF-α and IFN-γ). LicA (1 μM, 10 μM) decreased cytokine- and TCDD-induced, P450 1B1 gene expression and TCDD-induced xenobiotic response element luciferase reporter (IC50=12.3 μM), suggesting an antagonistic effect on the aryl hydrocarbon receptor, which regulates P450 1B1. Similarly, GI (5 μg/mL) reduced cytokine- and TCDD-induced P450 1B1 gene expression. Collectively, these data suggest that of the three licorice species that are used in botanical supplements, GI represents the most promising chemopreventive licorice extract for women’s health. Additionally

  13. Charmless hadronic B →(f1(1285 ),f1(1420 ))P decays in the perturbative QCD approach

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Xiao, Zhen-Jun; Li, Jing-Wu; Zou, Zhi-Tian

    2015-01-01

    We study 20 charmless hadronic B →f1P decays in the perturbative QCD (pQCD) formalism with B denoting Bu, Bd, and Bs mesons; P standing for the light pseudoscalar mesons; and f1 representing axial-vector mesons f1(1285 ) and f1(1420 ) that result from a mixing of quark-flavor f1 q[u/u ¯ +d d ¯ √{2 } ] and f1 s[s s ¯ ] states with the angle ϕf1.The estimations of C P -averaged branching ratios and C P asymmetries of the considered B →f1P decays, in which the Bs→f1P modes are investigated for the first time, are presented in the pQCD approach with ϕf 1˜24 ° from recently measured Bd /s→J /ψ f1(1285 ) decays. It is found that (a) the tree (penguin) dominant B+→f1π+(K+) decays with large branching ratios [O (10-6) ] and large direct C P violations (around 14%-28% in magnitude) simultaneously are believed to be clearly measurable at the LHCb and Belle II experiments; (b) the Bd→f1KS0 and Bs→f1(η ,η') decays with nearly pure penguin contributions and safely negligible tree pollution also have large decay rates in the order of 10-6- 10-5 , which can be confronted with the experimental measurements in the near future; (c) as the alternative channels, the B+→f1(π+,K+) and Bd→f1KS0 decays have the supplementary power in providing more effective constraints on the Cabibbo-Kobayashi-Maskawa weak phases α , γ , and β , correspondingly, which are explicitly analyzed through the large decay rates and the direct and mixing-induced C P asymmetries in the pQCD approach and are expected to be stringently examined by the measurements with high precision; (d) the weak annihilation amplitudes play important roles in the B+→f1(1420 )K+ , Bd→f1(1420 )KS0 , Bs→f1(1420 )η' decays, and so on, which would offer more evidence, once they are confirmed by the experiments, to identify the soft-collinear effective theory and the pQCD approach on the evaluations of annihilation diagrams and to help further understand the annihilation mechanism in the heavy

  14. Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus.

    PubMed

    Hori, Takanori; Barnor, Jacob; Huu, Tung Nguyen; Morinaga, Osamu; Hamano, Akiko; Ndzinu, Jerry; Frimpong, Angela; Minta-Asare, Keren; Amoa-Bosompem, Mildred; Brandful, James; Odoom, John; Bonney, Joseph; Tuffour, Isaac; Owusu, Baffour-Awuah; Ofosuhene, Mark; Atchoglo, Philip; Sakyiamah, Maxwell; Adegle, Richard; Appiah-Opong, Regina; Ampofo, William; Koram, Kwadwo; Nyarko, Alexander; Okine, Laud; Edoh, Dominic; Appiah, Alfred; Uto, Takuhiro; Yoshinaka, Yoshiyuki; Uota, Shin; Shoyama, Yukihiro; Yamaoka, Shoji

    2015-04-03

    Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

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

    Siddens, Lisbeth K.; Superfund Research Center, Oregon State University, Corvallis, OR 97331; Bunde, Kristi L.

    FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1,more » Nqo1 at 8 h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4 h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators. - Highlights: • Cyp1b1 null mice exhibit lower skin cancer sensitivity to DBC but not BaP or CTE. • Cyp1b1 expression impacts expression of other PAH metabolizing enzymes. • cis/trans-DBCDE-dA ratio significantly higher in the skin than the spleen, lung or liver • Potency of DBC and CTE in mouse skin is higher than predicted by RPFs.« less

  16. 26 CFR 1.150-1A - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... single facility or related facilities are part of the same plan of financing; (B) Short-term bonds to... Definitions. (a) through (b) [Reserved]. For guidance see § 1.150-1. (c) Definition of issue—(1) In general... bond is treated as sold on its issue date. (ii) Sold pursuant to the same plan of financing. The bonds...

  17. Annexin A1, Annexin A2, and Dyrk 1B are upregulated during GAS1-induced cell cycle arrest.

    PubMed

    Pérez-Sánchez, Gilberto; Jiménez, Adriana; Quezada-Ramírez, Marco A; Estudillo, Enrique; Ayala-Sarmiento, Alberto E; Mendoza-Hernández, Guillermo; Hernández-Soto, Justino; Hernández-Hernández, Fidel C; Cázares-Raga, Febe E; Segovia, Jose

    2018-05-01

    GAS1 is a pleiotropic protein that has been investigated because of its ability to induce cell proliferation, cell arrest, and apoptosis, depending on the cellular or the physiological context in which it is expressed. At this point, we have information about the molecular mechanisms by which GAS1 induces proliferation and apoptosis; but very few studies have been focused on elucidating the mechanisms by which GAS1 induces cell arrest. With the aim of expanding our knowledge on this subject, we first focused our research on finding proteins that were preferentially expressed in cells arrested by serum deprivation. By using a proteomics approach and mass spectrometry analysis, we identified 17 proteins in the 2-DE protein profile of serum deprived NIH3T3 cells. Among them, Annexin A1 (Anxa1), Annexin A2 (Anxa2), dual specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1B), and Eukaryotic translation initiation factor 3, F (eIf3f) were upregulated at transcriptional the level in proliferative NIH3T3 cells. Moreover, we demonstrated that Anxa1, Anxa2, and Dyrk1b are upregulated at both the transcriptional and translational levels by the overexpression of GAS1. Thus, our results suggest that the upregulation of Anxa1, Anxa2, and Dyrk1b could be related to the ability of GAS1 to induce cell arrest and maintain cell viability. Finally, we provided further evidence showing that GAS1 through Dyrk 1B leads not only to the arrest of NIH3T3 cells but also maintains cell viability. © 2017 Wiley Periodicals, Inc.

  18. Molecular Basis for Failure of “Atypical” C1 Domain of Vav1 to Bind Diacylglycerol/Phorbol Ester*

    PubMed Central

    Geczy, Tamas; Peach, Megan L.; El Kazzouli, Saïd; Sigano, Dina M.; Kang, Ji-Hye; Valle, Christopher J.; Selezneva, Julia; Woo, Wonhee; Kedei, Noemi; Lewin, Nancy E.; Garfield, Susan H.; Lim, Langston; Mannan, Poonam; Marquez, Victor E.; Blumberg, Peter M.

    2012-01-01

    C1 domains, the recognition motif of the second messenger diacylglycerol and of the phorbol esters, are classified as typical (ligand-responsive) or atypical (not ligand-responsive). The C1 domain of Vav1, a guanine nucleotide exchange factor, plays a critical role in regulation of Vav activity through stabilization of the Dbl homology domain, which is responsible for exchange activity of Vav. Although the C1 domain of Vav1 is classified as atypical, it retains a binding pocket geometry homologous to that of the typical C1 domains of PKCs. This study clarifies the basis for its failure to bind ligands. Substituting Vav1-specific residues into the C1b domain of PKCδ, we identified five crucial residues (Glu9, Glu10, Thr11, Thr24, and Tyr26) along the rim of the binding cleft that weaken binding potency in a cumulative fashion. Reciprocally, replacing these incompatible residues in the Vav1 C1 domain with the corresponding residues from PKCδ C1bC1b) conferred high potency for phorbol ester binding. Computer modeling predicts that these unique residues in Vav1 increase the hydrophilicity of the rim of the binding pocket, impairing membrane association and thereby preventing formation of the ternary C1-ligand-membrane binding complex. The initial design of diacylglycerol-lactones to exploit these Vav1 unique residues showed enhanced selectivity for C1 domains incorporating these residues, suggesting a strategy for the development of ligands targeting Vav1. PMID:22351766

  19. Interleukin 1B Variant -1473G/C (rs1143623) Influences Triglyceride and Interleukin 6 Metabolism

    PubMed Central

    Delgado-Lista, Javier; Garcia-Rios, Antonio; Perez-Martinez, Pablo; Solivera, Juan; Yubero-Serrano, Elena M.; Fuentes, Francisco; Parnell, Laurence D.; Shen, Jian; Gomez, Purificacion; Jimenez-Gomez, Yolanda; Gomez-Luna, Maria J.; Marin, Carmen; Belisle, Sarah E.; Rodriguez-Cantalejo, Fernando; Meydani, Simin N.; Ordovas, Jose M.; Perez-Jimenez, Francisco

    2011-01-01

    Context: IL1b (IL1B or IL1β), a key modulator of the immune response, exerts its functions mainly via IL6 regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susceptibility. Objective: We evaluated the influence of a genetic variant located in the promoter region of IL1B (-1473G/C) on fasting and postprandial lipids and IL6. Design, Setting, and Participants: A total of 477 people over age 65 yr were genotyped for IL1B -1473G/C, and we evaluated fasting lipids depending on genotype. Then, 88 healthy young men were also genotyped and were fed a saturated fatty acid-rich meal. Serial blood samples were drawn for 11 h after the meal, and lipid fractions and IL6 were assayed. Main Outcome and Interventions: Fasting lipids were studied in the aged persons. Fasting and postprandial measurements of lipids and IL6 were performed in the healthy young men. Results: In the aged persons, CC subjects (minor allele homozygotes) showed higher triglyceride (P = 0.002) and cholesterol (P = 0.011) levels. Healthy young male carriers of the minor C allele showed higher postprandial triglycerides (P = 0.037), and those carried into large triglyceride-rich lipoproteins (P = 0.004). In addition, they showed higher postprandial IL6 concentrations (P = 0.008). Conclusions: Our work shows that inflammatory genes may regulate fasting and postprandial lipids because the carriers of the minor allele of an IL gene variant have altered lipid metabolism. To reinforce these gene-phenotype findings, IL6 (the natural effector of IL1B) was increased in these persons. PMID:21307135

  20. Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes.

    PubMed

    Alshogran, Osama Y

    2017-10-01

    Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice.

  1. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice

    PubMed Central

    Zinker, Bradley A.; Rondinone, Cristina M.; Trevillyan, James M.; Gum, Rebecca J.; Clampit, Jill E.; Waring, Jeffrey F.; Xie, Nancy; Wilcox, Denise; Jacobson, Peer; Frost, Leigh; Kroeger, Paul E.; Reilly, Regina M.; Koterski, Sandra; Opgenorth, Terry J.; Ulrich, Roger G.; Crosby, Seth; Butler, Madeline; Murray, Susan F.; McKay, Robert A.; Bhanot, Sanjay; Monia, Brett P.; Jirousek, Michael R.

    2002-01-01

    The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA1C. Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50α, were increased and PI3-kinase p85α expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes. PMID:12169659

  2. ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1-dependent cyclin B1 degradation.

    PubMed

    Park, Yun Yeon; Ahn, Ju-Hyun; Cho, Min-Guk; Lee, Jae-Ho

    2018-04-27

    ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN 3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/C Cdc20 , we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/C Cdh1 , but not APC/C Cdc20 , facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half-life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/C Cdh1 -dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins.

  3. Current aspects in hemoglobin A1c detection: a review.

    PubMed

    Ang, Shu Hwang; Thevarajah, M; Alias, Yatimah; Khor, Sook Mei

    2015-01-15

    Type 2 diabetes mellitus (T2DM) is a pressing health issue that threatens global health and the productivity of populations worldwide. Despite its long-recognized role in diabetes management, glycated hemoglobin (HbA1c) only received WHO endorsement as a T2DM diagnostic tool in 2011. Although conventional plasma-specific tests have long been utilized to diagnose T2DM, the public should be informed that plasma-specific tests are not markedly better than HbA1c tests, particularly in terms of variability and convenience for diagnosing diabetes. In the midst of the debates associated with establishing HbA1c as the preeminent diabetes diagnostic tool, unceasing efforts to standardize HbA1c tests have played an integral part in achieving more efficient communication from laboratory to clinical practice and thus better diabetes care. This review discusses the current status of HbA1c tests in the diagnosis, prevention, treatment and management of T2DM across the globe, focusing on increasing the recognition of glycated hemoglobin variants with effective utilization of different HbA1c methods, updating the current status of HbA1c standardization programs, tapping into the potential of POC analyzers to establish a cost-effective HbA1c test for diabetes care, and inspiring the advancement of HbA1c biosensors for future clinical usage. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. The B(E2;4^+1->2^+1) / B(E2;2^+1->0^+1) Ratio in Even-Even Nuclei

    NASA Astrophysics Data System (ADS)

    Loelius, C.; Sharon, Y. Y.; Zamick, L.; G"Urdal, G.

    2009-10-01

    We considered 207 even-even nuclei throughout the chart of nuclides for which the NNDC Tables had data on the energies and lifetimes of the 2^+1 and 4^+1 states. Using these data we calculated for each nucleus the electric quadrupole transition strengths B(E2;4^+1->2^+1) and B(E2;2^+1->0^+1), as well as their ratio. The internal conversion coefficients were obtained by using the NNDC HSICC calculator. For each nucleus we plotted the B(E2) ratio against A, N, and Z. We found that for close to 90% of the nuclei considered the ratio had values between 0.5 and 2.5. Most of the outliers had magic numbers of protons or neutrons. Our ratio results were compared with the theoretical predictions for this ratio by different models--10/7 in the rotational model and 2 in the simplest vibrational model. In the rotational regions (for 150 < A < 180 and A > 220) the ratios were indeed close to 10/7. For the few nuclei thought to be vibrational the ratios were usually less than 2. Otherwise, we got a wide scatter of ratio values. Hence other models, including the NpNn scheme, must be considered in interpreting these results.

  5. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma

    PubMed Central

    Lewis, Michael J; Wiebe, John P; Heathcote, J Godfrey

    2004-01-01

    Background Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5α-reductase (5αR) and lower 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO activities. The resulting higher levels of 5α-reduced progesterone metabolites such as 5α-pregnane-3,20-dione (5αP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression. Methods Semi-quantitative RT-PCR was used to compare relative expression (as a ratio of 18S rRNA) of 5αR type 1 (SRD5A1), 5αR type 2 (SRD5A2), 3α-HSO type 2 (AKR1C3), 3α-HSO type 3 (AKR1C2) and 20α-HSO (AKR1C1) mRNAs in paired (tumorous and nontumorous) breast tissues from 11 patients, and unpaired tumor tissues from 17 patients and normal tissues from 10 reduction mammoplasty samples. Results Expression of 5αR1 and 5αR2 in 11/11 patients was higher (mean of 4.9- and 3.5-fold, respectively; p < 0.001) in the tumor as compared to the paired normal tissues. Conversely, expression of 3α-HSO2, 3α-HSO3 and 20α-HSO was higher (2.8-, 3.9- and 4.4-fold, respectively; p < 0.001) in normal than in tumor sample. The mean tumor:normal expression ratios for 5αR1 and 5αR2 were about 35–85-fold higher than the tumor:normal expression ratios for the HSOs. Similarly, in the unmatched samples, the tumor:normal ratios for 5αR were significantly higher than the ratios for the HSOs. Conclusions The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of SRD5A1 (5αR1) and SRD5A2 (5αR2

  6. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma.

    PubMed

    Lewis, Michael J; Wiebe, John P; Heathcote, J Godfrey

    2004-06-22

    Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5alpha-reductase (5alphaR) and lower 3alpha-hydroxysteroid oxidoreductase (3alpha-HSO) and 20alpha-HSO activities. The resulting higher levels of 5alpha-reduced progesterone metabolites such as 5alpha-pregnane-3,20-dione (5alphaP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3alpha-ol-20-one (3alphaHP) and 4-pregnen-20alpha-ol-3-one (20alphaDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression. Semi-quantitative RT-PCR was used to compare relative expression (as a ratio of 18S rRNA) of 5alphaR type 1 (SRD5A1), 5alphaR type 2 (SRD5A2), 3alpha-HSO type 2 (AKR1C3), 3alpha-HSO type 3 (AKR1C2) and 20alpha-HSO (AKR1C1) mRNAs in paired (tumorous and nontumorous) breast tissues from 11 patients, and unpaired tumor tissues from 17 patients and normal tissues from 10 reduction mammoplasty samples. Expression of 5alphaR1 and 5alphaR2 in 11/11 patients was higher (mean of 4.9- and 3.5-fold, respectively; p < 0.001) in the tumor as compared to the paired normal tissues. Conversely, expression of 3alpha-HSO2, 3alpha-HSO3 and 20alpha-HSO was higher (2.8-, 3.9- and 4.4-fold, respectively; p < 0.001) in normal than in tumor sample. The mean tumor:normal expression ratios for 5alphaR1 and 5alphaR2 were about 35-85-fold higher than the tumor:normal expression ratios for the HSOs. Similarly, in the unmatched samples, the tumor:normal ratios for 5alphaR were significantly higher than the ratios for the HSOs. The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of

  7. Bioactive constituents from Chinese natural medicines. XXXII. aminopeptidase N and aldose reductase inhibitors from Sinocrassula indica: structures of sinocrassosides B(4), B(5), C(1), and D(1)-D(3).

    PubMed

    Morikawa, Toshio; Xie, Haihui; Wang, Tao; Matsuda, Hisashi; Yoshikawa, Masayuki

    2008-10-01

    From the methanolic extract of the whole plant of Sinocrassula indica (Crassulaceae), six new flavonol glycosides, sinocrassosides B(4) (1), B(5) (2), C(1) (3), D(1) (4), D(2) (5), and D(3) (6), were isolated together with 30 compounds. The structures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. In addition, several constituents were found to show inhibitory effects on aminopeptidase N and aldose reductase.

  8. DHU1 negatively regulates UV-B signaling via its direct interaction with COP1 and RUP1.

    PubMed

    Kim, Sang-Hoon; Kim, Hani; Chung, Sunglan; Lee, Jae-Hoon

    2017-09-16

    Although DWD HYPERSENSITIVE TO UV-B 1 (DHU1) is reported to be a negative regulator in UV-B mediated cellular responses, its detailed role in UV-B signaling is still elusive. To further understand the action mechanism of DHU1 in UV-B response, physical and genetic interactions of DHU1 with various UV-B signaling components were investigated. Yeast two hybrid assay results suggested that DHU1 directly interacts with COP1 and RUP1, implying a functional connection with both COP1 and RUP1. In spite of the physical association between DHU1 and COP1, loss of DHU1 did not affect protein stability of COP1. Epistatic analysis showed that the functional loss of both DHU1 and UVR8 leads to alleviation of UV-B hypersensitivity displayed in dhu1-1. Moreover, phenotypic studies with dhu1-1 cop1-6 and dhu1-1 hy5-215 revealed that COP1 and HY5 are epistatic to DHU1, indicating that UV-B hypersensitivity of dhu1-1 requires both COP1 and HY5. In the case of dhu1-1 rup1-1, UV-B responsiveness was similar to that of both dhu1-1 and rup1-1, implying that DHU1 and RUP1 are required for each other's function. Collectively, these results show that the role of DHU1 as a negative regulator in UV-B response may be derived from its direct interaction with COP1 by sequestering COP1 from the active UVR8-COP1 complex, resulting in a decrease in the COP1 population that positively participates in UV-B signaling together with UVR8. Furthermore, this inhibitory role of DHU1 in UV-B signaling is likely to be functionally connected to RUP1. This study will serve as a platform to further understand more detailed action mechanism of DHU1 in UV-B response and DHU1-mediated core UV-B signaling in Arabidopsis. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Bax Activates Endophilin B1 Oligomerization and Lipid Membrane Vesiculation*

    PubMed Central

    Rostovtseva, Tatiana K.; Boukari, Hacène; Antignani, Antonella; Shiu, Brian; Banerjee, Soojay; Neutzner, Albert; Youle, Richard J.

    2009-01-01

    Endophilins participate in membrane scission events that occur during endocytosis and intracellular organelle biogenesis through the combined activity of an N-terminal BAR domain that interacts with membranes and a C-terminal SH3 domain that mediates protein binding. Endophilin B1 (Endo B1) was identified to bind Bax, a Bcl-2 family member that promotes apoptosis, through yeast two-hybrid protein screens. Although Endo B1 does not bind Bax in healthy cells, during apoptosis, Endo B1 interacts transiently with Bax and promotes cytochrome c release from mitochondria. To explore the molecular mechanism of action of Endo B1, we have analyzed its interaction with Bax in cell-free systems. Purified recombinant Endo B1 in solution displays a Stokes radius indicating a tetrameric quarternary structure. However, when incubated with purified Bax, it assembles into oligomers more than 4-fold greater in molecular weight. Although Endo B1 oligomerization is induced by Bax, Bax does not stably associate with the high molecular weight Endo B1 complex. Endo B1 oligomerization requires its C-terminal Src homology 3 domain and is not induced by Bcl-xL. Endo B1 combined with Bax reduces the size and changes the morphology of giant unilamellar vesicles by inducing massive vesiculation of liposomes. This activity of purified Bax protein to induce cell-free assembly of Endo B1 may reflect its activity in cells that regulates apoptosis and/or mitochondrial fusion. PMID:19805544

  10. Plant Equipment Package Modernization Program. Volume 4-1. Model Lines. Shell, HE, M483/M107-155MM Case, Cartridge, M115B1, M148A1B1, M150B1-105MM Shell, HEAT-T, M456A1-105MM Fuze, PD, M739

    DTIC Science & Technology

    1976-04-01

    Cartridge, M115B1, M148A1B1, M15#1B1-15MM J .. Shell, HEAT-T, M456A1-105MM Fuze, PD, M739 # prepared for Project Manager Munitions Production Base...ENGINEERS PLANT EQUIPMENT PACKAGE MODERNIZATION PROGRAM Volume 4-1 Report No. 75-86-R-4- MODEL LINE DEVELOPMENT FUZE,PD, M739 prepared for Project...In preparing the model line for the manufacture of piece parts for the M739 fuze, a number of facts became obvious and affect the detailed de- [ sign

  11. Hepatitis B, Hepatitis C and HIV-1 Coinfection in Two Informal Urban Settlements in Nairobi, Kenya.

    PubMed

    Kerubo, Glennah; Khamadi, Samoel; Okoth, Vincent; Madise, Nyovani; Ezeh, Alex; Ziraba, Abdhalah; Abdalla, Ziraba; Mwau, Matilu

    2015-01-01

    HIV-1 and Hepatitis B and C viruses coinfection is common in Sub-Saharan Africa due to similar routes of transmission and high levels of poverty. Most studies on HIV-1 and Hepatitis B and C viruses have occurred in hospital settings and blood transfusion units. Data on Hepatitis B and C viruses and HIV-1 coinfection in informal urban settlements in Kenya are scanty, yet they could partly explain the disproportionately high morbidity and mortality associated with HIV-1 infections in these slums. The objective of this study was to determine the prevalence of HIV and Hepatitis B and C dual infection in urban slums in Nairobi. Blood samples were collected from residents of Viwandani and Korogocho between 2006 and 2007. A structured questionnaire was used to obtain socio-demographic data from participants. Samples were screened for Hepatitis B surface antigen (HBsAg), anti-HCV and anti-HIV-1. Statistical analysis was done using STATA. Samples were successfully collected from 418 (32%) men and 890 (68%) females. The HIV-1, HBV and HCV prevalence was 20.4%, 13.3% and 0.76% respectively at the time of the study. Of the 268 (20.4%) HIV-1 positive participants, 56 (4.26%) had HBV while 6 (0.46%) had HCV. Of the 1041 HIV-1 negative participants, 117 (8.9%) had HBV while 4 (0.31%) had HCV. Only two people (0.15%) were co-infected with all the three viruses together. The odds of getting hepatitis infection were higher in HIV-1 participants (for HBV OR 2.08,p<0.005 and for HCV OR 5.93, p<0.005). HIV prevalence rates were similar in both informal settlements. HIV infection was highest in age group 35-39 years and among the divorced/separated or widowed. Prevalence of all viruses was highest in those who did not have any formal education. The HIV prevalence in these informal settlements suggests a higher rate than what is observed nationally. The prevalence rates of HBV are significantly higher in the HIV-1 positive and negative populations. HCV as well as triple HIV-1, HBV and

  12. Dlx1&2-Dependent Expression of Zfhx1b (Sip1, Zeb2) Regulates the Fate Switch Between Cortical and Striatal Interneurons

    PubMed Central

    McKinsey, Gabriel L.; Lindtner, Susan; Trzcinski, Brett; Visel, Axel; Pennacchio, Len A.; Huylebroeck, Danny; Higashi, Yujiro; Rubenstein, John L. R.

    2013-01-01

    Summary Mammalian pallial (cortical and hippocampal) and striatal interneurons are both generated in the embryonic subpallium, including the medial ganglionic eminence (MGE). Herein we demonstrate that the Zfhx1b (Sip1, Zeb2) zinc finger homeobox gene is required in the MGE, directly downstream of Dlx1&2, to generate cortical interneurons that express Cxcr7, MafB and cMaf. In its absence, Nkx2-1 expression is not repressed, and cells that ordinarily would become cortical interneurons appear to transform towards a subtype of GABAeric striatal interneurons. These results show that Zfhx1b is required to generate cortical interneurons, and suggest a mechanism for the epilepsy observed in humans with Zfhx1b mutations (Mowat-Wilson syndrome). PMID:23312518

  13. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Shortfall method. 1.412(c)(1)-2 Section 1.412(c... (CONTINUED) INCOME TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.412(c)(1)-2 Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a plan's...

  14. Hypervelocity Impact (HVI). Volume 8; Tile Small Targets A-1, Ag-1, B-1, and Bg-1

    NASA Technical Reports Server (NTRS)

    Gorman, Michael R.; Ziola, Steven M.

    2007-01-01

    During 2003 and 2004, the Johnson Space Center's White Sands Testing Facility in Las Cruces, New Mexico conducted hypervelocity impact tests on the space shuttle wing leading edge. Hypervelocity impact tests were conducted to determine if Micro-Meteoroid/Orbital Debris impacts could be reliably detected and located using simple passive ultrasonic methods. The objective of Targets A-1, Ag-1, B-1, and Bg-1 was to study hypervelocity impacts on the reinforced Shuttle Heat Shield Tiles of the Wing. Impact damage was detected using lightweight, low power instrumentation capable of being used in flight.

  15. 26 CFR 1.381(c)(5)-1 - Inventory method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 4 2013-04-01 2013-04-01 false Inventory method. 1.381(c)(5)-1 Section 1.381(c... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(5)-1 Inventory method. (a) Introduction—(1) Purpose. This section provides guidance regarding the inventory method an acquiring...

  16. 26 CFR 1.381(c)(5)-1 - Inventory method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 4 2014-04-01 2014-04-01 false Inventory method. 1.381(c)(5)-1 Section 1.381(c... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(5)-1 Inventory method. (a) Introduction—(1) Purpose. This section provides guidance regarding the inventory method an acquiring...

  17. 26 CFR 1.381(c)(5)-1 - Inventory method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 4 2012-04-01 2012-04-01 false Inventory method. 1.381(c)(5)-1 Section 1.381(c... (CONTINUED) INCOME TAXES (Continued) Insolvency Reorganizations § 1.381(c)(5)-1 Inventory method. (a) Introduction—(1) Purpose. This section provides guidance regarding the inventory method an acquiring...

  18. Use of a 1-dB decrease in C/N\\0x2080AS the GPS interference protection criterion : global positioning systems directorate.

    DOT National Transportation Integrated Search

    2017-03-30

    A 1 dB decrease in the carrier-to-noise (C/N) ratio is equivalent to a -6 dB interference-to-noise (I/N) ratio and a 1 dB increase in the noise floor ((I+N)/N). Regulations alternate between referencing the 1 dB decrease in C/N, -6 dB I/N ratio, and ...

  19. 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

    ... Frost, Aerospace Engineer, Engine Certification Office, FAA, Engine & Propeller Directorate, 12 New..., Massachusetts, on May 10, 2010. Peter A. White, Assistant Manager, Engine and Propeller Directorate, Aircraft... Airworthiness Directives; General Electric Company CF34-1A, -3A, -3A1, -3A2, -3B, and -3B1 Turbofan Engines...

  20. EBNA3C Augments Pim-1 Mediated Phosphorylation and Degradation of p21 to Promote B-Cell Proliferation

    PubMed Central

    Banerjee, Shuvomoy; Lu, Jie; Cai, Qiliang; Sun, Zhiguo; Jha, Hem Chandra; Robertson, Erle S.

    2014-01-01

    Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers. PMID:25121590

  1. Combined effect of ADH1B RS1229984, RS2066702 and ADH1C RS1693482/ RS698 alleles on alcoholism and chronic liver diseases.

    PubMed

    Tóth, Réka; Fiatal, Szilvia; Petrovski, Beáta; McKee, Martin; Adány, Róza

    2011-01-01

    The aim of this study was to analyze the combined effect of the most frequent alcohol dehydrogenase polymorphisms (Arg48His and Arg370Cys in ADH1B, Arg272Gln and Ile350Val in ADH1C) on the alcohol use habits, alcohol dependence and chronic liver diseases in Hungary. The study included men, aged 45-64 years. Altogether, 241 cases with chronic liver disease (CLD) and 666 randomly selected controls without CLD were analysed for all four polymorphisms. Associations between the polymorphisms, individually, and in combination, and excessive and problem drinking and CLD, were assessed using logistic regression. In this study we have identified a novel mutation, called ADH1B Arg370His. The ADH1C Arg272Gln and Ile350Val showed almost complete linkage. The 272Gln/35Val allele increased the risk of excessive and problem drinking in homozygous form (OR=1.582, p=0.035, CI=1.034-2.421, OR=1.780, p=0.016, CI=1.113-2.848, respectively). The joint analysis showed that when combined with the wild type ADH1C Arg272/Ile350 allele, the ADH1B 48His is protective against CLD (OR=0.368, p=0.019, CI=0.159-0.851). The results obtained in the study help not only to clarify the effects of different ADH SNPs but to better understand how these polymorphisms modify each other's effects in the development of alcoholism and related diseases.

  2. MUC1-C ACTIVATES BMI1 IN HUMAN CANCER CELLS

    PubMed Central

    Hiraki, Masayuki; Maeda, Takahiro; Bouillez, Audrey; Alam, Maroof; Tagde, Ashujit; Hinohara, Kunihiko; Suzuki, Yozo; Markert, Tahireh; Miyo, Masaaki; Komura, Kazumasa; Ahmad, Rehan; Rajabi, Hasan; Kufe, Donald

    2016-01-01

    BMI1 is a component of the PRC1 complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16INK4a tumor suppressor, we found that targeting MUC1-C is associated with induction of p16INK4a expression. In support of these results, analysis of three gene expresssion datasets demonstrated highly significant correlations between MUC1-C and BMI1 in breast cancers. These findings uncover a previously unrecognized role for MUC1-C in driving BMI1 expression and in directly interacting with this stem cell factor, linking MUC1-C with function of the PRC1 in epigenetic gene silencing. PMID:27893710

  3. 26 CFR 1.167(b)-1 - Straight line method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Straight line method. 1.167(b)-1 Section 1.167(b... Straight line method. (a) In general. Under the straight line method the cost or other basis of the... may be reduced to a percentage or fraction. The straight line method may be used in determining a...

  4. Two extreme young objects in Barnard 1-b

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

    Hirano, Naomi; Liu, Fang-chun, E-mail: hirano@asiaa.sinica.edu.tw

    2014-07-01

    Two submillimeter/millimeter sources in the Barnard 1b (B1-b) core, B1-bN and B1-bS, have been studied in dust continuum, H{sup 13}CO{sup +} J = 1-0, CO J = 2-1, {sup 13}CO J = 2-1, and C{sup 18}O J = 2-1. The spectral energy distributions of these sources from the mid-IR to 7 mm are characterized by very cold temperatures of T {sub dust} < 20 K and low bolometric luminosities of 0.15-0.31 L {sub ☉}. The internal luminosities of B1-bN and B1-bS are estimated to be <0.01-0.03 L {sub ☉} and ∼0.1-0.2 L {sub ☉}, respectively. Millimeter interferometric observations have shownmore » that these sources have already formed central compact objects of ∼100 AU sizes. Both B1-bN and B1-bS are driving the CO outflows with low characteristic velocities of ∼2-4 km s{sup –1}. The fractional abundance of H{sup 13}CO{sup +} at the positions of B1-bN and B1-bS is lower than the canonical value by a factor of four to eight. This implies that a significant fraction of CO is depleted onto dust grains in the dense gas surrounding these sources. The observed physical and chemical properties suggest that B1-bN and B1-bS are in an earlier evolutionary stage than most of the known class 0 protostars. In particular, the properties of B1-bN agree with those of the first hydrostatic core predicted by the MHD simulations. The CO outflow was also detected in the mid-IR source located at ∼15'' from B1-bS. Since the dust continuum emission was not detected in this source, the circumstellar material surrounding this source is less than 0.01 M {sub ☉}. It is likely that the envelope of this source was dissipated by the outflow from the protostar that is located to the southwest of B1-b.« less

  5. Chemoselective room temperature E1cB N-N cleavage of oxazolidinone hydrazides from enantioselective aldehyde α-hydrazination: synthesis of (+)-1,4-dideoxyallonojirimycin.

    PubMed

    Ferreira, Jasmin; Rees-Jones, Sophie C M; Ramaotsoa, Valerie; Msutu, Ath'enkosi; Hunter, Roger

    2016-02-07

    Room temperature E1cB N-N cleavage of oxazolidinone hydrazides via N-alkylation with diethyl bromomalonate and potassium or caesium carbonate as base in acetonitrile is presented. The new method has a much improved chemoselectivity, which is illustrated by a concise total synthesis of the piperidine iminosugar (+)-1,4-dideoxyallonojirimycin.

  6. The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells.

    PubMed

    Talman, Virpi; Amadio, Marialaura; Osera, Cecilia; Sorvari, Salla; Boije Af Gennäs, Gustav; Yli-Kauhaluoma, Jari; Rossi, Daniela; Govoni, Stefano; Collina, Simona; Ekokoski, Elina; Tuominen, Raimo K; Pascale, Alessia

    2013-07-01

    Protein kinase C (PKC) is a family of serine/threonine phosphotransferases ubiquitously expressed and involved in multiple cellular functions, such as proliferation, apoptosis and differentiation. The C1 domain of PKC represents an attractive drug target, especially for developing PKC activators. Dialkyl 5-(hydroxymethyl)isophthalates are a novel group of synthetic C1 domain ligands that exhibit antiproliferative effect in HeLa cervical carcinoma cells. Here we selected two isophthalates, HMI-1a3 and HMI-1b11, and characterized their effects in the human neuroblastoma cell line SH-SY5Y. Both of the active isophthalates exhibited significant antiproliferative and differentiation-inducing effects. Since HMI-1b11 did not impair cell survival even at the highest concentration tested (20μM), and supported neurite growth and differentiation of SH-SY5Y cells, we focused on studying its downstream signaling cascades and effects on gene expression. Consistently, genome-wide gene expression microarray and gene set enrichment analysis indicated that HMI-1b11 (10μM) induced changes in genes mainly related to cell differentiation. In particular, further studies revealed that HMI-1b11 exposure induced up-regulation of GAP-43, a marker for neurite sprouting and neuronal differentiation. These effects were induced by a 7-min HMI-1b11 treatment and specifically depended on PKCα activation, since pretreatment with the selective inhibitor Gö6976 abolished the up-regulation of GAP-43 protein observed at 12h. In parallel, we found that a 7-min exposure to HMI-1b11 induced PKCα accumulation to the cytoskeleton, an effect that was again prevented by pretreatment with Gö6976. Despite similar binding affinities to PKC, the isophthalates had different effects on PKC-dependent ERK1/2 signaling: HMI-1a3-induced ERK1/2 phosphorylation was transient, while HMI-1b11 induced a rapid but prolonged ERK1/2 phosphorylation. Overall our data are in accordance with previous studies showing that

  7. 26 CFR 1.501(c)(7)-1 - Social clubs.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 7 2011-04-01 2009-04-01 true Social clubs. 1.501(c)(7)-1 Section 1.501(c)(7)-1...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(c)(7)-1 Social clubs. (a) The exemption provided by... general, this exemption extends to social and recreation clubs which are supported solely by membership...

  8. 26 CFR 1.501(c)(7)-1 - Social clubs.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 7 2014-04-01 2013-04-01 true Social clubs. 1.501(c)(7)-1 Section 1.501(c)(7)-1...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(c)(7)-1 Social clubs. (a) The exemption provided by... general, this exemption extends to social and recreation clubs which are supported solely by membership...

  9. 26 CFR 1.501(c)(7)-1 - Social clubs.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 7 2010-04-01 2010-04-01 true Social clubs. 1.501(c)(7)-1 Section 1.501(c)(7)-1...) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(c)(7)-1 Social clubs. (a) The exemption provided by... general, this exemption extends to social and recreation clubs which are supported solely by membership...

  10. 26 CFR 1.402(g)(3)-1 - Employer contributions to purchase a section 403(b) contract under a salary reduction agreement.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...(b) contract under a salary reduction agreement. 1.402(g)(3)-1 Section 1.402(g)(3)-1 Internal Revenue... (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402(g)(3)-1 Employer contributions to... purposes of section 402(g)(3)(C), an elective deferral does not include a contribution that is made...

  11. 26 CFR 1.402(g)(3)-1 - Employer contributions to purchase a section 403(b) contract under a salary reduction agreement.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...(b) contract under a salary reduction agreement. 1.402(g)(3)-1 Section 1.402(g)(3)-1 Internal Revenue... (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402(g)(3)-1 Employer contributions to... purposes of section 402(g)(3)(C), an elective deferral does not include a contribution that is made...

  12. 26 CFR 1.402(g)(3)-1 - Employer contributions to purchase a section 403(b) contract under a salary reduction agreement.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...(b) contract under a salary reduction agreement. 1.402(g)(3)-1 Section 1.402(g)(3)-1 Internal Revenue... (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402(g)(3)-1 Employer contributions to... purposes of section 402(g)(3)(C), an elective deferral does not include a contribution that is made...

  13. 26 CFR 1.402(g)(3)-1 - Employer contributions to purchase a section 403(b) contract under a salary reduction agreement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...(b) contract under a salary reduction agreement. 1.402(g)(3)-1 Section 1.402(g)(3)-1 Internal Revenue... (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402(g)(3)-1 Employer contributions to... purposes of section 402(g)(3)(C), an elective deferral does not include a contribution that is made...

  14. 47 CFR 1.736 - Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B). (a) Where a complaint is filed pursuant to 47 U.S.C. 271... deadline contained in 47 U.S.C. 271(d)(6)(B) in the following manner: (1) The complainant shall so indicate... filed pursuant to 47 U.S.C. 271(d)(6)(B) will not be entertained by the Commission staff subsequent to...

  15. 47 CFR 1.736 - Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B). (a) Where a complaint is filed pursuant to 47 U.S.C. 271... deadline contained in 47 U.S.C. 271(d)(6)(B) in the following manner: (1) The complainant shall so indicate... filed pursuant to 47 U.S.C. 271(d)(6)(B) will not be entertained by the Commission staff subsequent to...

  16. 47 CFR 1.736 - Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B). (a) Where a complaint is filed pursuant to 47 U.S.C. 271... deadline contained in 47 U.S.C. 271(d)(6)(B) in the following manner: (1) The complainant shall so indicate... filed pursuant to 47 U.S.C. 271(d)(6)(B) will not be entertained by the Commission staff subsequent to...

  17. 47 CFR 1.736 - Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B). (a) Where a complaint is filed pursuant to 47 U.S.C. 271... deadline contained in 47 U.S.C. 271(d)(6)(B) in the following manner: (1) The complainant shall so indicate... filed pursuant to 47 U.S.C. 271(d)(6)(B) will not be entertained by the Commission staff subsequent to...

  18. 47 CFR 1.736 - Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Complaints filed pursuant to 47 U.S.C. 271(d)(6)(B). (a) Where a complaint is filed pursuant to 47 U.S.C. 271... deadline contained in 47 U.S.C. 271(d)(6)(B) in the following manner: (1) The complainant shall so indicate... filed pursuant to 47 U.S.C. 271(d)(6)(B) will not be entertained by the Commission staff subsequent to...

  19. Pharmacokinetic interactions between glimepiride and rosuvastatin in healthy Korean subjects: does the SLCO1B1 or CYP2C9 genetic polymorphism affect these drug interactions?

    PubMed Central

    Kim, Choon Ok; Oh, Eun Sil; Kim, Hohyun; Park, Min Soo

    2017-01-01

    To improve cardiovascular outcomes, dyslipidemia in patients with diabetes needs to be treated. Thus, these patients are likely to take glimepiride and rosuvastatin concomitantly. Therefore, this study aimed to evaluate the pharmacokinetic (PK) interactions between these two drugs in healthy males and to explore the effect of SLCO1B1 and CYP2C9 polymorphisms on their interactions in two randomized, open-label crossover studies. Glimepiride was studied in part 1 and rosuvastatin in part 2. Twenty-four participants were randomly assigned to each part. All subjects (n=24) completed part 1, and 22 subjects completed part 2. A total of 38 subjects among the participants of the PK interaction studies were enrolled in the genotype study to analyze their SLCO1B1 and CYP2C9 polymorphisms retrospectively (n=22 in part 1, n=16 in part 2). Comparison of the PK and safety of each drug alone with those of the drugs in combination showed that both glimepiride and rosuvastatin did not interact with each other and had tolerable safety profiles in all subjects. However, with regard to glimepiride PK, the SLCO1B1 521TC group had a significantly higher maximum plasma concentration (Cmax,ss) and area under the plasma concentration–time curve during the dose interval at steady state (AUCτ,ss) for glimepiride in combination with rosuvastatin than those for glimepiride alone. However, other significant effects of the SLCO1B1 or CYP2C9 polymorphism on the interaction between the two drugs were not observed. In conclusion, there were no significant PK interactions between the two drugs; however, the exposure to glimepiride could be affected by rosuvastatin in the presence of the SLCO1B1 polymorphism. PMID:28260863

  20. KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1.

    PubMed

    Wong, Sarah J; Gearhart, Micah D; Taylor, Alexander B; Nanyes, David R; Ha, Daniel J; Robinson, Angela K; Artigas, Jason A; Lee, Oliver J; Demeler, Borries; Hart, P John; Bardwell, Vivian J; Kim, Chongwoo A

    2016-10-04

    KDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repression. We investigated the molecular basis of recruitment using in vitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA-binding KDM2B/SKP1 heterodimer and the heterodimer of BCORL1 and PCGF1, a core component of PRC1.1. The crystal structure of the KDM2B/SKP1/BCORL1/PCGF1 complex illustrates the crucial role played by the PCGF1/BCORL1 heterodimer. The BCORL1 PUFD domain positions residues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B, which is unique to the PCGF1-containing PRC1.1 complex. The structure also suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex and the possible molecular consequences of BCOR PUFD internal tandem duplications found in pediatric kidney and brain tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Beyond HbA1c.

    PubMed

    Bloomgarden, Zachary

    2017-12-01

    It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience. The diaTribe Foundation convened a meeting on the topic of glycemic outcomes beyond HbA1c on 21 July 2017, in Bethesda (MD, USA), focusing on potential uses of continuous glucose monitoring (CGM). Understanding patterns of glycemia in people with diabetes has long been a focus of approaches to improving treatment, and over the past few years this has become an available modality for clinical practice. Glucose levels are not the only biologic parameters affecting HbA1c levels; HbA1c changes with anemia or, more subtly, with changes in rates of erythrocyte turnover not reflected in hemoglobin levels outside the normal range. Renal disease often is associated with lower HbA1c than would be predicted based on an individual's glycemic levels. Furthermore, HbA1c levels tend to increase with age and are higher in some ethnic groups; for example, people of African ethnicity have higher HbA1c levels than people of Northern European descent. Indeed, we have argued that even as a measure of mean glycemia HbA1c is inherently imprecise. Overall, for some 20% of people with diabetes, HbA1c levels are substantially higher, or substantially lower, than those that would be predicted from mean blood glucose levels. If one recognizes that HbA1c is, at best, a partial measure of mean glycemic exposure, one must surely accept that HbA1c does not reflect variability within a day, from day to day, and from period to period. Many glucose-lowering medicines, particularly the sulfonylureas and insulin, cause hypoglycemia, with consequent negative effects on quality of life and patient-reported outcomes, as well as association with weight gain and adverse macrovascular outcome; hypoglycemia will, of course, not be captured by HbA1c measurement. Based on these

  2. The HLA Dictionary 2001: a summary of HLA-A, -B, -C, -DRB1/3/4/5 and -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens.

    PubMed

    Schreuder, G M; Hurley, C K; Marsh, S G; Lau, M; Maiers, M; Kollman, C; Noreen, H J

    2001-12-01

    This report presents the serological equivalents of 123 HLA-A, 272 HLA-B and 155 HLA-DRB1 alleles. The equivalents cover over 64% of the presently identified HLA-A, -B and -DRB1 alleles. The dictionary is an update of the one published in 1999 (<1>Schreuder et al., 1999, Tissue Antigens, 54, 409) and also includes equivalents for HLA-C, DRB3, DRB4, DRB5 and DQB1 alleles. The data summarize information obtained by the WHO Nomenclature Committee for Factors of the HLA System, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP) and individual laboratories. In addition, a listing is provided of alleles that are expressed as antigens with serological reaction patterns that differ from the well-established HLA specificities. The equivalents provided will be useful in guiding searches for unrelated hematopoietic stem cell donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programmes where HLA typings from donors and from recipients on waiting lists represent mixtures of serological and molecular typings. The tables with HLA equivalents and a questionnaire for submission of serological reaction patterns for poorly identified allelic products will also be available on the WMDA web page: www.worldmarrow.org

  3. 26 CFR 1.402(g)(3)-1 - Employer contributions to purchase a section 403(b) contract under a salary reduction agreement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...(b) contract under a salary reduction agreement. 1.402(g)(3)-1 Section 1.402(g)(3)-1 Internal Revenue... Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402(g)(3)-1 Employer contributions to purchase a... purposes of section 402(g)(3)(C), an elective deferral does not include a contribution that is made...

  4. Identification of two allelic IgG1 C(H) coding regions (Cgamma1) of cat.

    PubMed

    Kanai, T H; Ueda, S; Nakamura, T

    2000-01-31

    Two types of cDNA encoding IgG1 heavy chain (gamma1) were isolated from a single domestic short-hair cat. Sequence analysis indicated a higher level of similarity of these Cgamma1 sequences to human Cgamma1 sequence (76.9 and 77.0%) than to mouse sequence (70.0 and 69.7%) at the nucleotide level. Predicted primary structures of both the feline Cgamma1 genes, designated as Cgamma1a and Cgamma1b, were similar to that of human Cgamma1 gene, for instance, as to the size of constant domains, the presence of six conserved cysteine residues involved in formation of the domain structure, and the location of a conserved N-linked glycosylation site. Sequence comparison between the two alleles showed that 7 out of 10 nucleotide differences were within the C(H)3 domain coding region, all leading to nonsynonymous changes in amino acid residues. Partial sequence analysis of genomic clones showed three nucleotide substitutions between the two Cgamma1 alleles in the intron between the CH2 and C(H)3 domain coding regions. In 12 domestic short-hair cats used in this study, the frequency of Cgamma1a allele (62.5%) was higher than that of the Cgamma1b allele (37.5%).

  5. Ammonia oxidation is not required for growth of Group 1.1c soil Thaumarchaeota.

    PubMed

    Weber, Eva B; Lehtovirta-Morley, Laura E; Prosser, James I; Gubry-Rangin, Cécile

    2015-03-01

    Thaumarchaeota are among the most abundant organisms on Earth and are ubiquitous. Within this phylum, all cultivated representatives of Group 1.1a and Group 1.1b Thaumarchaeota are ammonia oxidizers, and play a key role in the nitrogen cycle. While Group 1.1c is phylogenetically closely related to the ammonia-oxidizing Thaumarchaeota and is abundant in acidic forest soils, nothing is known about its physiology or ecosystem function. The goal of this study was to perform in situ physiological characterization of Group 1.1c Thaumarchaeota by determining conditions that favour their growth in soil. Several acidic grassland, birch and pine tree forest soils were sampled and those with the highest Group 1.1c 16S rRNA gene abundance were incubated in microcosms to determine optimal growth temperature, ammonia oxidation and growth on several organic compounds. Growth of Group 1.1c Thaumarchaeota, assessed by qPCR of Group 1.1c 16S rRNA genes, occurred in soil, optimally at 30°C, but was not associated with ammonia oxidation and the functional gene amoA could not be detected. Growth was also stimulated by addition of organic nitrogen compounds (glutamate and casamino acids) but not when supplemented with organic carbon alone. This is the first evidence for non-ammonia oxidation associated growth of Thaumarchaeota in soil. © FEMS 2015.

  6. X-ray diffraction analysis of 4- and 4'-substituted C n H2 n + 1O-C6H3(OH)-CH=N-C6H4-C m H2 m + 1 ( n/ m = 2/1 and 3/4) salicylideneanilines

    NASA Astrophysics Data System (ADS)

    Kuz'mina, L. G.; Navasardyan, M. A.; Mikhailov, A. A.

    2017-11-01

    X-ray diffraction study of two crystalline modifications of C2H5O-C6H3(OH)-CH=N-C6H4-CH3 ( 1a, sp. gr. P21/ n, and 1b, sp. gr. C2/c) and C3H7O-C6H3(OH)-CH=N-C6H4-C4H9 ( 2, sp. gr. P212121) has been performed. The 1a crystal structure contains two independent molecules. The molecules are conformationally nonrigid with respect to the mutual rotation of benzene rings; the dihedral angles between their planes are 29.19° and 26.00° in the independent molecules of 1a, 18.72° in the molecule of 1b, and 50.35° in the molecule of 2. The crystal packing of the compounds is discussed.

  7. Downregulation of miR-29a/b/c in placenta accreta inhibits apoptosis of implantation site intermediate trophoblast cells by targeting MCL1.

    PubMed

    Gu, Yongzhong; Bian, Yuehong; Xu, Xiaofei; Wang, Xietong; Zuo, Changting; Meng, Jinlai; Li, Hongyan; Zhao, Shigang; Ning, Yunnan; Cao, Yongzhi; Huang, Tao; Yan, Junhao; Chen, Zi-Jiang

    2016-12-01

    Placenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. Expression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction. Western blotting was used to analyze expression of the MCL1 protein in HTR8/SVneo trophoblast cells with altered expression of miR-29a/b/c. To determine their role in apoptosis, miR-29a/b/c were overexpressed in HTR-8/SVneo cells, and levels of apoptosis were analyzed by flow cytometry. Luciferase activity assays were used to determine whether MCL1 is a target gene of miR-29a/b/c. Expression of miR-29a/b/c was significantly lower in creta sites compared to noncreta sites (p = 0.018, 0.041, and 0.022, respectively), but expression of MCL1 was upregulated in creta sites (p = 0.039). MCL1 expression was significantly downregulated in HTR-8/SVneo cells overexpressing miR-29a/b/c (p = 0.002, 0.008, and 0.013, respectively). Luciferase activity assays revealed that miR-29a/b/c directly target the 3' untranslated region of MCL1 in 293T cells. Over-expression of miR-29a/b/c induced apoptosis in the HTR-8/SVneo trophoblast cell line. Moreover, histopathological evaluation revealed that the number of implantation site intermediate trophoblast (ISIT) cells was increased in creta sites and that these cells were positive for MCL1. Our results demonstrate that in placenta accreta, miR-29a/b/c inhibits apoptosis of ISIT cells by targeting MCL1. These findings provide new insights into the pathogenesis of placenta accreta. Copyright © 2016 Elsevier Ltd. All rights

  8. A Categorification of the Crystal Isomorphism B 1,1 B + B(Lambda i) = B(Lambdasigma (i) and a Graphical Calculus for the Shifted Symmetric Functions

    NASA Astrophysics Data System (ADS)

    Kvinge, Henry

    We prove two results at the intersection of Lie theory and the representation theory of symmetric groups, Hecke algebras, and their generalizations. The first is a categorification of the crystal isomorphism B. (1,1) tensor B1,1B(Lambdai ) ≅ B(Lambdasigma (i)). Here B(Lambdai and B(Lambda sigma(i)) are two affine type highest weight crystals of weight Lambdai and Lambdasigma (i) respectively, sigma is a specific map from the Dynkin indexing set I to itself, and B1,1 is a Kirillov-Reshetikhin crystal. We show that this crystal isomorphism is in fact the shadow of a richer module-theoretic phenomenon in the representation theory of Khovanov-Lauda-Rouquier algebras of classical affine type. Our second result identifies the center EndH'( 1) of Khovanov's Heisenberg category H', as the algebra of shifted symmetric functions Lambda* of Okounkov and Olshanski, i.e. End H'(1) ≅ Lambda*. This isomorphism provides us with a graphical calculus for Lambda*. It also allows us to describe EndH'(1) in terms of the transition and co-transition measure of Kerov and the noncommutative probability spaces of Biane.

  9. Suppression of complement regulatory protein C1 inhibitor in vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action

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

    Zhang, Haimou; Qin, Gangjian; Liang, Gang

    Increased expression of adhesion molecules by activated endothelium is a critical feature of vascular inflammation associated with the several diseases such as endotoxin shock and sepsis/septic shock. Our data demonstrated complement regulatory protein C1 inhibitor (C1INH) prevents endothelial cell injury. We hypothesized that C1INH has the ability of an anti-endothelial activation associated with suppression of expression of adhesion molecule(s). C1INH blocked leukocyte adhesion to endothelial cell monolayer in both static assay and flow conditions. In inflammatory condition, C1INH reduced vascular cell adhesion molecule (VCAM-1) expression associated with its cytoplasmic mRNA destabilization and nuclear transcription level. Studies exploring the underlying mechanismmore » of C1INH-mediated suppression in VCAM-1 expression were related to reduction of NF-{kappa}B activation and nuclear translocation in an I{kappa}B{alpha}-dependent manner. The inhibitory effects were associated with reduction of inhibitor I{kappa}B kinase activity and stabilization of the NF-{kappa}B inhibitor I{kappa}B. These findings indicate a novel role for C1INH in inhibition of vascular endothelial activation. These observations could provide the basis for new therapeutic application of C1INH to target inflammatory processes in different pathologic situations.« less

  10. Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients.

    PubMed

    Jada, Srinivasa Rao; Lim, Robert; Wong, Chiung Ing; Shu, Xiaochen; Lee, Soo Chin; Zhou, Qingyu; Goh, Boon Cher; Chowbay, Balram

    2007-09-01

    The objectives of the present study were (i) to study the pharmacogenetics of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A in three distinct healthy Asian populations (Chinese, Malays and Indians), and (ii) to investigate the polygenic influence of these polymorphic variants in irinotecan-induced neutropenia in Asian cancer patients. Pharmacokinetic and pharmacogenetic analyses were done after administration of irinotecan as a 90-min intravenous infusion of 375 mg/m(2) once every 3 weeks (n = 45). Genotypic-phenotypic correlates showed a non-significant influence of UGT1A1*28 and ABCG2 c.421C>A polymorphisms on the pharmacokinetics of SN-38 (P > 0.05), as well as severity of neutropenia (P > 0.05). Significantly higher exposure levels to SN-38 (P = 0.018), lower relative extent of glucuronidation (REG; P = 0.006) and higher biliary index (BI; P = 0.003) were found in cancer patients homozygous for the UGT1A1*6 allele compared with patients harboring the reference genotype. The mean absolute neutrophil count (ANC) was 85% lower and the prevalence of grade 4 neutropenia (ANC < or = 500/microL) was 27% in patients homozygous for UGT1A1*6 compared with the reference group. Furthermore, the presence of the UGT1A1*6 allele was associated with an approximately 3-fold increased risk of developing severe grade 4 neutropenia compared with patients harboring the reference genotype. These exploratory findings suggest that homozygosity for UGT1A1*6 allele may be associated with altered SN-38 disposition and may increase the risk of severe neutropenia in Asian cancer patients, particularly in the Chinese cancer patients who comprised 80% (n = 36) of the patient population in the present study.

  11. Vapor-liquid equilibria for the systems composed of 1-chloro-1,1-difluoroethane, 1,1-dichloro-1-fluoroethane, and 1,1,1-trichloroethane at 50.1 C

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

    Kang, Y.W.; Lee, Y.Y.

    1996-03-01

    Isothermal vapor-liquid equilibria for the three binary systems 1-chloro-1,1-difluoroethane + 1,1-dichloro-1-fluoroethane, 1-chloro-1,1-difluoroethane + 1,1,1-trichloroethane, and 1,1-dichloro-1-fluoroethane + 1,1,1-trichloroethane and the ternary system 1-chloro-1,1-difluoromethane + 1,1-dichloro-1-fluoroethane + 1,1,1-trichloroethane have been measured at 50.1 C. The experimental data for the binary systems are correlated with the Peng-Robinson equation of state, and the relevant parameters are presented. The predicted results for the ternary system were found to be in good agreement with the experimental data.

  12. 26 CFR 1.501(c)(7)-1 - Social clubs.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 7 2013-04-01 2013-04-01 false Social clubs. 1.501(c)(7)-1 Section 1.501(c)(7... (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(c)(7)-1 Social clubs. (a) The exemption... general, this exemption extends to social and recreation clubs which are supported solely by membership...

  13. 26 CFR 1.501(c)(7)-1 - Social clubs.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 7 2012-04-01 2012-04-01 false Social clubs. 1.501(c)(7)-1 Section 1.501(c)(7... (CONTINUED) INCOME TAXES (CONTINUED) Exempt Organizations § 1.501(c)(7)-1 Social clubs. (a) The exemption... general, this exemption extends to social and recreation clubs which are supported solely by membership...

  14. Scalable Directed Assembly of Highly Crystalline 2,7-Dioctyl[1]benzothieno[3,2- b][1]benzothiophene (C8-BTBT) Films.

    PubMed

    Chai, Zhimin; Abbasi, Salman A; Busnaina, Ahmed A

    2018-05-30

    Assembly of organic semiconductors with ordered crystal structure has been actively pursued for electronics applications such as organic field-effect transistors (OFETs). Among various film deposition methods, solution-based film growth from small molecule semiconductors is preferable because of its low material and energy consumption, low cost, and scalability. Here, we show scalable and controllable directed assembly of highly crystalline 2,7-dioctyl[1]benzothieno[3,2- b][1]benzothiophene (C8-BTBT) films via a dip-coating process. Self-aligned stripe patterns with tunable thickness and morphology over a centimeter scale are obtained by adjusting two governing parameters: the pulling speed of a substrate and the solution concentration. OFETs are fabricated using the C8-BTBT films assembled at various conditions. A field-effect hole mobility up to 3.99 cm 2 V -1 s -1 is obtained. Owing to the highly scalable crystalline film formation, the dip-coating directed assembly process could be a great candidate for manufacturing next-generation electronics. Meanwhile, the film formation mechanism discussed in this paper could provide a general guideline to prepare other organic semiconducting films from small molecule solutions.

  15. Genetic variations of the SLCO1B1 gene in the Chinese, Malay and Indian populations of Singapore.

    PubMed

    Ho, Woon Fei; Koo, Seok Hwee; Yee, Jie Yin; Lee, Edmund Jon Deoon

    2008-01-01

    OATP1B1 is a liver-specific transporter that mediates the uptake of various endogenous and exogenous compounds including many clinically used drugs from blood into hepatocytes. This study aims to identify genetic variations of SLCO1B1 gene in three distinct ethnic groups of the Singaporean population (n=288). The coding region of the gene encoding the transporter protein was screened for genetic variations in the study population by denaturing high-performance liquid chromatography and DNA sequencing. Twenty-five genetic variations of SLCO1B1, including 10 novel ones, were found: 13 in the coding exons (9 nonsynonymous and 4 synonymous variations), 6 in the introns, and 6 in the 3' untranslated region. Four novel nonsynonymous variations: 633A>G (Ile211Met), 875C>T (Ala292Val), 1837T>C (Cys613Arg), and 1877T>A (Leu626Stop) were detected as heterozygotes. Among the novel nonsynonymous variations, 633A>G, 1837T>C, and 1877T>A were predicted to be functionally significant. These data would provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of OATP1B1 in Asians.

  16. Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1.

    PubMed

    Gale, Daniel P; Molyneux, Karen; Wimbury, David; Higgins, Patricia; Levine, Adam P; Caplin, Ben; Ferlin, Anna; Yin, Peiran; Nelson, Christopher P; Stanescu, Horia; Samani, Nilesh J; Kleta, Robert; Yu, Xueqing; Barratt, Jonathan

    2017-07-01

    IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O -glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in white and Chinese populations. Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. White patients with IgAN exhibited significantly higher Gd-IgA1 levels than did Chinese patients. Among individuals without IgAN, Gd-IgA1 levels did not correlate with kidney function. Gd-IgA1 level heritability (h 2 ), estimated by comparing midparental and offspring Gd-IgA1 levels, was 0.39. Genome-wide association analysis by linear regression identified alleles at a single locus spanning the C1GALT1 gene that strongly associated with Gd-IgA1 level ( β =0.26; P =2.35×10 -9 ). This association was replicated in a genome-wide association study of separate cohorts comprising 308 patients with membranous GN from the UK ( P <1.00×10 -6 ) and 622 controls with normal kidney function from the UK ( P <1.00×10 -10 ), and in a candidate gene study of 704 Chinese patients with IgAN ( P <1.00×10 -5 ). The same extended haplotype associated with elevated Gd-IgA1 levels in all cohorts studied. C1GALT1 encodes a galactosyltransferase enzyme that is important in O -galactosylation of glycoproteins. These findings demonstrate that common variation at C1GALT1 influences Gd-IgA1 level in the population, which independently associates with risk of progressive IgAN, and that the pathogenic importance of changes in IgA1 O -glycosylation may vary between white and Chinese patients with IgAN. Copyright © 2017 by the American Society of Nephrology.

  17. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 12 2011-04-01 2011-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business...

  18. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 12 2014-04-01 2014-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business...

  19. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 12 2013-04-01 2013-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business...

  20. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 12 2012-04-01 2012-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES (CONTINUED) Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business...

  1. A novel monoclonal antibody, C41, reveals IL-13Ralpha1 expression by murine germinal center B cells and follicular dendritic cells.

    PubMed

    Poudrier, J; Graber, P; Herren, S; Berney, C; Gretener, D; Kosco-Vilbois, M H; Gauchat, J F

    2000-11-01

    Responsiveness to IL-13 involves at least two chains, IL-4Ralpha and IL-13Ralpha1. Although mouse B cells express IL-4Ralpha, little is known about their expression of IL-13Ralpha chains. To investigate this topic further, we have generated a monoclonal antibody (C41) specific for murine IL-13Ralpha1. Using C41, IL-13Ralpha1 expression was detected on germinal center (GC) B cells by flow cytometry and immunohistochemistry. In addition, IL-13Ralpha1 was observed on follicular dendritic cells, but not interdigitating dendritic cells in the T cell areas. Furthermore, resting B cells also expressed IL-13Ralpha1, and in the presence of IL-13 produced increased amounts of IgM in response to in vitro CD40 stimulation. However, C41 was unable to neutralize this bioactivity. The distribution of IL-13Ralpha1 on murine B cells and during GC reactions suggests a role for IL-13 during B cell differentiation.

  2. Induction of cytochromes P450 1A1 and 1B1 in human lung adenocarcinoma CL5 cells by frying-meat emission particulate.

    PubMed

    Wang, H-W; Chen, T-L; Yang, P-C; Ma, Y-C; Yu, C-C; Ueng, T-H

    2002-05-01

    The effect of airborne frying-meat emission particulate (FMEP) on cytochrome P450 (P450)-dependent monooxygenase was determined using human lung adenocarcinoma cell line CL5 treated with organic extract of FMEP prepared from beef, fish or pork. Treatment with fish FMEP extract caused greater increases of intracellular peroxide production and glutathione content than did beef and pork FMEP extracts. Treatment with 200 microg/ml beef, fish or pork FMEP extract for 6 h increased benzo[a]pyrene hydroxylase, 7-ethoxyresorufin and methoxyresorufin O-dealkylases activities in S9. Immunoblot analysis of S9 proteins from control cells and cells treated with FMEP extracts revealed that the airborne particulates increased proteins immunorelated to CYP1A1 and CYP1B1. Northern blot analysis of total cellular RNA from controls and cells treated with FMEP extracts showed that the cooking by-products increased the levels of CYP1A1 and CYP1B1 mRNA. Treatment with 1 microM dibenzo[a,h]anthracene for 6 h increased monooxygenase activities, CYP1A1 and CYP1B1 protein and mRNA levels in CL5 cells. Beef FMEP extract and dibenzo[a,h]anthracene also induced CYP1A1 and CYP1B1 in human lung carcinoma NCI-H322 cells. The present finding demonstrates that airborne particulates generated during the frying of beef, fish and pork can induce carcinogen-metabolizing CYP1A1 and CYP1B1 in the human lung-derived cell line CL5.

  3. Global standardisation of HbA1c.

    PubMed

    Lai, Leslie C

    2008-12-01

    HbA1c is used for assessing glycaemic control in patients with diabetes. It is also used for treatment goals and as a target for therapeutic intervention. The Direct Control and Complications Trial in the USA showed that HbA1c can be used to predict the risk of complications. Hence, it is important for HbA1c assays to be standardised. The National Glycohemoglobin Standardization Program (NGSP) in the USA was formed in 1996 so that HbA1c results from different laboratories would be comparable to those reported in the DCCT study. There were also HbA1c standardisation programmes in Sweden and Japan. These three standardisation programmes are, in fact, direct comparison methods (DCMs), and yield different HbA1c results. In 1994, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) established a Working Group on Standardisation of HbA1c. This working group has developed a global HbA1c reference system with very much improved intra-assay and inter-assay coefficients of variation. Recommendations have been made to report HbA1c results as IFCC-HbA1c values in SI units (mmol HbA1c/mol Hb) and NGSP-HbA1c (%) as well as estimated average glucose (eAG), once a tight relationship has been shown to exist between eAG and HbA1c.

  4. Structure investigation of maltacine B1a, B1b, B2a and B2b: cyclic peptide lactones of the maltacine complex from Bacillus subtilis.

    PubMed

    Hagelin, Gunnar

    2005-04-01

    A new complex of cyclic peptide lactone antibiotics from Bacillus subtilis, which we named maltacines, has recently been described. The structure elucidation of four of them is reported in this paper. The amino acid sequences and structures of the peptides were found by MSn of the ring-opened linear peptides that gave uninterrupted sequences of Bn and Y''n ions. The identities of three unknown residues in the sequences were solved by a combination of derivatization with phenyl isothiocyanate (PITC), high-resolution mass spectrometry and H/D exchange. The nature and position of the cyclic structure were revealed by a chemoselective ring opening with Na18OH and was found to be a lactone formed between a hydroxyl of residue number 4 and the C-terminal amino acid number 12. For verification of the structure of the B2+ ion, peptides with different combinations of P/Q and P/K at the N-terminus were synthesized. The structures of the four peptides were found to be as follows: B1a/B2a, cyclo-4,12(P-Q-Y-HNLeu-A-E-T-Y-Orn-103-Y-I-OH); and B1b/B2b, cyclo-4,12(P-Q-Y-HNLeu-A-E-T-Y-K-103-Y-I-OH). Copyright 2005 John Wiley & Sons, Ltd.

  5. Axial resonances a$$_{1}$$(1260), b$$_{1}$$(1235) and their decays from the lattice

    DOE PAGES

    Lang, C. B.; Leskovec, Luka; Mohler, Daniel; ...

    2014-04-28

    The light axial-vector resonancesmore » $$a_1(1260)$$ and $$b_1(1235)$$ are explored in Nf=2 lattice QCD by simulating the corresponding scattering channels $$\\rho\\pi$$ and $$\\omega\\pi$$. Interpolating fields $$\\bar{q} q$$ and $$\\rho\\pi$$ or $$\\omega\\pi$$ are used to extract the s-wave phase shifts for the first time. The $$\\rho$$ and $$\\omega$$ are treated as stable and we argue that this is justified in the considered energy range and for our parameters $$m_\\pi\\simeq 266~$$MeV and $$L\\simeq 2~$$fm. We neglect other channels that would be open when using physical masses in continuum. Assuming a resonance interpretation a Breit-Wigner fit to the phase shift gives the $$a_1(1260)$$ resonance mass $$m_{a1}^{res}=1.435(53)(^{+0}_{-109})$$ GeV compared to $$m_{a1}^{exp}=1.230(40)$$ GeV. The $$a_1$$ width $$\\Gamma_{a1}(s)=g^2 p/s$$ is parametrized in terms of the coupling and we obtain $$g_{a_1\\rho\\pi}=1.71(39)$$ GeV compared to $$g_{a_1\\rho\\pi}^{exp}=1.35(30)$$ GeV derived from $$\\Gamma_{a1}^{exp}=425(175)$$ MeV. In the $$b_1$$ channel, we find energy levels related to $$\\pi(0)\\omega(0)$$ and $$b_1(1235)$$, and the lowest level is found at $$E_1 \\gtrsim m_\\omega+m_\\pi$$ but is within uncertainty also compatible with an attractive interaction. Lastly, assuming the coupling $$g_{b_1\\omega\\pi}$$ extracted from the experimental width we estimate $$m_{b_1}^{res}=1.414(36)(^{+0}_{-83})$$.« less

  6. The effect of excision of the posterior arch of C1 on C1/C2 fusion using transarticular screws.

    PubMed

    Chang, K C; Samartzis, D; Fuego, S M; Dhatt, S S; Wong, Y W; Cheung, W Y; Luk, K D K; Cheung, K M C

    2013-07-01

    Transarticular screw fixation with autograft is an established procedure for the surgical treatment of atlantoaxial instability. Removal of the posterior arch of C1 may affect the rate of fusion. This study assessed the rate of atlantoaxial fusion using transarticular screws with or without removal of the posterior arch of C1. We reviewed 30 consecutive patients who underwent atlantoaxial fusion with a minimum follow-up of two years. In 25 patients (group A) the posterior arch of C1 was not excised (group A) and in five it was (group B). Fusion was assessed on static and dynamic radiographs. In selected patients CT imaging was also used to assess fusion and the position of the screws. There were 15 men and 15 women with a mean age of 51.2 years (23 to 77) and a mean follow-up of 7.7 years (2 to 11.6). Stable union with a solid fusion or a stable fibrous union was achieved in 29 patients (97%). In Group A, 20 patients (80%) achieved a solid fusion, four (16%) a stable fibrous union and one (4%) a nonunion. In Group B, stable union was achieved in all patients, three having a solid fusion and two a stable fibrous union. There was no statistically significant difference between the status of fusion in the two groups. Complications were noted in 12 patients (40%); these were mainly related to the screws, and included malpositioning and breakage. The presence of an intact or removed posterior arch of C1 did not affect the rate of fusion in patients with atlantoaxial instability undergoing C1/C2 fusion using transarticular screws and autograft.

  7. Allele frequencies in the VRN-A1, VRN-B1 and VRN-D1 vernalization response and PPD-B1 and PPD-D1 photoperiod sensitivity genes, and their effects on heading in a diverse set of wheat cultivars (Triticum aestivum L.).

    PubMed

    Kiss, Tibor; Balla, Krisztina; Veisz, Ottó; Láng, László; Bedő, Zoltán; Griffiths, Simon; Isaac, Peter; Karsai, Ildikó

    2014-01-01

    Heading of cereals is determined by complex genetic and environmental factors in which genes responsible for vernalization and photoperiod sensitivity play a decisive role. Our aim was to use diagnostic molecular markers to determine the main allele types in VRN - A1 , VRN - B1 , VRN - D1 , PPD - B1 and PPD - D1 in a worldwide wheat collection of 683 genotypes and to investigate the effect of these alleles on heading in the field. The dominant VRN - A1 , VRN - B1 and VRN - D1 alleles were present at a low frequency. The PPD - D1a photoperiod-insensitive allele was carried by 57 % of the cultivars and was most frequent in Asian and European cultivars. The PPD - B1 photoperiod-insensitive allele was carried by 22 % of the genotypes from Asia, America and Europe. Nine versions of the PPD - B1 -insensitive allele were identified based on gene copy number and intercopy structure. The allele compositions in PPD - D1 , PPD - B1 and VRN - D1 significantly influenced heading and together explained 37.5 % of the phenotypic variance. The role of gene model increased to 39.1 % when PPD - B1 intercopy structure was taken into account instead of overall PPD - B1 type (sensitive vs. insensitive). As a single component, PPD - D1 had the most important role (28.0 % of the phenotypic variance), followed by PPD - B1 (12.3 % for PPD - B1 _overall, and 15.1 % for PPD - B1 _intercopy) and VRN - D1 (2.2 %). Significant gene interactions were identified between the marker alleles within PPD - B1 and between VRN - D1 and the two PPD1 genes. The earliest heading genotypes were those with the photoperiod-insensitive allele in PPD - D1 and PPD - B1 , and with the spring allele for VRN - D1 and the winter alleles for VRN - A1 and VRN - B1 . This combination could only be detected in genotypes from Southern Europe and Asia. Late-heading genotypes had the sensitivity alleles for both PPD1 genes, regardless of the allelic composition of the VRN1 genes. There was a 10-day difference in

  8. Menadione induces G2/M arrest in gastric cancer cells by down-regulation of CDC25C and proteasome mediated degradation of CDK1 and cyclin B1

    PubMed Central

    Lee, Min Ho; Cho, Yoonjung; Kim, Do Hyun; Woo, Hyun Jun; Yang, Ji Yeong; Kwon, Hye Jin; Yeon, Min Ji; Park, Min; Kim, Sa-Hyun; Moon, Cheol; Tharmalingam, Nagendran; Kim, Tae Ue; Kim, Jong-Bae

    2016-01-01

    Menadione (vitamin K3) has been reported to induce apoptotic cell death and growth inhibition in various types of cancer cells. However, involvement of menadione in cell cycle control has not been considered in gastric cancer cells yet. In the current study, we have investigated whether menadione is involved in the cell cycle regulation and suppression of growth in gastric cancer cells. In the cell cycle analysis, we found that menadione induced G2/M cell cycle arrest in AGS cells. To elucidate the underlying mechanism, we investigated the cell cycle regulatory molecules involved in the G2/M cell cycle transition. After 24 h of menadione treatment, the protein level of CDK1, CDC25C and cyclin B1 in AGS cells was decreased in a menadione dose-dependent manner. In the time course experiment, the protein level of CDC25C decreased in 6 h, and CDK1and cyclin B1 protein levels began to decrease after 18 h of menadione treatment. We found that mRNA level of CDC25C decreased by menadione treatment in 6 h. Menadione did not have an influence on mRNA level of CDK1 and cyclin B1 though the protein levels were decreased. However, the decreased protein levels of CDK1 and cyclin B1 were recovered by inhibition of proteasome. Collectively, these results suggest that menadione inhibits growth of gastric cancer cells by reducing expression of CDC25C and promoting proteasome mediated degradation of CDK1 and cyclin B1 thereby blocking transition of the cell cycle from G2 phase to M phase. PMID:28077999

  9. 26 CFR 1.1402(c)-1 - Trade or business.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Trade or business. 1.1402(c)-1 Section 1.1402(c... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(c)-1 Trade or business. In order for an individual to have net earnings from self-employment, he must carry on a trade or business, either as an...

  10. 26 CFR 1.678(c)-1 - Trusts for support.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Trusts for support. 1.678(c)-1 Section 1.678(c... (CONTINUED) INCOME TAXES Grantors and Others Treated As Substantial Owners § 1.678(c)-1 Trusts for support... cotrustee, to apply the income of the trust to the support or maintenance of a person whom the holder is...

  11. Antihyperalgesic activity of a novel nonpeptide bradykinin B1 receptor antagonist in transgenic mice expressing the human B1 receptor

    PubMed Central

    Fox, Alyson; Kaur, Satbir; Li, Bifang; Panesar, Moh; Saha, Uma; Davis, Clare; Dragoni, Ilaria; Colley, Sian; Ritchie, Tim; Bevan, Stuart; Burgess, Gillian; McIntyre, Peter

    2005-01-01

    We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP-SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. NVP-SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (Ki 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (Ki 7.7 nM), NVP-SAA164 showed no affinity for the rat B1 receptor expressed in Cos-7 cells. In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1-KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1-KO) mice following LPS treatment. Freund's complete adjuvant-induced mechanical hyperalgesia was similar in wild-type and hB1-KI mice, but was significantly reduced in mB1-KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild-type and hB1-KI mice, but was absent in mB1-KO animals. Oral administration of NVP-SAA164 produced a dose-related reversal of FCA-induced mechanical hyperalgesia and desArg10KD-induced hyperalgesia in hB1-KI mice, but was inactive against inflammatory pain in wild-type mice. These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP-SAA164 is a novel orally active B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man. PMID:15685199

  12. c-Myc Represses Transcription of Epstein-Barr Virus Latent Membrane Protein 1 Early after Primary B Cell Infection.

    PubMed

    Price, Alexander M; Messinger, Joshua E; Luftig, Micah A

    2018-01-15

    Recent evidence has shown that the Epstein-Barr virus (EBV) oncogene LMP1 is not expressed at high levels early after EBV infection of primary B cells, despite its being essential for the long-term outgrowth of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 increased 50-fold between 7 days postinfection and the LCL state. Metabolic labeling of nascent transcribed mRNA indicated that this was primarily a transcription-mediated event. EBNA2, the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, were recruited to the LMP1 locus similarly early and late after infection. However, the activating histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to that in infected B cells early after infection. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression of c-Myc in an LCL model system repressed LMP1 transcription. Finally, we found that chemical inhibition of c-Myc both in LCLs and early after primary B cell infection increased LMP1 expression. These data support a model in which high levels of endogenous c-Myc activity induced early after primary B cell infection directly repress LMP1 transcription. IMPORTANCE EBV is a highly successful pathogen that latently infects more than 90% of adults worldwide and is also causally associated with a number of B cell malignancies. During the latent life cycle, EBV expresses a set of viral oncoproteins and noncoding RNAs with the potential to promote cancer. Critical among these is the viral latent membrane protein LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here we show that transcription of the LMP1 gene can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV oncogenes will allow us

  13. Cloning and characterization of the mouse alpha1C/A-adrenergic receptor gene and analysis of an alpha1C promoter in cardiac myocytes: role of an MCAT element that binds transcriptional enhancer factor-1 (TEF-1).

    PubMed

    O'Connell, T D; Rokosh, D G; Simpson, P C

    2001-05-01

    alpha1-Adrenergic receptor (AR) subtypes in the heart are expressed by myocytes but not by fibroblasts, a feature that distinguishes alpha1-ARs from beta-ARs. Here we studied myocyte-specific expression of alpha1-ARs, focusing on the subtype alpha1C (also called alpha1A), a subtype implicated in cardiac hypertrophic signaling in rat models. We first cloned the mouse alpha1C-AR gene, which consisted of two exons with an 18 kb intron, similar to the alpha1B-AR gene. The receptor coding sequence was >90% homologous to that of rat and human. alpha1C-AR transcription in mouse heart was initiated from a single Inr consensus sequence at -588 from the ATG; this and a putative polyadenylation sequence 8.5 kb 3' could account for the predominant 11 kb alpha1C mRNA in mouse heart. A 5'-nontranscribed fragment of 4.4 kb was active as a promoter in cardiac myocytes but not in fibroblasts. Promoter activity in myocytes required a single muscle CAT (MCAT) element, and this MCAT bound in vitro to recombinant and endogenous transcriptional enhancer factor-1. Thus, alpha1C-AR transcription in cardiac myocytes shares MCAT dependence with other cardiac-specific genes, including the alpha- and beta-myosin heavy chains, skeletal alpha-actin, and brain natriuretic peptide. However, the mouse alpha1C gene was not transcribed in the neonatal heart and was not activated by alpha1-AR and other hypertrophic agonists in rat myocytes, and thus differed from other MCAT-dependent genes and the rat alpha1C gene.

  14. Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1).

    PubMed

    Bachvarov, D R; Hess, J F; Menke, J G; Larrivée, J F; Marceau, F

    1996-05-01

    Two subtypes of mammalian bradykinin receptors, B1 and B2 (BDKRB1 and BDKRB2), have been defined based on their pharmacological properties. The B1 type kinin receptors have weak affinity for intact BK or Lys-BK but strong affinity for kinin metabolites without the C-terminal arginine (e.g., des-Arg9-BK and Lys-des-Arg9-BK, also called des-Arg10-kallidin), which are generated by kininase I. The B1 receptor expression is up-regulated following tissue injury and inflammation (hyperemia, exudation, hyperalgesia, etc.). In the present study, we have cloned and sequenced the gene encoding human B1 receptor from a human genomic library. The human B1 receptor gene contains three exons separated by two introns. The first and the second exon are noncoding, while the coding region and the 3'-flanking region are located entirely on the third exon. The exon-intron arrangement of the human B1 receptor gene shows significant similarity with the genes encoding the B2 receptor subtype in human, mouse, and rat. Sequence analysis of the 5'-flanking region revealed the presence of a consensus TATA box and of numerous candidate transcription factor binding sequences. Primer extension experiments have shown the existence of multiple transcription initiation sites situated downstream and upstream from the consensus TATA box. Genomic Southern blot analysis indicated that the human B1 receptor is encoded by a single-copy gene.

  15. Contribution of cytochrome P450 1B1 to hypertension and associated pathophysiology: a novel target for antihypertensive agents.

    PubMed

    Malik, Kafait U; Jennings, Brett L; Yaghini, Fariborz A; Sahan-Firat, Seyhan; Song, Chi Young; Estes, Anne M; Fang, Xiao R

    2012-08-01

    The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone (DOCA)-salt-, and N(ω)-nitro-L-arginine methyl ester-induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II-induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3',5'-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Contribution of Cytochrome P450 1B1 to Hypertension and Associated Pathophysiology: A Novel Target for Antihypertensive Agents

    PubMed Central

    Malik, Kafait U.; Jennings, Brett L.; Yaghini, Fariborz A.; Sahan-Firat, Seyhan; Song, Chi Young; Estes, Anne M.; Fang, Xiao R.

    2012-01-01

    The aim of this review is to discuss the contribution of cytochrome P450 (CYP) 1B1 in vascular smooth muscle cell growth, hypertension, and associated pathophysiology. CYP1B1 is expressed in cardiovascular and renal tissues, and mediates angiotensin II (Ang II)-induced activation of NADPH oxidase and generation of reactive oxygen species (ROS), and vascular smooth muscle cell migration, proliferation, and hypertrophy. Moreover, CYP1B1 contributes to the development and/or maintenance of hypertension produced by Ang II-, deoxycorticosterone Nω-nitro-(DOCA)-salt-, and L-arginine methyl ester-induced hypertension and in spontaneously hypertensive rats. The pathophysiological changes, including cardiovascular hypertrophy, increased vascular reactivity, endothelial and renal dysfunction, injury and inflammation associated with Ang II- and/or DOCA-salt induced hypertension in rats, and Ang II-induced hypertension in mice are minimized by inhibition of CYP1B1 activity with 2,4,3′,5′-tetramethoxystilbene or by Cyp1b1 gene disruption in mice. These pathophysiological changes appear to be mediated by increased production of ROS via CYP1B1-dependent NADPH oxidase activity and extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Src. PMID:22210049

  17. Suppression of gastric cancer dissemination by ephrin-B1-derived peptide.

    PubMed

    Tanaka, Masamitsu; Kamata, Reiko; Yanagihara, Kazuyoshi; Sakai, Ryuichi

    2010-01-01

    Interaction of the Eph family of receptor protein tyrosine kinases and their ligands, ephrin family members, induces bidirectional signaling through cell-cell contacts. High expression of B-type ephrin is associated with high invasion potential of tumors, and we previously observed that signaling through the C-terminus of ephrin-B1 mediates the migration and invasion of cells, and is involved in the promotion of carcinomatous peritonitis in vivo. Here we show that the intracellular introduction of a synthetic peptide derived from ephrin-B1 C-terminus blocks ephrin-B1 mediated signaling in scirrhous gastric cancer cells. Treatment of cancer cells with a fusion peptide consisting of HIV-TAT and amino acids 331-346 of ephrin-B1 (PTD-EFNB1-C) suppressed the activation of RhoA, mediated by the association of ephrin-B1 with an adaptor protein Dishevelled, and also inhibited extracellular secretion of metalloproteinase. Moreover, injection of PTD-EFNB1-C peptide into the peritoneal cavity of nude mice suppressed carcinomatous peritonitis of intraperitoneally transplanted scirrhous gastric cancer cells. These results indicate the possible application of ephrin-B1 C-terminal peptide to develop novel protein therapy for scirrhous gastric carcinoma, especially in the stage of tumor progression, including peritoneal dissemination.

  18. 12. 'Portal Strut for 1 208'101/2' C. to C. ...

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

    12. 'Portal Strut for 1 - 208'-10-1/2' C. to C. End Pins S. Tr. Thro. Skew Span, 6th Crossing of Sacramento River, So. Pac. Co., The Phoenix Bridge Co., C.O. 836D, Drawing No. 12, Scale - 1' = 1', Engineer - B.M. Krohn, May 22nd `01, J.C.S.' - Southern Pacific Railroad Shasta Route, Bridge No. 301.85, Milepost 301.85, Pollard Flat, Shasta County, CA

  19. PITPNC1 recruits RAB1B to the Golgi network to drive malignant secretion

    PubMed Central

    Halberg, Nils; Sengelaub, Caitlin A.; Navrazhina, Kristina; Molina, Henrik; Uryu, Kunihiro; Tavazoie, Sohail F.

    2017-01-01

    SUMMARY Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular and cellular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and over-expressed in metastatic breast, melanoma and colon cancer. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3 to the trans-Golgi, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy. PMID:26977884

  20. Genetic polymorphisms of genes coding to alcohol-metabolizing enzymes in western Mexicans: association of CYP2E1*c2/CYP2E1*5B allele with cirrhosis and liver function.

    PubMed

    García-Bañuelos, Jesús; Panduro, Arturo; Gordillo-Bastidas, Daniela; Gordillo-Bastidas, Elizabeth; Muñoz-Valle, José Francisco; Gurrola-Díaz, Carmen M; Sánchez-Enríquez, Sergio; Ruiz-Madrigal, Bertha; Bastidas-Ramírez, Blanca Estela

    2012-03-01

    Alcoholic cirrhosis constitutes a major public health problem in the world where ADH1B, ALDH2, and CYP2E1 polymorphisms could be playing an important role. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy control individuals (C) and patients with alcoholic cirrhosis (AC) from western Mexico. Ninety C and 41 patients with AC were studied. Genotype and allele frequency were determined through polymerase chain reaction-restriction fragment length polymorphisms. Polymorphic allele distribution in AC was 1.6%ADH1B*2, 0.0%ALDH2*2, and 19.5%CYP2E1*c2; in C: 6.1%ADH1B*2, 0%ALDH2*2, and 10.6%CYP2E1*c2. CYP2E1*c2 polymorphic allele and c1/c2 genotype frequency were significantly higher (p < 0.05 and p < 0.01, respectively) in patients with AC when compared to C. Patients with AC, carrying the CYP2E1*c2 allele, exhibited more decompensated liver functioning evaluated by total bilirubin and prothrombin time, than c1 allele carrying patients (p < 0.05). Cirrhosis severity, assessed by Child's Pugh score and mortality, was higher in patients carrying the c2 allele, although not statistically significant. In this study, CYP2E1*c2 allele was associated with susceptibility to AC; meanwhile, ADH1B*2 and ALDH2*2 alleles were not. CYP2E1*c2 allele was associated with AC severity, which could probably be attributed to the oxidative stress promoted by this polymorphic form. Further studies to clearly establish CYP2E1*c2 clinical relevance in the development of alcohol-induced liver damage and its usefulness as a probable prognostic marker, should be performed. Also, increasing the number of patients and including a control group conformed by alcoholic patients free of liver damage may render more conclusive results. These findings contribute to the understanding of the influence of gene variations in AC development among populations, alcohol metabolism, and pharmacogenetics. Copyright © 2011 by the Research Society on Alcoholism.

  1. Tissue Distribution and Metabolism of Aflatoxin B1-14C in Broiler Chickens

    PubMed Central

    Mabee, Michael S.; Chipley, John R.

    1973-01-01

    The effects of administering low levels of aflatoxin B1-14C by crop intubation daily for 14 days to broiler chickens were determined. Studies on the distribution of 14C in the blood, selected organs, tissues, and excreta were conducted. No toxic effects were observed in broiler chickens during the 14 days of the experiment. The broiler chickens excreted 90.64% of the 14C administered. Of the 14C retained, 11.04, 9.83, 4.30, 12.52, 31.66, and 30.63% were detected in the blood, liver, heart, gizzard, breast, and leg, respectively. Chemical assay of those samples demonstrating radioactivity revealed that 81.2% of the radioactivity in these substrates was not extractable by classical extraction procedures while approximately 10% was extractable. Treatment of aqueous extracts for conjugated steroids by treatments with beta-glucuronidase revealed that 31.5% of the 14C detected in the aqueous extract was a liberated glucuronide conjugate of aflatoxin M1-14C. PMID:4715554

  2. Spontaneous control of HIV-1 viremia in a subject with protective HLA-B plus HLA-C alleles and HLA-C associated single nucleotide polymorphisms.

    PubMed

    Moroni, Marco; Ghezzi, Silvia; Baroli, Paolo; Heltai, Silvia; De Battista, Davide; Pensieroso, Simone; Cavarelli, Mariangela; Dispinseri, Stefania; Vanni, Irene; Pastori, Claudia; Zerbi, Pietro; Tosoni, Antonella; Vicenzi, Elisa; Nebuloni, Manuela; Wong, Kim; Zhao, Hong; McHugh, Sarah; Poli, Guido; Lopalco, Lucia; Scarlatti, Gabriella; Biassoni, Roberto; Mullins, James I; Malnati, Mauro S; Alfano, Massimo

    2014-12-05

    Understanding the mechanisms by which some individuals are able to naturally control HIV-1 infection is an important goal of AIDS research. We here describe the case of an HIV-1(+) woman, CASE1, who has spontaneously controlled her viremia for the last 14 of her 20 years of infection. CASE1 has been clinically monitored since 1993. Detailed immunological, virological and histological analyses were performed on samples obtained between 2009 and 2011. As for other Elite Controllers, CASE1 is characterized by low to undetectable levels of plasma HIV-1 RNA, peripheral blood mononuclear cell (PBMC) associated HIV-1 DNA and reduced in vitro susceptibility of target cells to HIV-1 infection. Furthermore, a slow rate of virus evolution was demonstrated in spite the lack of assumption of any antiretroviral agent. CASE1 failed to transmit HIV-1 to either her sexual male partner or to her child born by vaginal delivery. Normal values and ratios of T and B cells were observed, along with normal histology of the intestinal mucosa. Attempts to isolate HIV-1 from her PBMC and gut-derived cells were unsuccessful, despite expression of normal cell surface levels of CD4, CCRC5 and CXCR4. CASE1 did not produce detectable anti-HIV neutralizing antibodies in her serum or genital mucosal fluid although she displayed potent T cell responses against HIV-1 Gag and Nef. CASE1 also possessed multiple genetic polymorphisms, including HLA alleles (B*14, B*57, C*06 and C*08.02) and HLA-C single nucleotide polymorphisms (SNPs, rs9264942 C/C and rs67384697 del/del), that have been previously individually associated with spontaneous control of plasma viremia, maintenance of high CD4(+) T cell counts and delayed disease progression. CASE1 has controlled her HIV-1 viremia below the limit of detection in the absence of antiretroviral therapy for more than 14 years and has not shown any sign of immunologic deterioration or disease progression. Co-expression of multiple protective HLA alleles, HLA-C

  3. Both alpha(1A)- and alpha(1B)-adrenergic receptors crosstalk to down regulate beta(1)-ARs in mouse heart: coupling to differential PTX-sensitive pathways.

    PubMed

    Rorabaugh, Boyd R; Gaivin, Robert J; Papay, Robert S; Shi, Ting; Simpson, Paul C; Perez, Dianne M

    2005-11-01

    Adrenergic receptors (ARs) play an important role in the regulation of cardiac function. Cardiac inotropy is primarily regulated by beta(1)-ARs. However, alpha(1)-ARs may play an important role in inotropy during heart failure. Previous work has suggested that the alpha(1B)-AR modulates beta(1)-AR function in the heart. The potential role of the alpha(1A)-AR has not been previously studied. We used transgenic mice that express constitutively active mutant (CAM) forms of the alpha(1A)-AR or alpha(1B)-AR regulated by their endogenous promoters. Expression of the CAM alpha(1A)-AR or CAM alpha(1B)-AR had no effect on basal cardiac function (developed pressure, +dP/dT, -dP/dT, heart rate, flow rate). However, both alpha(1)-AR subtypes significantly decreased isoproterenol-stimulated +dP/dT. Pertussis toxin had no effect on +dP/dT in CAM alpha(1A)-AR hearts but restored +dP/dT to non-transgenic values in CAM alpha(1B)-AR hearts. Radioligand binding indicated a selective decrease in the density of beta(1)-ARs in both CAM mice. However, G-proteins, cAMP, or the percentage of high and low affinity states were unchanged in either transgenic compared with control. These data demonstrate that CAM alpha(1A)- and alpha(1B)-ARs both down regulate beta(1)-AR-mediated inotropy in the mouse heart. However, alpha(1)-AR subtypes are coupled to different beta-AR mediated signaling pathways with the alpha(1B)-AR being pertussis toxin sensitive.

  4. C-terminal region of the UV-B photoreceptor UVR8 initiates signaling through interaction with the COP1 protein

    PubMed Central

    Cloix, Catherine; Kaiserli, Eirini; Heilmann, Monika; Baxter, Katherine J.; Brown, Bobby A.; O’Hara, Andrew; Smith, Brian O.; Christie, John M.; Jenkins, Gareth I.

    2012-01-01

    UV-B light initiates photomorphogenic responses in plants. Arabidopsis UV RESISTANCE LOCUS8 (UVR8) specifically mediates these responses by functioning as a UV-B photoreceptor. UV-B exposure converts UVR8 from a dimer to a monomer, stimulates the rapid accumulation of UVR8 in the nucleus, where it binds to chromatin, and induces interaction of UVR8 with CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1), which functions with UVR8 to control photomorphogenic UV-B responses. Although the crystal structure of UVR8 reveals the basis of photoreception, it does not show how UVR8 initiates signaling through interaction with COP1. Here we report that a region of 27 amino acids from the C terminus of UVR8 (C27) mediates the interaction with COP1. The C27 region is necessary for UVR8 function in the regulation of gene expression and hypocotyl growth suppression in Arabidopsis. However, UVR8 lacking C27 still undergoes UV-B–induced monomerization in both yeast and plant protein extracts, accumulates in the nucleus in response to UV-B, and interacts with chromatin at the UVR8-regulated ELONGATED HYPOCOTYL5 (HY5) gene. The UV-B–dependent interaction of UVR8 and COP1 is reproduced in yeast cells and we show that C27 is both necessary and sufficient for the interaction of UVR8 with the WD40 domain of COP1. Furthermore, we show that C27 interacts in yeast with the REPRESSOR OF UV-B PHOTOMORPHOGENESIS proteins, RUP1 and RUP2, which are negative regulators of UVR8 function. Hence the C27 region has a key role in UVR8 function. PMID:22988111

  5. Hemoglobin A1c (HbA1c) changes over time among adolescent and young adult participants in the T1D exchange clinic registry.

    PubMed

    Clements, Mark A; Foster, Nicole C; Maahs, David M; Schatz, Desmond A; Olson, Beth A; Tsalikian, Eva; Lee, Joyce M; Burt-Solorzano, Christine M; Tamborlane, William V; Chen, Vincent; Miller, Kellee M; Beck, Roy W

    2016-08-01

    Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes. Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements. HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory. Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Interleukin 1 β (IL-1B) and IL-1 antagonist receptor (IL-1RN) gene polymorphisms are associated with the genetic susceptibility and steroid dependence in patients with ulcerative colitis.

    PubMed

    Yamamoto-Furusho, Jesús K; Santiago-Hernández, Jean J; Pérez-Hernández, Nonanzit; Ramírez-Fuentes, Silvestre; Fragoso, José Manuel; Vargas-Alarcón, Gilberto

    2011-07-01

    Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Among cytokines induced in UC, interleukin 1 antagonist (IL-1ra) and interleukin 1 β (IL-1β) seems to have a central role because of its immunoregulatory and proinflammatory activities. To determine the association between IL-1RA and IL-1B gene polymorphisms and the clinical features of UC in the Mexican Mestizo population. Five polymorphisms in the IL-1 gene cluster members IL-1B (rs16944), IL1F10 (rs3811058), and IL-1RN (rs419598, rs315952, and rs315951) were genotyped by 5' exonuclease TaqMan genotyping assays in a group of 200 Mexican patients with UC and 248 ethnically matched unrelated healthy controls. We found a significant increased frequencies of IL-1RN6/1 TC (rs315952) and RN6/2 CC (rs315951) and decreased frequency of IL-1B-511 TC (rs16944) genotypes in UC patients as compared with healthy controls. In the subgroup analysis, we found a significant association between the RN6/2 GG (rs315951) and IL-1B-511 CC (rs16944) genotypes and the presence of steroid-dependence in UC patients (pC=00001, OR=15.6 and pC=0.008, OR=4.09, respectively). Patients with UC showed increased frequencies of IL-1RN "CTC" and "TCG" haplotypes when compared with healthy controls (P=0.019, OR=1.43 and P<10(-7), OR=2.63, respectively). Two haplotypes (TTG and CTG) showed decreased frequency in patients when compared with healthy controls (P=9×10(-7), OR=0.11 and P=8×10(-6), OR=0.11, respectively). IL-1 RN and IL-1B polymorphisms were associated with the genetic susceptibility to develop UC and might be associated with the presence of steroid-dependence in UC patients.

  7. 75 FR 3159 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... DEPARTMENT OF THE TREASURY Internal Revenue Service 26 CFR Part 1 [TD 9475] RIN 1545-BF83 Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY... transactions as reorganizations described in section 368(a)(1)(D) where no stock and/or securities of the...

  8. Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors.

    PubMed

    Choi, Min-Koo; Shin, Ho Jung; Choi, Young-Lim; Deng, Jian-Wei; Shin, Jae-Gook; Song, Im-Sook

    2011-01-01

    The purpose of this study was to investigate the effect of genetic variations in organic anion-transporting polypeptide 1B1 (OATP1B1) and Na(+)/taurocholate co-transporting polypeptide (NTCP) on the uptake of various statins having different affinities for these transporters. The functional activities and simultaneous expression of NTCP and OATP1B1 were confirmed by the uptake of taurocholate and estrone-3-sulphate as representative substrates for NTCP and OATP1B1, respectively, and by an immunofluorescence analysis. The substrate specificities of NTCP and OATP1B1 for statins and the effects of genetic variations on the uptake of rosuvastatin, pitavastatin, and atorvastatin were measured. Based on the K(m) values and intrinsic clearances of the three statins, pitavastatin was taken up more efficiently than rosuvastatin and atorvastatin by OATP1B1. Consequently, the cellular accumulation of pitavastatin was modulated according to the genetic variation of OATP1B1 (OATP1B1*15), rather than NTCP*2. In contrast, NTCP*2 displayed greater transport of atorvastatin and rosuvastatin, compared with NTCP wild type. Thus, the measurements of decreased rosuvastatin and atorvastatin transport by OATP1B1*15 were confounded by the presence of NTCP and its genetic variant, NTCP*2. In conclusion, the functional consequences of genetic variants of NTCP and OATP1B1 may be different for various statins, depending on the substrate specificity of the OATP1B1 and NTCP transporters.

  9. Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth

    PubMed Central

    KANO, YOSHIHIRO; KONNO, MASAMITSU; OHTA, KATSUYA; HARAGUCHI, NAOTSUGU; NISHIKAWA, SHIMPEI; KAGAWA, YOSHINORI; HAMABE, ATSUSHI; HASEGAWA, SHINICHIRO; OGAWA, HISATAKA; FUKUSUMI, TAKAHITO; NOGUCHI, YUKO; OZAKI, MIYUKI; KUDO, TOSHIHIRO; SAKAI, DAISUKE; SATOH, TAROH; ISHII, MASARU; MIZOHATA, EIICHI; INOUE, TAKESHI; MORI, MASAKI; DOKI, YUICHIRO; ISHII, HIDESHI

    2013-01-01

    Although esophageal cancer is highly heterogeneous and the involvement of epigenetic regulation of cancer stem cells is highly suspected, the biological significance of epigenetically modified molecules that regulate different subpopulations remains to be firmly established. Using esophageal cancer cells, we investigated the functional roles of the H3K4 demethylase Jumonji/Arid1b (Jarid1b) (Kdm5b/Plu-1/Rbp2-h1), an epigenetic factor that is required for continuous cell growth in melanoma. JARID1B knockdown resulted in the suppression of esophageal cancer cell growth, sphere formation and invasion ability and was associated with loss of epithelial marker expression. However, these inhibitory effects observed on tumor formation were reverted subsequent to subcutaneous inoculation of these cells into immune-deficient mice. These results indicated that JARID1B plays a role in maintaining cancer stem cells in the esophagus and justifies the rationale for studying the effects of continuous inhibition of this epigenetic factor in esophageal cancer. PMID:24649241

  10. Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

    PubMed Central

    Li, Jianchao; He, Yunyun; Weck, Meredith L.; Lu, Qing; Tyska, Matthew J.; Zhang, Mingjie

    2017-01-01

    Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a. PMID:28439001

  11. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 4 2014-04-01 2014-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a... (4), the acquiring corporation shall compute its depreciation allowance by the same method used by...

  12. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 4 2012-04-01 2012-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES (Continued) Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a... (4), the acquiring corporation shall compute its depreciation allowance by the same method used by...

  13. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 4 2011-04-01 2011-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a) Carryover... (4), the acquiring corporation shall compute its depreciation allowance by the same method used by...

  14. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 4 2013-04-01 2013-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a... (4), the acquiring corporation shall compute its depreciation allowance by the same method used by...

  15. 26 CFR 1.381(c)(6)-1 - Depreciation method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Depreciation method. 1.381(c)(6)-1 Section 1.381... (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(6)-1 Depreciation method. (a) Carryover... (4), the acquiring corporation shall compute its depreciation allowance by the same method used by...

  16. 26 CFR 1.381(c)(8)-1 - Installment method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 4 2014-04-01 2014-04-01 false Installment method. 1.381(c)(8)-1 Section 1.381... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(8)-1 Installment method. (a... the installment method, then the acquiring corporation shall be treated as the distributor or...

  17. 26 CFR 1.381(c)(8)-1 - Installment method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 4 2012-04-01 2012-04-01 false Installment method. 1.381(c)(8)-1 Section 1.381... (CONTINUED) INCOME TAXES (Continued) Insolvency Reorganizations § 1.381(c)(8)-1 Installment method. (a... the installment method, then the acquiring corporation shall be treated as the distributor or...

  18. 26 CFR 1.381(c)(8)-1 - Installment method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 4 2013-04-01 2013-04-01 false Installment method. 1.381(c)(8)-1 Section 1.381... (CONTINUED) INCOME TAXES (CONTINUED) Insolvency Reorganizations § 1.381(c)(8)-1 Installment method. (a... the installment method, then the acquiring corporation shall be treated as the distributor or...

  19. Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population

    PubMed Central

    Millá, Elena; Mañé, Begoña; Duch, Susana; Hernan, Imma; Borràs, Emma; Planas, Ester; Dias, Miguel de Sousa; Carballo, Miguel

    2013-01-01

    Purpose To identify myocilin (MYOC) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in a Spanish population with different clinical forms of familial glaucoma or ocular hypertension (OHT). Methods Index patients from 226 families participated in this study. Patients were diagnosed with familial glaucoma or OHT by complete ophthalmologic examination. Screening for MYOC mutations was performed in 207 index patients: 96 with adult-onset primary open-angle glaucoma (POAG), 21 with primary congenital glaucoma (PCG), 18 with juvenile-onset open-angle glaucoma (JOAG), five with Axenfeld-Rieger syndrome (ARS), and 67 with other types of glaucoma. One hundred two of the families (including all those in whom a MYOC mutation was detected) were also screened for CYP1B1 mutations: 45 POAG, 25 PCG, 21 JOAG, four ARS, and seven others. Results We examined 292 individuals (patients and relatives) with a positive family history of glaucoma or OHT. We identified two novel MYOC variants, p.Lys39Arg and p.Glu218Lys, in two families with POAG, and six previously reported MYOC mutations in seven families with POAG (four), JOAG (one), PCG (one), and normotensive glaucoma (one). CYP1B1 mutations were found in 16 index patients with PCG (nine), POAG (three), JOAG (two), and ARS (two). Conclusions The high percentage (9/25=36%) of mutations in CYP1B1 found in non-consanguineous patients with congenital glaucoma mandates genetic testing. However, the percentage of mutations (9/207=4.4%) in MYOC associated with glaucoma is relatively low in our population. The variable phenotype expression of glaucoma, even in families, cannot be explained with a digenic mechanism between MYOC and CYP1B1. PMID:23922489

  20. 75 FR 3160 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-20

    ... DEPARTMENT OF THE TREASURY Internal Revenue Service 26 CFR Part 1 [TD 9475] RIN 1545-BF83 Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY... reorganizations described in section 368(a)(1)(D) where no stock and/or securities of the acquiring corporation is...

  1. Gene-Gene Combination Effect and Interactions among ABCA1, APOA1, SR-B1, and CETP Polymorphisms for Serum High-Density Lipoprotein-Cholesterol in the Japanese Population

    PubMed Central

    Nakamura, Akihiko; Niimura, Hideshi; Kuwabara, Kazuyo; Takezaki, Toshiro; Morita, Emi; Wakai, Kenji; Hamajima, Nobuyuki; Nishida, Yuichiro; Turin, Tanvir Chowdhury; Suzuki, Sadao; Ohnaka, Keizo; Uemura, Hirokazu; Ozaki, Etsuko; Hosono, Satoyo; Mikami, Haruo; Kubo, Michiaki; Tanaka, Hideo

    2013-01-01

    Background/Objective Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population. Methods The study population comprised 1,535 men and 1,515 women aged 35–69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region. Principal Findings Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001). Conclusions The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present. PMID:24376512

  2. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802(b)-1 Tax on life..., and ending after August 16, 1954, section 802(b) imposes a tax on the 1954 life insurance company...

  3. Reduced physiologically-based pharmacokinetic model of repaglinide: impact of OATP1B1 and CYP2C8 genotype and source of in vitro data on the prediction of drug-drug interaction risk.

    PubMed

    Gertz, Michael; Tsamandouras, Nikolaos; Säll, Carolina; Houston, J Brian; Galetin, Aleksandra

    2014-09-01

    To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model. Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T>C were used to estimate hepatic uptake clearance (CLuptake) in different genotype groups applying a population approach in NONMEM v.7.2. Estimated repaglinide CLuptake corresponded to 217 and 113 μL/min/10(6) cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies. The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.

  4. 26 CFR 1.381(c)(8)-1 - Installment method.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Installment method. 1.381(c)(8)-1 Section 1.381... (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(8)-1 Installment method. (a) Carryover... corporation has elected under section 453 and the regulations thereunder to report on the installment method...

  5. 26 CFR 1.381(c)(8)-1 - Installment method.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 4 2011-04-01 2011-04-01 false Installment method. 1.381(c)(8)-1 Section 1.381... (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(8)-1 Installment method. (a) Carryover... corporation has elected under section 453 and the regulations thereunder to report on the installment method...

  6. 26 CFR 1.410(b)-4 - Nondiscriminatory classification test.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... unsafe harbor percentage, as defined in paragraph (c)(4)(ii) of this section, and (B) The classification... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Nondiscriminatory classification test. 1.410(b.... § 1.410(b)-4 Nondiscriminatory classification test. (a) In general. A plan satisfies the...

  7. Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases.

    PubMed

    Sengerová, Blanka; Allerston, Charles K; Abu, Mika; Lee, Sook Y; Hartley, Janet; Kiakos, Konstantinos; Schofield, Christopher J; Hartley, John A; Gileadi, Opher; McHugh, Peter J

    2012-07-27

    Human SNM1A and SNM1B/Apollo have both been implicated in the repair of DNA interstrand cross-links (ICLs) by cellular studies, and SNM1B is also required for telomere protection. Here, we describe studies on the biochemical characterization of the SNM1A and SNM1B proteins. The results reveal some fundamental differences in the mechanisms of the two proteins. Both SNM1A and SNM1B digest double-stranded and single-stranded DNA with a 5'-to-3' directionality in a reaction that is stimulated by divalent cations, and both nucleases are inhibited by the zinc chelator o-phenanthroline. We find that SNM1A has greater affinity for single-stranded DNA over double-stranded DNA that is not observed with SNM1B. Although both proteins demonstrate a low level of processivity on low molecular weight DNA oligonucleotide substrates, when presented with high molecular weight DNA, SNM1A alone is rendered much more active, being capable of digesting kilobase-long stretches of DNA. Both proteins can digest past ICLs induced by the non-distorting minor groove cross-linking agent SJG-136, albeit with SNM1A showing a greater capacity to achieve this. This is consistent with the proposal that SNM1A and SNM1B might exhibit some redundancy in ICL repair. Together, our work establishes differences in the substrate selectivities of SNM1A and SNM1B that are likely to be relevant to their in vivo roles and which might be exploited in the development of selective inhibitors.

  8. Expression and inducibility of CYP1A1, 1A2, 1B1 by β-naphthoflavone and CYP2B22, CYP3As by rifampicin in heart regions and coronary arteries of pig.

    PubMed

    Messina, Andrea; Puccinelli, Emanuela; Gervasi, Pier Giovanni; Longo, Vincenzo

    2013-02-01

    In this study, the constitutive and inducible expression of the CYP genes (1A1, 1A2, 1B1, 2B22, 3A22, 3A29 and 3A46), related transcriptional factors (AhR, CAR, PXR, and Nrf2) and the antioxidant enzymes SOD, catalase, GSSH-reductase and GSH-peroxidase were investigated in the liver, heart regions and coronary arteries of control pigs and pigs treated with β-naphthoflavone (βNF) or with rifampicin (RIF). Real-time PCR experiments and enzymatic or immunoblot assays showed that CYP1A1 was predominantly enhanced by βNF in a similar manner in all the heart regions, whereas antioxidant enzyme activity was not affected. The rifampicin treatment resulted in an induction of CYP2B22 and CYP3As, at the transcriptional, activity and protein level in liver but not in heart nor in the coronary arteries, despite the expression of CAR and PXR in the cardiac tissues. These results obtained in vivo suggest that pig cardiac tissues may represent a useful model for humans. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies... August 16, 1954, section 802(b) imposes a tax on the 1954 life insurance company taxable income of all...

  10. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans.

    PubMed

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C

    2013-01-01

    The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene-environment interactions in relation to health risks is needed. The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.

  11. Regulation of anoikis by Deleted in Breast Cancer-1 (DBC1) through NF-κB

    PubMed Central

    Park, Sun Hee; Riley, Philip; Frisch, Steven M

    2013-01-01

    Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in Breast Cancer-1 protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-β, stimulating its kinase activity, promoting NF-κB transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-κB target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-β-NF-κB signaling pathway that regulates anoikis. PMID:23588592

  12. A Case of Vitamin-D-Dependent Rickets Type 1A with Normal 1,25-Dihydroxyvitamin D Caused by Two Novel Mutations of the CYP27B1 Gene.

    PubMed

    Giannakopoulos, Aris; Efthymiadou, Alexandra; Chrysis, Dionisios

    2017-01-01

    Vitamin-D-dependent rickets 1A (VDDR-1A) is caused by mutations of the renal CYP27B1 gene and is a rare form of rickets. Herein, we report a 20-month-old toddler who presented with inability to walk and failure to thrive. The clinical, biochemical and radiological findings were consistent with a diagnosis of rickets, specifically of the genetic type due to increased 25-OH vitamin D stores. Our patient was a compound heterozygote with 2 novel mutations: c.242G>A(p.Gly81Glu) and c.1144C>G (p.Pro382Ala) in the CYP27B1 gene. Analysis of both mutations with in silico models predicted a deleterious effect on 25-OH vitamin D 1α-hydroxylase function. Interestingly, the levels of 1,25-(OH)2 vitamin D were within normal limits. Our patient was initiated on 1α-hydroxyvitamin D (alfacalcidol) and supplemental calcium. Monitoring of bone metabolism showed a normalization of all bone metabolism serum indices after 3 months of therapy and, thereafter, only alfacalcidol was given at a maintenance dose. The clinical follow-up showed a dramatic improvement in musculoskeletal activity, and the patient regained acceleration in height and weight appropriate for his age. This rare case report of VDDR-1A with normal levels of 1,25-(OH)2 vitamin D enhances our awareness for this type of rickets in clinical practice. © 2016 S. Karger AG, Basel.

  13. 13. 'Transverse Bracing for 1 208'101/2' C. to C. ...

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

    13. 'Transverse Bracing for 1 - 208'-10-1/2' C. to C. End Pins S. Tr. Thro. Skew Span, 6th Crossing of Sacramento River, So. Pac. Co., The Phoenix Bridge Co., C.O. 836D, Drawing No. 7, Scale - 1' = 1', Engineer - B.M. Krohn, May 11th `01, Slaughter' - Southern Pacific Railroad Shasta Route, Bridge No. 301.85, Milepost 301.85, Pollard Flat, Shasta County, CA

  14. Identification of nucleotides in the 5'UTR and amino acids substitutions that are essential for the infectivity of 5'UTR-NS5A recombinant of hepatitis C virus genotype 1b (strain Con1).

    PubMed

    Li, Jinqian; Feng, Shengjun; Liu, Xi; Guo, Mingzhe; Chen, Mingxiao; Chen, Yiyi; Rong, Liang; Xia, Jinyu; Zhou, Yuanping; Zhong, Jin; Li, Yi-Ping

    2018-05-01

    Genotype 1b strain Con1 represents an important reference in the study of hepatitis C virus (HCV). Here, we aimed to develop an advanced infectious Con1 recombinant. We found that previously identified mutations A1226G/F1464L/A1672S/Q1773H permitted culture adaption of Con1 Core-NS5A (C-5A) recombinant containing 5'UTR and NS5B-3'UTR from JFH1 (genotype 2a), thus acquired additional mutations L725H/F886L/D2415G. C-5A containing all seven mutations (C-5A_7m) replicated efficiently in Huh7.5 and Huh7.5.1 cells and had an increased infectivity in SEC14L2-expressing Huh7.5.1 cells. Incorporation of Con1 NS5B was deleterious to C-5A_7m, however Con1 5'UTR was permissive but attenuated the virus. Nucleotides G1, A4, and G35 primarily accounted for the viral attenuation without affecting RNA translation. C-5A_7m was inhibited dose-dependently by simeprevir and daclatasvir, and substitutions at A4, A29, A34, and G35 conferred resistance to miR-122 antagonism. The novel Con1 5'UTR-NS5A recombinant, adaptive mutations, and critical nucleotides described here will facilitate future studies of HCV culture systems and virus-host interaction. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Analysis of the Rotational Structure in the High-Resolution Infrared Spectrum of TRANS-HEXATRIENE-1-13C1

    NASA Astrophysics Data System (ADS)

    Craig, Norman C.; Tian, Hengfeng; Blake, Thomas A.

    2011-06-01

    Hexatriene-1-13C1 was synthesized by reaction of 2,4-pentadienal and (methyl-13C)-triphenylphosphonium iodide (Wittig reagent). The trans isomer was isolated by preparative gas chromatography, and the high-resolution (0.0015 Cm-1) infrared spectrum was recorded on a Bruker IFS 125HR instrument. The rotational structure in two C-type bands was analyzed. For this species the bands at 1010.7 and 893.740 Cm-1 yielded composite ground state rotational constants of A0 = 0.872820(1), B0 = 0.0435868(4), and C0 = 0.0415314(2) Cm-1. The ground state rotational constants for the 1-13C species were also predicted with Gaussian 03 software and the B3LYP/cc-pVTZ model. After scaling by the ratio of the observed and predicted ground state rotational constants for the normal species, the predicted ground state rotational constants for the 1-13C species agreed within 0.005 % with the observed values. Similar good agreement between observed and calculated values (0.016 %) was found for the three 13C species of the cis isomer. We conclude that ground state rotational constants for single heavy atom substitution can be calculated with adequate accuracy for use in determining semi-experimental equilibrium structures of small molecules. It will be unnecessary to synthesize the other two 13C species of trans-hexatriene. R. D. Suenram, B. H. Pate, A. Lesarri, J. L. Neill, S. Shipman, R. A. Holmes, M. C. Leyden, N. C. Craig J. Phys. Chem. A 113, 1864-1868 (2009).

  16. 26 CFR 1.414(c)-6 - Effective date.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., 1974. (b) Existing plans. In the case of a plan in existence on January 1, 1974, unless paragraph (c... § 1.410(a)-2(c). (c) Existing plans electing new provisions. In the case of a plan in existence on....410 (a)-2 (d). (d) Application. For purposes of the Employee Retirement Income Security Act of 1974...

  17. 26 CFR 1.414(c)-6 - Effective date.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., 1974. (b) Existing plans. In the case of a plan in existence on January 1, 1974, unless paragraph (c... § 1.410(a)-2(c). (c) Existing plans electing new provisions. In the case of a plan in existence on....410 (a)-2 (d). (d) Application. For purposes of the Employee Retirement Income Security Act of 1974...

  18. Supersymmetric U(1)Y‧⊗ U(1)B-L extension of the Standard Model

    NASA Astrophysics Data System (ADS)

    Montero, J. C.; Pleitez, V.; Sánchez-Vega, B. L.; Rodriguez, M. C.

    2017-06-01

    We build a supersymmetric version with SU(3)C ⊗ SU(2)L ⊗ U(1)Y‧⊗ U(1)B-L gauge symmetry, where Y‧ is a new charge and B and L are the usual baryonic and leptonic numbers. The model has three right-handed neutrinos with identical B - L charges, and can accommodate all fermion masses at the tree level. In particular, the type I seesaw mechanism is implemented for the generation of the active neutrino masses. We obtain the mass spectra of all sectors and for the scalar one we also give the flat directions allowed by the model.

  19. 26 CFR 1.414(b)-1 - Controlled group of corporations.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Controlled group of corporations. 1.414(b)-1...(b)-1 Controlled group of corporations. (a) Defintion of controlled group of corporations. For purposes of this section, the term “controlled group of corporations” has the same meaning as is assigned...

  20. 26 CFR 1.414(b)-1 - Controlled group of corporations.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Controlled group of corporations. 1.414(b)-1...(b)-1 Controlled group of corporations. (a) Defintion of controlled group of corporations. For purposes of this section, the term “controlled group of corporations” has the same meaning as is assigned...

  1. 26 CFR 1.414(b)-1 - Controlled group of corporations.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Controlled group of corporations. 1.414(b)-1...(b)-1 Controlled group of corporations. (a) Defintion of controlled group of corporations. For purposes of this section, the term “controlled group of corporations” has the same meaning as is assigned...

  2. 26 CFR 1.414(b)-1 - Controlled group of corporations.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Controlled group of corporations. 1.414(b)-1...(b)-1 Controlled group of corporations. (a) Defintion of controlled group of corporations. For purposes of this section, the term “controlled group of corporations” has the same meaning as is assigned...

  3. Structure-activity analysis and biological studies of chensinin-1b analogues.

    PubMed

    Dong, Weibing; Dong, Zhe; Mao, Xiaoman; Sun, Yue; Li, Fei; Shang, Dejing

    2016-06-01

    Chensinin-1b shows a potent and broad-spectrum bactericidal activity and no hemolytic activity and thus is a potential therapeutic agent against bacterial infection. The NMR structure of chensinin-1b consists of a partially α-helical region (residues 8-14) in a membrane-mimic environment that is distinct from other common antimicrobial peptides. However, further analysis of the structural features of chensinin-1b is required to better understand its bactericidal activity. In this study, a series of N- and C-terminally truncated or amino acid-substituted chensinin-1b analogues were synthesized. Next, the bactericidal activity and bacterial membrane effects of the analogues were investigated. The results indicated that the N-terminal residues play a more significant role than the C-terminal residues in the antimicrobial activity of chensinin-1b. The removal of five amino acids from the C-terminus of chensinin-1b did not affect its biological properties, but helix disruption significantly decreased bactericidal activity. The substitution of positively charged residues increased the helicity and antimicrobial activity of the peptide. We also identified a novel analogue [R(4),R(10)]C1b(3-13) that exhibited similar bactericidal properties with its parent peptide chensinin-1b. Electrostatic interactions between the selected analogues and lipopolysaccharides or cells were detected using isothermal titration calorimetry or zeta potential. The thermodynamic parameters ΔH and ΔS for [R(4),R(10)]C1b(3-13) were -20.48kcalmol(-1) and -0.0408kcalmol(-1)deg(-1), respectively. Chensinin-1b yielded similar results of -26.36kcalmol(-1) and -0.0559kcalmol(-1)deg(-1) for ΔH and ΔS, respectively. These results are consistence with their antimicrobial activities. Lastly, membrane depolarization studies showed that selected analogues exerted bactericidal activity by damaging the cytoplasmic membrane. Antimicrobial peptide chensinin-1b is a candidate for the development of new drugs

  4. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

    PubMed

    Wu, Jing; Tao, Wei-Wei; Chong, Dan-Yang; Lai, Shan-Shan; Wang, Chuang; Liu, Qi; Zhang, Tong-Yu; Xue, Bin; Li, Chao-Jun

    2018-03-15

    Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

  5. Quantitation of CYP1A1 and 1B1 mRNA in polycyclic aromatic hydrocarbon-treated human T-47D and HepG2 cells by a modified bDNA assay using fluorescence detection.

    PubMed

    Wu, Susan J; Spink, David C; Spink, Barbara C; Kaminsky, Laurence S

    2003-01-15

    The quantitation of mRNA, essential for assessing mechanisms of enzyme regulation, is normally carried out using reverse transcriptase-polymerase chain reaction (RT-PCR). An alternative method uses a signal-amplification nucleic acid probe assay, which measures RNA directly by the QuantiGene Expression Kit and incorporates branched DNA technology from Bayer and luminometer-based readings of a chemilumigenic alkaline phosphatase substrate. To broaden the utility of this assay, we investigated substitution of a fluorescent substrate, 2'-(2-benzothiazol)-6'-hydroxybenzothiazole phosphate and a fluorometer, and applied the method to quantitation of CYP1A1 and 1B1 mRNA in human T-47D and HepG2 cells following induction by benzo[a]pyrene (B[a]P) and dibenzo[a,h]anthracene (DB[a,h]A). The fluorescence response increased linearly for 200 min without photobleaching and increased linearly (r2=0.997) up to at least 0.2 microg total RNA. The data revealed that at 0.5 and 1.0 microM inducing agent, the induction of CYP1A1 mRNA in HepG2 cells by DB[a,h]A exceeded that by B[a]P by 18- and 6-fold, respectively. In T-47D cells B[a]P induced CYP1A1 mRNA by 23-fold and CYP1B1 mRNA by 3.9-fold. A B[a]P cocontaminant in the environment, arsenite, did not affect B[a]P-induced levels of CYP1A1 or 1B1 mRNA in these cells. The modified analytical system provides a rapid-throughput, reproducible, and less labor-intensive method than RT-PCR for quantifying cellular mRNA levels.

  6. 26 CFR 1.411(b)(5)-1 - Reduction in rate of benefit accrual under a defined benefit plan.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... satisfy the age discrimination rules under section 411(b)(1)(H). Paragraph (c) of this section describes... balance of a hypothetical account maintained for the participant if the accumulated benefit of the... meaning of § 1.411(d)-3(g)(6) that is contingent on a participant's severance from employment and...

  7. 26 CFR 1.411(b)(5)-1 - Reduction in rate of benefit accrual under a defined benefit plan.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... satisfy the age discrimination rules under section 411(b)(1)(H). Paragraph (c) of this section describes... balance of a hypothetical account maintained for the participant if the accumulated benefit of the... meaning of § 1.411(d)-3(g)(6) that is contingent on a participant's severance from employment and...

  8. 26 CFR 1.410(b)-1 - Minimum coverage requirements (before 1994).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... plan satisfies section 410(b)(1) if it satisfies the requirements of paragraph (b)(1) or (b)(2) of this... this subparagraph if it benefits— (i) Seventy percent or more of all employees, or (ii) Eighty percent... requirements of section 410(b)(1) and this subparagraph if it benefits such employees as qualify under a...

  9. Characterization of the Human SNM1A and SNM1B/Apollo DNA Repair Exonucleases*

    PubMed Central

    Sengerová, Blanka; Allerston, Charles K.; Abu, Mika; Lee, Sook Y.; Hartley, Janet; Kiakos, Konstantinos; Schofield, Christopher J.; Hartley, John A.; Gileadi, Opher; McHugh, Peter J.

    2012-01-01

    Human SNM1A and SNM1B/Apollo have both been implicated in the repair of DNA interstrand cross-links (ICLs) by cellular studies, and SNM1B is also required for telomere protection. Here, we describe studies on the biochemical characterization of the SNM1A and SNM1B proteins. The results reveal some fundamental differences in the mechanisms of the two proteins. Both SNM1A and SNM1B digest double-stranded and single-stranded DNA with a 5′-to-3′ directionality in a reaction that is stimulated by divalent cations, and both nucleases are inhibited by the zinc chelator o-phenanthroline. We find that SNM1A has greater affinity for single-stranded DNA over double-stranded DNA that is not observed with SNM1B. Although both proteins demonstrate a low level of processivity on low molecular weight DNA oligonucleotide substrates, when presented with high molecular weight DNA, SNM1A alone is rendered much more active, being capable of digesting kilobase-long stretches of DNA. Both proteins can digest past ICLs induced by the non-distorting minor groove cross-linking agent SJG-136, albeit with SNM1A showing a greater capacity to achieve this. This is consistent with the proposal that SNM1A and SNM1B might exhibit some redundancy in ICL repair. Together, our work establishes differences in the substrate selectivities of SNM1A and SNM1B that are likely to be relevant to their in vivo roles and which might be exploited in the development of selective inhibitors. PMID:22692201

  10. A first detection of singlet to triplet conversion from the 1 1B u- to the 1 3A g state and triplet internal conversion from the 1 3A g to the 1 3B u state in carotenoids: dependence on the conjugation length

    NASA Astrophysics Data System (ADS)

    Rondonuwu, Ferdy S.; Watanabe, Yasutaka; Fujii, Ritsuko; Koyama, Yasushi

    2003-07-01

    Subpicosecond time-resolved absorption spectra were recorded in the visible region for a set of photosynthetic carotenoids having different numbers of conjugated double bonds ( n), which include neurosporene ( n=9), spheroidene ( n=10), lycopene ( n=11), anhydrorhodovibrin ( n=12) and spirilloxanthin ( n=13). Singular-value decomposition and global fitting of the spectral-data matrices lead us to a branched relaxation scheme including both (1) the singlet internal conversion in the sequence of 1 1B u+ → 1 1B u- → 2 1A g- → 1 1A g-(ground), and (2) the singlet-to-triplet conversion of 1 1B u- → 1 3A g followed by triplet internal conversion of 1 3A g → 1 3B u.

  11. Measurement of sigma Lambda b0/sigma B0 x B(Lambda b0-->Lambda c+pi-)/B(B0-->D+pi-) in pp collisions at square root s=1.96 TeV.

    PubMed

    Abulencia, A; Adelman, J; Affolder, T; Akimoto, T; Albrow, M G; Ambrose, D; Amerio, S; Amidei, D; Anastassov, A; Anikeev, K; Annovi, A; Antos, J; Aoki, M; Apollinari, G; Arguin, J-F; Arisawa, T; Artikov, A; Ashmanskas, W; Attal, A; Azfar, F; Azzi-Bacchetta, P; Azzurri, P; Bacchetta, N; Badgett, W; Barbaro-Galtieri, A; Barnes, V E; Barnett, B A; Baroiant, S; Bartsch, V; Bauer, G; Bedeschi, F; Behari, S; Belforte, S; Bellettini, G; Bellinger, J; Belloni, A; Benjamin, D; Beretvas, A; Beringer, J; Berry, T; Bhatti, A; Binkley, M; Bisello, D; Blair, R E; Blocker, C; Blumenfeld, B; Bocci, A; Bodek, A; Boisvert, V; Bolla, G; Bolshov, A; Bortoletto, D; Boudreau, J; Boveia, A; Brau, B; Brigliadori, L; Bromberg, C; Brubaker, E; Budagov, J; Budd, H S; Budd, S; Budroni, S; Burkett, K; Busetto, G; Bussey, P; Byrum, K L; Cabrera, S; Campanelli, M; Campbell, M; Canelli, F; Canepa, A; Carillo, S; Carlsmith, D; Carosi, R; Casarsa, M; Castro, A; Catastini, P; Cauz, D; Cavalli-Sforza, M; Cerri, A; Cerrito, L; Chang, S H; Chen, Y C; Chertok, M; Chiarelli, G; Chlachidze, G; Chlebana, F; Cho, I; Cho, K; Chokheli, D; Chou, J P; Choudalakis, G; Chuang, S H; Chung, K; Chung, W H; Chung, Y S; Ciljak, M; Ciobanu, C I; Ciocci, M A; Clark, A; Clark, D; Coca, M; Compostella, G; Convery, M E; Conway, J; Cooper, B; Copic, K; Cordelli, M; Cortiana, G; Crescioli, F; Cuenca Almenar, C; Cuevas, J; Culbertson, R; Cully, J C; Cyr, D; DaRonco, S; D'Auria, S; Davies, T; D'Onofrio, M; Dagenhart, D; de Barbaro, P; De Cecco, S; Deisher, A; De Lentdecker, G; Dell'Orso, M; Delli Paoli, F; Demortier, L; Deng, J; Deninno, M; De Pedis, D; Derwent, P F; Di Giovanni, G P; Dionisi, C; Di Ruzza, B; Dittmann, J R; DiTuro, P; Dörr, C; Donati, S; Donega, M; Dong, P; Donini, J; Dorigo, T; Dube, S; Efron, J; Erbacher, R; Errede, D; Errede, S; Eusebi, R; Fang, H C; Farrington, S; Fedorko, I; Fedorko, W T; Feild, R G; Feindt, M; Fernandez, J P; Field, R; Flanagan, G; Foland, A; Forrester, S; Foster, G W; Franklin, M; Freeman, J C; Furic, I; Gallinaro, M; Galyardt, J; Garcia, J E; Garberson, F; Garfinkel, A F; Gay, C; Gerberich, H; Gerdes, D; Giagu, S; Giannetti, P; Gibson, A; Gibson, K; Gimmell, J L; Ginsburg, C; Giokaris, N; Giordani, M; Giromini, P; Giunta, M; Giurgiu, G; Glagolev, V; Glenzinski, D; Gold, M; Goldschmidt, N; Goldstein, J; Gomez, G; Gomez-Ceballos, G; Goncharov, M; González, O; Gorelov, I; Goshaw, A T; Goulianos, K; Gresele, A; Griffiths, M; Grinstein, S; Grosso-Pilcher, C; Group, R C; Grundler, U; Guimaraes da Costa, J; Gunay-Unalan, Z; Haber, C; Hahn, K; Hahn, S R; Halkiadakis, E; Hamilton, A; Han, B-Y; Han, J Y; Handler, R; Happacher, F; Hara, K; Hare, M; Harper, S; Harr, R F; Harris, R M; Hartz, M; Hatakeyama, K; Hauser, J; Heijboer, A; Heinemann, B; Heinrich, J; Henderson, C; Herndon, M; Heuser, J; Hidas, D; Hill, C S; Hirschbuehl, D; Hocker, A; Holloway, A; Hou, S; Houlden, M; Hsu, S-C; Huffman, B T; Hughes, R E; Husemann, U; Huston, J; Incandela, J; Introzzi, G; Iori, M; Ishizawa, Y; Ivanov, A; Iyutin, B; James, E; Jang, D; Jayatilaka, B; Jeans, D; Jensen, H; Jeon, E J; Jindariani, S; Jones, M; Joo, K K; Jun, S Y; Jung, J E; Junk, T R; Kamon, T; Karchin, P E; Kato, Y; Kemp, Y; Kephart, R; Kerzel, U; Khotilovich, V; Kilminster, B; Kim, D H; Kim, H S; Kim, J E; Kim, M J; Kim, S B; Kim, S H; Kim, Y K; Kimura, N; Kirsch, L; Klimenko, S; Klute, M; Knuteson, B; Ko, B R; Kondo, K; Kong, D J; Konigsberg, J; Korytov, A; Kotwal, A V; Kovalev, A; Kraan, A C; Kraus, J; Kravchenko, I; Kreps, M; Kroll, J; Krumnack, N; Kruse, M; Krutelyov, V; Kubo, T; Kuhlmann, S E; Kuhr, T; Kusakabe, Y; Kwang, S; Laasanen, A T; Lai, S; Lami, S; Lammel, S; Lancaster, M; Lander, R L; Lannon, K; Lath, A; Latino, G; Lazzizzera, I; Le, Y; LeCompte, T; Lee, J; Lee, J; Lee, Y J; Lee, S W; Lefèvre, R; Leonardo, N; Leone, S; Levy, S; Lewis, J D; Lin, C; Lin, C S; Lindgren, M; Lipeles, E; Lister, A; Litvintsev, D O; Liu, T; Lockyer, N S; Loginov, A; Loreti, M; Loverre, P; Lu, R-S; Lucchesi, D; Lujan, P; Lukens, P; Lungu, G; Lyons, L; Lys, J; Lysak, R; Lytken, E; Mack, P; MacQueen, D; Madrak, R; Maeshima, K; Makhoul, K; Maki, T; Maksimovic, P; Malde, S; Manca, G; Margaroli, F; Marginean, R; Marino, C; Marino, C P; Martin, A; Martin, M; Martin, V; Martínez, M; Maruyama, T; Mastrandrea, P; Masubuchi, T; Matsunaga, H; Mattson, M E; Mazini, R; Mazzanti, P; McFarland, K S; McIntyre, P; McNulty, R; Mehta, A; Mehtala, P; Menzemer, S; Menzione, A; Merkel, P; Mesropian, C; Messina, A; Miao, T; Miladinovic, N; Miles, J; Miller, R; Mills, C; Milnik, M; Mitra, A; Mitselmakher, G; Miyamoto, A; Moed, S; Moggi, N; Mohr, B; Moore, R; Morello, M; Movilla Fernandez, P; Mülmenstädt, J; Mukherjee, A; Muller, Th; Mumford, R; Murat, P; Nachtman, J; Nagano, A; Naganoma, J; Nakano, I; Napier, A; Necula, V; Neu, C; Neubauer, M S; Nielsen, J; Nigmanov, T; Nodulman, L; Norniella, O; Nurse, E; Oh, S H; Oh, Y D; Oksuzian, I; Okusawa, T; Oldeman, R; Orava, R; Osterberg, K; Pagliarone, C; Palencia, E; Papadimitriou, V; Paramonov, A A; Parks, B; Pashapour, S; Patrick, J; Pauletta, G; Paulini, M; Paus, C; Pellett, D E; Penzo, A; Phillips, T J; Piacentino, G; Piedra, J; Pinera, L; Pitts, K; Plager, C; Pondrom, L; Portell, X; Poukhov, O; Pounder, N; Prakoshyn, F; Pronko, A; Proudfoot, J; Ptohos, F; Punzi, G; Pursley, J; Rademacker, J; Rahaman, A; Ranjan, N; Rappoccio, S; Reisert, B; Rekovic, V; Renton, P; Rescigno, M; Richter, S; Rimondi, F; Ristori, L; Robson, A; Rodrigo, T; Rogers, E; Rolli, S; Roser, R; Rossi, M; Rossin, R; Ruiz, A; Russ, J; Rusu, V; Saarikko, H; Sabik, S; Safonov, A; Sakumoto, W K; Salamanna, G; Saltó, O; Saltzberg, D; Sánchez, C; Santi, L; Sarkar, S; Sartori, L; Sato, K; Savard, P; Savoy-Navarro, A; Scheidle, T; Schlabach, P; Schmidt, E E; Schmidt, M P; Schmitt, M; Schwarz, T; Scodellaro, L; Scott, A L; Scribano, A; Scuri, F; Sedov, A; Seidel, S; Seiya, Y; Semenov, A; Sexton-Kennedy, L; Sfyrla, A; Shapiro, M D; Shears, T; Shepard, P F; Sherman, D; Shimojima, M; Shochet, M; Shon, Y; Shreyber, I; Sidoti, A; Sinervo, P; Sisakyan, A; Sjolin, J; Slaughter, A J; Slaunwhite, J; Sliwa, K; Smith, J R; Snider, F D; Snihur, R; Soderberg, M; Soha, A; Somalwar, S; Sorin, V; Spalding, J; Spinella, F; Spreitzer, T; Squillacioti, P; Stanitzki, M; Staveris-Polykalas, A; St Denis, R; Stelzer, B; Stelzer-Chilton, O; Stentz, D; Strologas, J; Stuart, D; Suh, J S; Sukhanov, A; Sun, H; Suzuki, T; Taffard, A; Takashima, R; Takeuchi, Y; Takikawa, K; Tanaka, M; Tanaka, R; Tecchio, M; Teng, P K; Terashi, K; Thom, J; Thompson, A S; Thomson, E; Tipton, P; Tiwari, V; Tkaczyk, S; Toback, D; Tokar, S; Tollefson, K; Tomura, T; Tonelli, D; Torre, S; Torretta, D; Tourneur, S; Trischuk, W; Tseng, J; Tsuchiya, R; Tsuno, S; Turini, N; Ukegawa, F; Unverhau, T; Uozumi, S; Usynin, D; Vallecorsa, S; van Remortel, N; Varganov, A; Vataga, E; Vázquez, F; Velev, G; Veramendi, G; Veszpremi, V; Vidal, R; Vila, I; Vilar, R; Vine, T; Vollrath, I; Volobouev, I; Volpi, G; Würthwein, F; Wagner, P; Wagner, R G; Wagner, R L; Wagner, J; Wagner, W; Wallny, R; Wang, S M; Warburton, A; Waschke, S; Waters, D; Wester, W C; Whitehouse, B; Whiteson, D; Wicklund, A B; Wicklund, E; Williams, G; Williams, H H; Wilson, P; Winer, B L; Wittich, P; Wolbers, S; Wolfe, C; Wright, T; Wu, X; Wynne, S M; Yagil, A; Yamamoto, K; Yamaoka, J; Yamashita, T; Yang, C; Yang, U K; Yang, Y C; Yao, W M; Yeh, G P; Yoh, J; Yorita, K; Yoshida, T; Yu, G B; Yu, I; Yu, S S; Yun, J C; Zanello, L; Zanetti, A; Zaw, I; Zhang, X; Zhou, J; Zucchelli, S

    2007-03-23

    We present the first observation of the baryon decay Lambda b0-->Lambda c+pi- followed by Lambda c+-->pK-pi+ in 106 pb-1 pp collisions at square root s=1.96 TeV in the CDF experiment. In order to reduce systematic error, the measured rate for Lambda b0 decay is normalized to the kinematically similar meson decay B0-->D+pi- followed by D+-->pi+K-pi+. We report the ratio of production cross sections (sigma) times the ratio of branching fractions (B) for the momentum region integrated above pT>6 GeV/c and pseudorapidity range |eta|<1.3: sigma(pp-->Lambda b0X)/sigma(pp-->B0X)xB(Lambda b0-->Lambda c+pi-)/B(B0-->D+pi-)=0.82+/-0.08(stat)+/-0.11(syst)+/-0.22[B(Lambda c+-->pK-pi+)].

  12. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer.

    PubMed

    Bouillez, A; Rajabi, H; Jin, C; Samur, M; Tagde, A; Alam, M; Hiraki, M; Maeda, T; Hu, X; Adeegbe, D; Kharbanda, S; Wong, K-K; Kufe, D

    2017-07-13

    Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→︀ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→︀ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.

  13. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

    PubMed Central

    Sainz, Bruno; Barretto, Naina; Martin, Danyelle N.; Hiraga, Nobuhiko; Imamura, Michio; Hussain, Snawar; Marsh, Katherine A.; Yu, Xuemei; Chayama, Kazuaki; Alrefai, Waddah A.; Uprichard, Susan L.

    2011-01-01

    Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ~170 million individuals infected and current interferon-based treatment having toxic side-effects and marginal efficacy, more effective antivirals are critically needed1. Although HCV protease inhibitors were just FDA approved, analogous to HIV therapy, optimal HCV therapy likely will require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a promising multi-faceted target for antiviral intervention; however, to date FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-Like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection as silencing or antibody-mediated blocking of NPC1L1 impairs cell-cultured-derived HCV (HCVcc) infection initiation. In addition, the clinically-available FDA-approved NPC1L1 antagonist ezetimibe2,3 potently blocks HCV uptake in vitro via a virion cholesterol-dependent step prior to virion-cell membrane fusion. Importantly, ezetimibe inhibits infection of all major HCV genotypes in vitro, and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor, but also discovered a new antiviral target and potential therapeutic agent. PMID:22231557

  14. Molecular mechanism of serine/threonine protein phosphatase 1 (PP1cα-PP1r7) in spermatogenesis of Toxocara canis.

    PubMed

    Ma, Guang Xu; Zhou, Rong Qiong; Song, Zhen Hui; Zhu, Hong Hong; Zhou, Zuo Yong; Zeng, Yuan Qin

    2015-09-01

    Toxocariasis is one of the most important, but neglected, zoonoses, which is mainly caused by Toxocara canis. To better understand the role of serine/threonine protein phosphatase 1 (PP1) in reproductive processes of male adult T. canis, differential expression analysis was used to reveal the profiles of PP1 catalytic subunit α (PP1cα) gene Tc-stp-1 and PP1 regulatory subunit 7 (PP1r7) gene TcM-1309. Indirect fluorescence immunocytochemistry was carried out to determine the subcellular distribution of PP1cα. Double-stranded RNA interference (RNAi) assays were employed to illustrate the function and mechanism of PP1cα in male adult reproduction. Real-time quantitative PCR (qPCR) showed transcriptional consistency of Tc-stp-1 and TcM-1309 in sperm-producing germline tissues and localization research showed cytoplasmic distribution of PP1cα in sf9 cells, which indicated relevant involvements of PP1cα and PP1r7 in spermatogenesis. Moreover, spatiotemporal transcriptional differences of Tc-stp-1 were determined by gene knockdown analysis, which revealed abnormal morphologies and blocked meiotic divisions of spermatocytes by phenotypic aberration scanning, thereby highlighting the crucial involvement of PP1cα in spermatogenesis. These results revealed a PP1cα-PP1r7 mechanism by which PP1 regulates kinetochore-microtubule interactions in spermatogenesis and provided important clues to identify novel drug or vaccine targets for toxocariasis control. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. B1-control receive array coil (B-RAC) for reducing B1+ inhomogeneity in abdominal imaging at 3T-MRI

    NASA Astrophysics Data System (ADS)

    Kaneko, Yukio; Soutome, Yoshihisa; Habara, Hideta; Bito, Yoshitaka; Ochi, Hisaaki

    2018-02-01

    B1+ inhomogeneity in the human body increases as the nuclear magnetic resonance (NMR) frequency increases. Various methods have thus been developed to reduce B1+ inhomogeneity, such as a dielectric pad, a coupling coil, parallel transmit, and radio-frequency (RF) shimming. However, B1+ inhomogeneity still remains in some cases of abdominal imaging. In this study, we developed a B1-control receive array coil (B-RAC). Unlike the conventional receive array coil, B-RAC reduces B1+ inhomogeneity by using additional PIN diodes to generate the inductive loop during the RF transmit period. The inductive loop can generate dense and sparse regions of the magnetic flux, which can be used to compensate for B1+ inhomogeneity. First, B-RAC is modeled in the numerical simulation, and the spatial distributions of B1+ in a phantom and a human model were analyzed. Next, we fabricated a 12-channel B-RAC and measured receive sensitivity and B1+ maps in a 3T-MRI experiment. It was demonstrated that B-RAC can reduce B1+ inhomogeneity in the phantom and human model without increasing the maximum local specific absorption rate (SAR) in the body. B-RAC was also found to have almost the same the receive sensitivity as the conventional receive coil. Using RF shimming combined with B-RAC was revealed to more effectively reduce B1+ inhomogeneity than using only RF shimming. Therefore, B-RAC can reduce B1+ inhomogeneity while maintaining the receive sensitivity.

  16. The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens.

    PubMed

    Schreuder, G M; Hurley, C K; Marsh, S G; Lau, M; Maiers, M; Kollman, C; Noreen, H

    1999-11-01

    This report presents serologic equivalents of 90 HLA-A, 190 HLA-B, and 145 HLA-DRB1 alleles. The equivalents cover over 70% of the presently identified HLA-A, -B, and -DRB1 alleles. The dictionary is an update of the one published in 1997 and now also includes equivalents for HLA-C, DRB3, DRB4, DRB5, and DQB1 alleles. The data summarize information obtained by the WHO HLA Nomenclature Committee, the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP), and by individual laboratories. In addition, a listing is provided of alleles that are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities and that often lack official WHO nomenclature. The provided equivalents will be useful in guiding searches for unrelated donors in which patients and/or potential donors are typed by either serology or DNA-based methods. These equivalents will also serve typing and matching procedures for organ transplant programs where HLA typings from donors and from recipients on waiting lists represent mixtures of serologic and molecular typings. Some guidelines are provided for the use of appropriate WHO HLA nomenclature for serologic typings and for generic and allele specific typings obtained with molecular methods. The tables with HLA equivalents and the questionnaire for submission of serology on poorly identified alleles will also be available at the WMDA web page: www.bmdw.org/wmda.

  17. Cystatin C is not a good candidate biomarker for HNF1A-MODY.

    PubMed

    Nowak, Natalia; Szopa, Magdalena; Thanabalasingham, Gaya; McDonald, Tim J; Colclough, Kevin; Skupien, Jan; James, Timothy J; Kiec-Wilk, Beata; Kozek, Elzbieta; Mlynarski, Wojciech; Hattersley, Andrew T; Owen, Katharine R; Malecki, Maciej T

    2013-10-01

    Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.

  18. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies. (a) For taxable years beginning after December 31, 1953, but before January 1, 1955...

  19. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies. (a) For taxable years beginning after December 31, 1953, but before January 1, 1955...

  20. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 8 2014-04-01 2014-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES (CONTINUED) Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies. (a) For taxable years beginning after December 31, 1953, but before January 1, 1955...

  1. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a) Actuarial... bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general, see...

  2. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a... collectively bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general, see...

  3. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a... collectively bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general, see...

  4. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a... collectively bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general, see...

  5. 26 CFR 1.412(c)(1)-1 - Determinations to be made under funding method-terms defined.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...-terms defined. 1.412(c)(1)-1 Section 1.412(c)(1)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT..., Stock Bonus Plans, Etc. § 1.412(c)(1)-1 Determinations to be made under funding method—terms defined. (a... collectively bargained plans, see § 1.412(c)(1)-2; for principles applicable to funding methods in general, see...

  6. 11. 'Erection Plan, 1 208'101/2' C. to C. End ...

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

    11. 'Erection Plan, 1 - 208'-10-1/2' C. to C. End Pins S. Tr. Thro. Skew Span, 6th Crossing Sacramento River, Pacific System, Southern Pacific Company, The Phoenix Bridge Co., C.O. 836D, Drawing No. 13, Scale 1/8' = 1'0', Engineer, B.M. Krohn, Draftsman, W.L. Clegg, Date, May 25th 1901' - Southern Pacific Railroad Shasta Route, Bridge No. 301.85, Milepost 301.85, Pollard Flat, Shasta County, CA

  7. Fluorescent-responsive synthetic C1b domains of protein kinase Cδ as reporters of specific high-affinity ligand binding.

    PubMed

    Ohashi, Nami; Nomura, Wataru; Narumi, Tetsuo; Lewin, Nancy E; Itotani, Kyoko; Blumberg, Peter M; Tamamura, Hirokazu

    2011-01-19

    Protein kinase C (PKC) is a critical cell signaling pathway involved in many disorders such as cancer and Alzheimer-type dementia. To date, evaluation of PKC ligand binding affinity has been performed by competitive studies against radiolabeled probes that are problematic for high-throughput screening. In the present study, we have developed a fluorescent-based binding assay system for identifying ligands that target the PKC ligand binding domain (C1 domain). An environmentally sensitive fluorescent dye (solvatochromic fluorophore), which has been used in multiple applications to assess protein-binding interactions, was inserted in proximity to the binding pocket of a novel PKCδ C1b domain. These resultant fluorescent-labeled δC1b domain analogues underwent a significant change in fluorescent intensity upon ligand binding, and we further demonstrate that the fluorescent δC1b domain analogues can be used to evaluate ligand binding affinity.

  8. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 5 2013-04-01 2013-04-01 false Shortfall method. 1.412(c)(1)-2 Section 1.412(c... Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a plan's underlying funding method for purposes of section 412. As such, the use of the shortfall...

  9. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 5 2012-04-01 2011-04-01 true Shortfall method. 1.412(c)(1)-2 Section 1.412(c... Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a plan's underlying funding method for purposes of section 412. As such, the use of the shortfall...

  10. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Shortfall method. 1.412(c)(1)-2 Section 1.412(c... Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a plan's underlying funding method for purposes of section 412. As such, the use of the shortfall...

  11. 26 CFR 1.412(c)(1)-2 - Shortfall method.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 5 2011-04-01 2011-04-01 false Shortfall method. 1.412(c)(1)-2 Section 1.412(c... Shortfall method. (a) In general—(1) Shortfall method. The shortfall method is a funding method that adapts a plan's underlying funding method for purposes of section 412. As such, the use of the shortfall...

  12. A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report.

    PubMed

    Babiker, Amir M I; Al Gadi, Iman; Al-Jurayyan, Nasir A M; Al Nemri, Abdulrahman M H; Al Haboob, Ali Abdu N; Al Boukai, Ahmed Amer; Al Zahrani, Ali; Habib, Hanan Ahmed

    2014-11-05

    Rickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1. We report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory). The deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1.

  13. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans

    PubMed Central

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C.

    2013-01-01

    Background The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene–environment interactions in relation to health risks is needed. Objectives The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. Results The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p′-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Conclusion Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies. PMID:23785672

  14. 39 CFR 3010.13 - Proceedings for Type 1-A and Type 1-B rate adjustment filings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Proceedings for Type 1-A and Type 1-B rate... (Type 1-A and 1-B Rate Adjustments) § 3010.13 Proceedings for Type 1-A and Type 1-B rate adjustment... include: (1) The general nature of the proceeding; (2) A reference to legal authority to which the...

  15. Synthesis of N1-tritylethane-1,1,2,2-d4-1,2-diamine: a novel mono-protected C-deuterated ethylenediamine synthon

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

    Yang, Jun; Hong, Kunlun; Bonnesen, Peter V

    2012-01-01

    A convenient and high-yield synthesis for N1-tritylethane-1,1,2,2-d4-1,2-diamine, a novel mono-protected ethylenediamine-C-d4, is reported. N1-tritylethane-1,1,2,2-d4-1,2-diamine was prepared in three steps from ethylene oxide-d4 in a combined yield in the range 68-76%. Also reported is a synthesis of ethylenediamine-C-d4 in two steps from 1,2-dibromoethane-d4 in a combined yield in the range 61-65%.

  16. Potentiation of C1-esterase inhibitor by heparin and interactions with C1s protease as assessed by surface plasmon resonance.

    PubMed

    Rajabi, Mohsen; Struble, Evi; Zhou, Zhaohua; Karnaukhova, Elena

    2012-01-01

    Human C1-esterase inhibitor (C1-INH) is a multifunctional plasma protein with a wide range of inhibitory and non-inhibitory properties, mainly recognized as a key down-regulator of the complement and contact cascades. The potentiation of C1-INH by heparin and other glycosaminoglycans (GAGs) regulates a broad spectrum of C1-INH activities in vivo both in normal and disease states. SCOPE OF RESEARCH: We have studied the potentiation of human C1-INH by heparin using Surface Plasmon Resonance (SPR), circular dichroism (CD) and a functional assay. To advance a SPR for multiple-unit interaction studies of C1-INH we have developed a novel (consecutive double capture) approach exploring different immobilization and layout. Our SPR experiments conducted in three different design versions showed marked acceleration in C1-INH interactions with complement protease C1s as a result of potentiation of C1-INH by heparin (from 5- to 11-fold increase of the association rate). Far-UV CD studies suggested that heparin binding did not alter C1-INH secondary structure. Functional assay using chromogenic substrate confirmed that heparin does not affect the amidolytic activity of C1s, but does accelerate its consumption due to C1-INH potentiation. This is the first report that directly demonstrates a significant acceleration of the C1-INH interactions with C1s due to heparin by using a consecutive double capture SPR approach. The results of this study may be useful for further C-INH therapeutic development, ultimately for the enhancement of current C1-INH replacement therapies. Published by Elsevier B.V.

  17. Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1.

    PubMed

    Sanford, Daniel C; Barnewall, Roy E; Vassar, Michelle L; Niemuth, Nancy; Metcalfe, Karen; House, Robert V; Henderson, Ian; Shearer, Jeffry D

    2010-09-01

    A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

  18. Analytical performances of a new enzymatic assay for hemoglobin A1c.

    PubMed

    Jaisson, Stéphane; Desmons, Aurore; Renard, Benoît; Chevelle, Benjamin; Leroy, Nathalie; Gillery, Philippe

    2014-07-01

    HbA1c is considered the gold standard for the follow-up of diabetic patients and a new diagnostic tool for diabetes mellitus, which implies the availability of reliable assay methods. We have evaluated a new assay developed by Abbott Laboratories, based on the enzymatic quantification of HbA1c by a fructosyl dipeptide oxidase using Architect analyzers. Precision, linearity, correlation with a HPLC method, accuracy and potential impact interferences on HbA1c measurement have been evaluated. Intra-day and between-day CVs were lower than 1.2% and linearity was excellent from 19 mmol/mol (3.9%) to 163 mmol/mol (17.1%). The results were well correlated with those obtained by the HPLC (Variant II device, kit NU - BioRad): HbA1c [Architect, mmol/mol]=0.986×HbA1c [Variant II, mmol/mol]+0.713 (r=0.998, n=109). This method provided consistent results with IFCC titrated quality control samples. Classical interferences in HbA1c assays (i.e. labile HbA1c, carbamylated hemoglobin, triglycerides or bilirubin) did not have an impact on HbA1c quantification by this method. This new enzymatic assay proved to be a robust and reliable method for HbA1c measurement suitable for routine practice in clinical chemistry laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains.

    PubMed

    Shahzad, Shakeel; Ashraf, M Adnan; Sajid, M; Shahzad, Aqeel; Rafique, Azhar; Mahmood, M Shahid

    2018-02-02

    Multiple drug resistant super bugs of Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) are becoming challenge for healthcare professionals. In this study, vitamins were evaluated for synergistic activity with the antibiotics. Synergistic effect between antibiotic and stock solutions of vitamins is evaluated by using Kirby-Bauer disc diffusion assay. Distilled water and propylene glycol were used as solvent for water soluble vitamins and fat-soluble vitamins respectively. The final concentration of 10mg/ml of each water-soluble vitamin B1 (Thiamine), B2 (Riboflavin), B6 (Pyridoxine) B12 (Methylcobalamin), C (Ascorbic acid) and 0.1mg/ml of each fat soluble vitamin A (retinol), D (cholecalciferol) E (αTocopherol) K (Menadione) were used with the antibiotics. The results depicted that vitamin K and E have better synergistic activity with piperacillin-tazobactam, imipenem and doripenem antibiotics against A. baumannii. While vitamin B1, B2 and B12 showed remarkable synergistic activity with linezolid against MRSA. Vitamin B1 was further tested to have better synergism with antibiotics oxacillin, tetracycline, rifampicin and linezolid against MRSA. The fat-soluble vitamins E and K were good in synergism against Gram negative A. baumannii while water soluble vitamins as B1, B2 and B12 were effective against MRSA but not against A. baumannii. This synergistic action of vitamins with the antibiotics can be used as a tool to treat multiple drug resistant super bugs with further evaluation at molecular level. Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  20. Evaluation of Interferon Resistance in Newly Established Genotype 1b Hepatitis C Virus Cell Culture System

    PubMed Central

    Taniguchi, Miki; Tasaka-Fujita, Megumi; Nakagawa, Mina; Watanabe, Takako; Kawai-Kitahata, Fukiko; Otani, Satoshi; Goto, Fumio; Nagata, Hiroko; Kaneko, Shun; Nitta, Sayuri; Murakawa, Miyako; Nishimura-Sakurai, Yuki; Azuma, Seishin; Itsui, Yasuhiro; Mori, Kenichi; Yagi, Shintaro; Kakinuma, Sei; Asahina, Yasuhiro; Watanabe, Mamoru

    2016-01-01

    Background and Aims: The hepatitis C virus (HCV) genotype 1b is known to exhibit treatment resistance with respect to interferon (IFN) therapy. Substitution of amino acids 70 and 91 in the core region of the 1b genotype is a significant predictor of liver carcinogenesis and poor response to pegylated-IFN-α and ribavirin therapy. However, the molecular mechanism has not yet been clearly elucidated because of limitations of the HCV genotype 1b infectious model. Recently, the TPF1-M170T HCV genotype 1b cell culture system was established, in which the clone successfully replicates and infects Huh-7-derived Huh7-ALS32.50 cells. Therefore, the purpose of this study was to compare IFN resistance in various HCV clones using this system. Methods: HCV core amino acid substitutions R70Q and L91M were introduced to the TPF1-M170T clone and then transfected into Huh7-ALS32.50 cells. To evaluate the production of each virus, intracellular HCV core antigens were measured. Results were confirmed with Western blot analysis using anti-NS5A antibodies, and IFN sensitivity was subsequently measured. Results: Each clone was transfected successfully compared with JFH-1, with a significant difference in intracellular HCV core antigen (p < 0.05), an indicator of continuous HCV replication. Among all clones, L91M showed the highest increase in the HCV core antigen and HCV protein. There was no significant resistance against IFN treatment in core substitutions; however, IFN sensitivity was significantly different between the wildtype core and JFH-1 (p < 0.05). Conclusions: A novel genotype 1b HCV cell culture was constructed with core amino acid substitutions, which demonstrated IFN resistance of genotype 1b. This system will be useful for future analyses into the mechanisms of HCV genotype 1b treatment. PMID:27047766

  1. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia.

    PubMed

    Kamran, Shawana; Raca, Gordana; Nazir, Kamran

    2015-01-01

    The RCSD1 gene has recently been identified as a novel gene fusion partner of the ABL1 gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL). The RCSD1 gene is located at 1q23 and ABL1 is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9)(q23;q34). Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH) studies, and Chromosomal Microarray Analysis (CMA). The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the IKZF1 gene. Deletions and mutations of IKZF1 are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of IKZF1 gene with the t(1;9)(q24;q34) and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL.

  2. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia

    PubMed Central

    Kamran, Shawana; Nazir, Kamran

    2015-01-01

    The RCSD1 gene has recently been identified as a novel gene fusion partner of the ABL1 gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL). The RCSD1 gene is located at 1q23 and ABL1 is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9)(q23;q34). Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH) studies, and Chromosomal Microarray Analysis (CMA). The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the IKZF1 gene. Deletions and mutations of IKZF1 are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of IKZF1 gene with the t(1;9)(q24;q34) and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL. PMID:26600955

  3. Making the invisible visible: searching for human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) in Brazilian patients with viral hepatitis B and C.

    PubMed

    Caterino-de-Araujo, Adele; Alves, Fabiana Aparecida; Campos, Karoline Rodrigues; Lemos, Marcílio Figueiredo; Moreira, Regina Célia

    2018-02-01

    With this study, the authors hope to alert clinicians regarding the presence of human T-cell lymphotropic virus type 1 and 2 (HTLV-1/-2) infections in patients with viral hepatitis B and C in Brazil. HTLV-1/-2 were detected in 1.3% of hepatitis B virus (HBV)- and 5.3% of hepatitis C virus (HCV)-infected blood samples sent for laboratory viral load measurements. A partial association of human immunodeficiency virus (HIV)-1 and HTLV-1/-2 infection was detected in patients with HCV (HIV+, 27.3%), whereas this association was almost 100% in HBV-infected patients (HIV+, all except one). The high prevalence of HTLV-1/-2 infection among patients with hepatitis C was of concern, as HTLV-1/-2 could change the natural course of subsequent liver disease. The authors suggest including HTLV-1/-2 serology in the battery of tests used when following patients with viral hepatitis in Brazil, regardless of the HIV status.

  4. 76 FR 49300 - Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-10

    ... Corporate Reorganizations; Distributions Under Sections 368(a)(1)(D) and 354(b)(1)(B); Correction AGENCY... in section 368(a)(1)(D) where no stock and/or securities of the acquiring corporation is issued and... guidance regarding the determination of the basis of stock or securities in a reorganization described in...

  5. IRE1α links Nck1 deficiency to attenuated PTP1B expression in HepG2 cells.

    PubMed

    Li, Hui; Li, Bing; Larose, Louise

    2017-08-01

    PTP1B, a prototype of the non-receptor subfamily of the protein tyrosine phosphatase superfamily, plays a key role in regulating intracellular signaling from various receptor and non-receptor protein tyrosine kinases. Previously, we reported that silencing Nck1 in human hepatocellular carcinoma HepG2 cells enhances basal and growth factor-induced activation of the PI3K-Akt pathway through attenuating PTP1B expression. However, the underlying mechanism by which Nck1 depletion represses PTP1B expression remains unclear. In this study, we found that silencing Nck1 attenuates PTP1B expression in HepG2 cells through down-regulation of IRE1α. Indeed, we show that silencing Nck1 in HepG2 cells leads to decreased IRE1α expression and signaling. Accordingly, IRE1α depletion using siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation, reproducing the effects of silencing Nck1 on activation of this pathway. In addition, depletion of IRE1α also leads to reduced PTP1B expression, which was rescued by ectopic expression of IRE1α in Nck1-depleted cells. Mechanistically, we found that silencing either Nck1 or IRE1α in HepG2 cells decreases PTP1B mRNA levels and stability. However, despite miR-122 levels, a miRNA targeting PTP1B 3' UTR and inducing PTP1B mRNA degradation in HepG2 cells, are increased in both Nck1- and IRE1α-depleted HepG2 cells, a miR-122 antagomir did not rescue PTP1B expression in these cells. Overall, this study highlights an important role for Nck1 in fine-tuning IRE1α expression and signaling that regulate PTP1B expression and subsequent activation of the PI3K-Akt pathway in HepG2 cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Ammonia oxidation is not required for growth of Group 1.1c soil Thaumarchaeota

    PubMed Central

    Weber, Eva B.; Lehtovirta-Morley, Laura E.; Prosser, James I.; Gubry-Rangin, Cécile

    2015-01-01

    Thaumarchaeota are among the most abundant organisms on Earth and are ubiquitous. Within this phylum, all cultivated representatives of Group 1.1a and Group 1.1b Thaumarchaeota are ammonia oxidizers, and play a key role in the nitrogen cycle. While Group 1.1c is phylogenetically closely related to the ammonia-oxidizing Thaumarchaeota and is abundant in acidic forest soils, nothing is known about its physiology or ecosystem function. The goal of this study was to perform in situ physiological characterization of Group 1.1c Thaumarchaeota by determining conditions that favour their growth in soil. Several acidic grassland, birch and pine tree forest soils were sampled and those with the highest Group 1.1c 16S rRNA gene abundance were incubated in microcosms to determine optimal growth temperature, ammonia oxidation and growth on several organic compounds. Growth of Group 1.1c Thaumarchaeota, assessed by qPCR of Group 1.1c 16S rRNA genes, occurred in soil, optimally at 30°C, but was not associated with ammonia oxidation and the functional gene amoA could not be detected. Growth was also stimulated by addition of organic nitrogen compounds (glutamate and casamino acids) but not when supplemented with organic carbon alone. This is the first evidence for non-ammonia oxidation associated growth of Thaumarchaeota in soil. PMID:25764563

  7. MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer.

    PubMed

    Maeda, Takahiro; Hiraki, Masayuki; Jin, Caining; Rajabi, Hasan; Tagde, Ashujit; Alam, Maroof; Bouillez, Audrey; Hu, Xiufeng; Suzuki, Yozo; Miyo, Masaaki; Hata, Tsuyoshi; Hinohara, Kunihiko; Kufe, Donald

    2018-01-01

    The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8 + T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment. Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205-15. ©2017 AACR . ©2017 American Association for Cancer Research.

  8. Design synthesis and evaluation of the inhibitory selectivity of novel trans-resveratrol analogues on human recombinant CYP1A1 CYP1A2 and CYP1B1

    USDA-ARS?s Scientific Manuscript database

    A series of trans-stilbene derivatives containing 4’-thiomethyl substituent were synthesized and evaluated for inhibitory activities on human recombinant cytochrome P450(s): CYP1A1, CYP1A2, and CYP1B1. CYP1A2-related metabolism of stilbene derivatives was estimated by using NADPH oxidation assay. A...

  9. A combined transmission spectrum of the Earth-sized exoplanets TRAPPIST-1 b and c.

    PubMed

    de Wit, Julien; Wakeford, Hannah R; Gillon, Michaël; Lewis, Nikole K; Valenti, Jeff A; Demory, Brice-Olivier; Burgasser, Adam J; Burdanov, Artem; Delrez, Laetitia; Jehin, Emmanuël; Lederer, Susan M; Queloz, Didier; Triaud, Amaury H M J; Van Grootel, Valérie

    2016-09-01

    Three Earth-sized exoplanets were recently discovered close to the habitable zone of the nearby ultracool dwarf star TRAPPIST-1 (ref. 3). The nature of these planets has yet to be determined, as their masses remain unmeasured and no observational constraint is available for the planetary population surrounding ultracool dwarfs, of which the TRAPPIST-1 planets are the first transiting example. Theoretical predictions span the entire atmospheric range, from depleted to extended hydrogen-dominated atmospheres. Here we report observations of the combined transmission spectrum of the two inner planets during their simultaneous transits on 4 May 2016. The lack of features in the combined spectrum rules out cloud-free hydrogen-dominated atmospheres for each planet at ≥10σ levels; TRAPPIST-1 b and c are therefore unlikely to have an extended gas envelope as they occupy a region of parameter space in which high-altitude cloud/haze formation is not expected to be significant for hydrogen-dominated atmospheres. Many denser atmospheres remain consistent with the featureless transmission spectrum-from a cloud-free water-vapour atmosphere to a Venus-like one.

  10. GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer

    PubMed Central

    Cirillo, Francesca; Pellegrino, Michele; Malivindi, Rocco; Rago, Vittoria; Avino, Silvia; Muto, Luigina; Dolce, Vincenza; Vivacqua, Adele; Rigiracciolo, Damiano Cosimo; De Marco, Paola; Sebastiani, Anna; Abonante, Sergio; Nakajima, Miki; Lappano, Rosamaria; Maggiolini, Marcello

    2017-01-01

    The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of E2 leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer. In this scenario, it is worth mentioning that CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in breast cancer cells. In the present study, we evaluated whether the G protein estrogen receptor namely GPER may provide an alternate route toward the expression and function of CYP1B1 in ER-negative breast cancer cells, in main players of the tumor microenvironment as cancer associated fibroblasts (CAFs) that were obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1 regulation through the involvement of a half-ERE sequence located within the CYP1B1 promoter region. As a biological counterpart, we found that both GPER and CYP1B1 mediate growth effects in vitro and in vivo. Altogether, our data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. Estrogen-CYP1B1 landscape via GPER should be taken into account in setting novel pharmacological approaches targeting breast cancer development. PMID:29290975

  11. GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer.

    PubMed

    Cirillo, Francesca; Pellegrino, Michele; Malivindi, Rocco; Rago, Vittoria; Avino, Silvia; Muto, Luigina; Dolce, Vincenza; Vivacqua, Adele; Rigiracciolo, Damiano Cosimo; De Marco, Paola; Sebastiani, Anna; Abonante, Sergio; Nakajima, Miki; Lappano, Rosamaria; Maggiolini, Marcello

    2017-12-05

    The cytochrome P450 1B1 (CYP1B1) is a heme-thiolate monooxygenase involved in both estrogen biosynthesis and metabolism. For instance, CYP1B1 catalyzes the hydroxylation of E2 leading to the production of 4-hydroxyestradiol that may act as a potent carcinogenic agent. In addition, CYP1B1 is overexpressed in different tumors including breast cancer. In this scenario, it is worth mentioning that CYP1B1 expression is triggered by estrogens through the estrogen receptor (ER)α in breast cancer cells. In the present study, we evaluated whether the G protein estrogen receptor namely GPER may provide an alternate route toward the expression and function of CYP1B1 in ER-negative breast cancer cells, in main players of the tumor microenvironment as cancer associated fibroblasts (CAFs) that were obtained from breast cancer patients, in CAFs derived from a cutaneous metastasis of an invasive mammary ductal carcinoma and in breast tumor xenografts. Our results show that GPER along with the EGFR/ERK/c-Fos transduction pathway can lead to CYP1B1 regulation through the involvement of a half-ERE sequence located within the CYP1B1 promoter region. As a biological counterpart, we found that both GPER and CYP1B1 mediate growth effects in vitro and in vivo . Altogether, our data suggest that estrogens in ER-negative cell contexts may engage the alternate GPER signaling toward CYP1B1 regulation. Estrogen-CYP1B1 landscape via GPER should be taken into account in setting novel pharmacological approaches targeting breast cancer development.

  12. Association of HLA-A, B, DRB1 alleles and haplotypes with HIV-1 infection in Chongqing, China

    PubMed Central

    2009-01-01

    Background The human immunodeficiency virus type 1(HIV-1) epidemic in Chongqing, China, is increasing rapidly with the dominant subtype of CRF07_BC over the past 3 years. Since human leukocyte antigen (HLA) polymorphisms have shown strong association with susceptibility/resistance to HIV-1 infection from individuals with different ethnic backgrounds, a recent investigation on frequencies of HLA class I and class II alleles in a Chinese cohort also indicated that similar correlation existed in HIV infected individuals from several provinces in China, however, such information is unavailable in Chongqing, southwest China. Methods In this population-based study, we performed polymerase chain reaction analysis with sequence-specific oligonucleotide probes (PCR-SSOP) for intermediate-low-resolution HLA typing in a cohort of 549 HIV-1 infected individuals, another 2475 healthy subjects from the Han nationality in Chongqing, China, were selected as population control. We compared frequencies of HLA-A, B, DRB1 alleles, haplotypes and genotypes between the two groups, and analyzed their association with HIV-1 susceptibility or resistance. Results The genetic profile of HLA (A, B, DRB1) alleles of HIV-1 infected individuals from Chongqing Han of China was obtained. Several alleles of HLA-B such as B*46 (P = 0.001, OR = 1.38, 95%CI = 1.13-1.68), B*1501G(B62) (P = 0.013, OR = 1.42, 95%CI = 1.08-1.88), B*67 (P = 0.022, OR = 2.76, 95%CI = 1.16-6.57), B*37 (P = 0.014, OR = 1.93, 95%CI = 1.14-3.28) and B*52 (P = 0.038, OR = 1.64, 95%CI = 1.03-2.61) were observed to have association with susceptibility to HIV-1 infection in this population. In addition, the haplotype analysis revealed that A*11-B*46, A*24-B*54 and A*01-B*37 for 2-locus, and A*11-B*46-DRB1*09, A*02-B*46-DRB1*08, A*11-B*4001G-DRB1*15, A*02-B*4001G-DRB1*04, A*11-B*46-DRB1*08 and A*02-B*4001G-DRB1*12 for 3-locus had significantly overrepresented in HIV-1 infected individuals, whereas A*11-B*1502G, A*11-B*1502G-DRB1

  13. Association of HLA-A, B, DRB1 alleles and haplotypes with HIV-1 infection in Chongqing, China.

    PubMed

    Huang, Xia; Ling, Hua; Mao, Wei; Ding, Xianbin; Zhou, Quanhua; Han, Mei; Wang, Fang; Cheng, Lei; Xiong, Hongyan

    2009-12-12

    The human immunodeficiency virus type 1(HIV-1) epidemic in Chongqing, China, is increasing rapidly with the dominant subtype of CRF07_BC over the past 3 years. Since human leukocyte antigen (HLA) polymorphisms have shown strong association with susceptibility/resistance to HIV-1 infection from individuals with different ethnic backgrounds, a recent investigation on frequencies of HLA class I and class II alleles in a Chinese cohort also indicated that similar correlation existed in HIV infected individuals from several provinces in China, however, such information is unavailable in Chongqing, southwest China. In this population-based study, we performed polymerase chain reaction analysis with sequence-specific oligonucleotide probes (PCR-SSOP) for intermediate-low-resolution HLA typing in a cohort of 549 HIV-1 infected individuals, another 2475 healthy subjects from the Han nationality in Chongqing, China, were selected as population control. We compared frequencies of HLA-A, B, DRB1 alleles, haplotypes and genotypes between the two groups, and analyzed their association with HIV-1 susceptibility or resistance. The genetic profile of HLA (A, B, DRB1) alleles of HIV-1 infected individuals from Chongqing Han of China was obtained. Several alleles of HLA-B such as B*46 (P = 0.001, OR = 1.38, 95%CI = 1.13-1.68), B*1501G(B62) (P = 0.013, OR = 1.42, 95%CI = 1.08-1.88), B*67 (P = 0.022, OR = 2.76, 95%CI = 1.16-6.57), B*37 (P = 0.014, OR = 1.93, 95%CI = 1.14-3.28) and B*52 (P = 0.038, OR = 1.64, 95%CI = 1.03-2.61) were observed to have association with susceptibility to HIV-1 infection in this population. In addition, the haplotype analysis revealed that A*11-B*46, A*24-B*54 and A*01-B*37 for 2-locus, and A*11-B*46-DRB1*09, A*02-B*46-DRB1*08, A*11-B*4001G-DRB1*15, A*02-B*4001G-DRB1*04, A*11-B*46-DRB1*08 and A*02-B*4001G-DRB1*12 for 3-locus had significantly overrepresented in HIV-1 infected individuals, whereas A*11-B*1502G, A*11-B*1502G-DRB1*12 and A*33-B*58-DRB1*13 were

  14. Interaction of IL1B and IL1RN polymorphisms, smoking habit, gender, and ethnicity with aggressive and chronic periodontitis susceptibility.

    PubMed

    Ribeiro, Magali Silveira Monteiro; Pacheco, Renata Botelho Antunes; Fischer, Ricardo Guimarães; Macedo, Jacyara Maria Brito

    2016-01-01

    Although the interleukin-1 (IL-1) plays a critical role in the pathogenesis of periodontitis, associations between IL1 gene cluster polymorphisms and the disease remains unclear. To investigate the importance of IL1B-511C>T (rs16944), IL1B +3954C>T (rs1143634), and IL1RN intron 2 variable number tandem repeat (VNTR) (rs2234663) polymorphisms, individually or in combination, as the risk factors of periodontitis in a Southeastern Brazilian population with a high degree of miscegenation. A total of 145 individuals, with aggressive (aggressive periodontitis [AgP], n = 43) and chronic (chronic periodontitis [CP], n = 52) periodontitis, and controls (n = 50) were genotyped by polymerase chain reaction (PCR) (IL1RN intron 2 VNTR) or PCR-restriction fragment length polymorphism (PCR-RFLP) (IL1B-511 C>T and IL1B + 3954C>T) techniques. The independent t-test, Chi-square, and Fisher's exact tests were used. The SNPStats program was used for haplotype estimation and multiplicative interaction analyses. The IL1B +3954T allele represented risk for CP (odds ratio [OR] = 2.84), particularly in smokers (OR = 4.43) and females (OR = 6.00). The minor alleles IL1RN*2 and *3 increased the risk of AgP (OR = 2.18), especially the IL1RN*2*2 genotype among  white Brazilians (OR = 7.80). Individuals with the combinations of the IL1B + 3954T and IL1RN*2 or *3-containing genotypes were at increased risk of developing CP (OR = 4.50). Considering the three polymorphisms (rs16944, rs1143634, and rs2234663), the haplotypes TC2 and CT1 represented risk for AgP (OR = 3.41) and CP (OR = 6.39), respectively. Our data suggest that the IL1B +3954C>T and IL1RN intron 2 VNTR polymorphisms are potential candidates for genetic biomarkers of periodontitis, particularly in specific groups of individuals.

  15. Origin and Evolution of the Unique Hepatitis C Virus Circulating Recombinant Form 2k/1b

    PubMed Central

    Thomas, Xiomara V.; Koekkoek, Sylvie M.; Schinkel, Janke; Molenkamp, Richard; van de Laar, Thijs J.; Takebe, Yutaka; Tanaka, Yasuhito; Mizokami, Masashi; Rambaut, Andrew

    2012-01-01

    Since its initial identification in St. Petersburg, Russia, the recombinant hepatitis C virus (HCV) 2k/1b has been isolated from several countries throughout Eurasia. The 2k/1b strain is the only recombinant HCV to have spread widely, raising questions about the epidemiological background in which it first appeared. In order to further understand the circumstances by which HCV recombinants might be formed and spread, we estimated the date of the recombination event that generated the 2k/1b strain using a Bayesian phylogenetic approach. Our study incorporates newly isolated 2k/1b strains from Amsterdam, The Netherlands, and has employed a hierarchical Bayesian framework to combine information from different genomic regions. We estimate that 2k/1b originated sometime between 1923 and 1956, substantially before the first detection of the strain in 1999. The timescale and the geographic spread of 2k/1b suggest that it originated in the former Soviet Union at about the time that the world's first centralized national blood transfusion and storage service was being established. We also reconstructed the epidemic history of 2k/1b using coalescent theory-based methods, matching patterns previously reported for other epidemic HCV subtypes. This study demonstrates the practicality of jointly estimating dates of recombination from flanking regions of the breakpoint and further illustrates that rare genetic-exchange events can be particularly informative about the underlying epidemiological processes. PMID:22114341

  16. Statin-induced myopathy SLCO1B1 521T > C is associated with prediabetes, high body mass index and normal lipid profile in Emirati population.

    PubMed

    Saber-Ayad, Maha; Manzoor, Shaista; El-Serafi, Ahmed; Mahmoud, Ibrahim; Abusnana, Salah; Sulaiman, Nabil

    2018-05-01

    Statin-induced myopathy has been linked to the C allele of a single nucleotide polymorphism (SNP) (rs4149056) of SLCO1B1 gene. This effect is more significant, but not restricted to simvastatin. Many studies have included European, American, African and Southeast Asian ancestries, but few were carried out on Middle Eastern population. To detect the prevalence of SLCO1B1 rs4149056 (521T > C) in Emirati population. We recruited 282 Emiratis through the UAE National Diabetes and Lifestyle Project. Ethical approval was obtained before the study starts. Besides basic data collection, venous blood samples were collected. Fasting blood glucose, Lipid profile, and insulin levels were measured. Genotyping for rs4149056 (521T > C) was tested in triplicates through Real Time-PCR using TaqMan® Drug Metabolism Genotyping Assay. rs2306283 (388A > G) was analyzed for comparison. In addition, presence of minor alleles of both SNPs define stronger association with statin-induced myopathy. The study included 282 individuals, 52.8% were males with median age of 39.5 years. 10% had Diabetes Mellitus and 23% were hypertensive. Median of body mass index (BMI) was 27.68 kg/m 2 in males and 28.38 kg/m 2 in females. One-hundred ninety-seven (69.9%) showed abnormal lipid profile (either increased LDL-cholesterol or triglycerides or both). For rs4149056, C allele was present in 21.3% (2.8% homozygous C and 18.4% heterozygous CT). Although homozygous C genotype prevalence was low, compared with Caucasians (4%) and Africans (0%), C allele was associated with a trend of having higher BMI and abnormal lipid profile. C allele subjects were all pre-diabetics with mean glycated hemoglobin above 6%. Mean BMI in CC, CT, and TT genotypes was 30.91 ± 4.4, 29.48 ± 4.2, 27.96 ± 5.5 kg/m 2 respectively, with lack of such a trend observed with the different genotypes of the rs2306283 (used for comparison). Abnormal lipid profile was observed in 7/8(87.5%), 38/52(73.1

  17. [In vitro study of vitamins B1, B2 and B6 adsorption on zeolite].

    PubMed

    Basić, Zorica; Kilibarda, Vesna; Dobrić, Silva; Resanović, Radmila

    2011-01-01

    Zeolites are the hydratised alumosilicates of alcali and earthalcali cations, which have a long three-dimensional crystal structure. Preparations on the basis of zeolites are used for adsorption of organic and nonorganic toxic substances and they, also, find more and more use in veterinary and human medicine and pharmacy. The aim of this study was to evaluate the possibilities of zeolite to adsorb vitamins B1, B2 and B6 in acid and neutral solutions, as well as the characteristics of the process (saturability, reversibility and competitiveness). The specific and sensitive HPLC method with fluorescent detector was used for determination of vitamins B1, B2 and B6. Analyte separation and detection were carried out by applying the reverse-phase method on column C18. An in vitro experiment was done by testing the influence of pH value (2 and 7), concentration of vitamin solution (1, 2 and 5 mg/L), the length of contact with zeolite (10-180 min) and cation competitiveness on the exchange capacity, which is achieved by media and zeolite contact, as well as a possible vitamins desorption through changing pH value of the solution at 37 degrees C. Jon competitiveness was examined by adding commercial feed mixture (grower) with a defined content of the examined vitamins in zeolite solutions the pH = 2 and pH = 7. Vitamins B1, B2 and B6 were stable in both pH=2 and pH = 7 solutions at 37 degrees C, in the defined time intervals. In acid solution concentrations of vitamins significantly declined in the first 10 min, with no significant decline in further 30 min for all the three concentrations tests. In neutral solution, after the addition of 1% zeolite, decrease in vitamins concentrations was slightly lower than in acid solution, but also significant in the first 10 min of the contact with zeolite. It was found that zeolite, which adsorbed vitamins in acid solution, transferred in the neutral one released a significant quantity of adsorbed vitamins after 30 min of extraction

  18. 1-Nitropyrene (1-NP) induces apoptosis and apparently a non-apoptotic programmed cell death (paraptosis) in Hepa1c1c7 cells

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

    Asare, Nana; Landvik, Nina E.; Lagadic-Gossmann, Dominique

    2008-07-15

    Mechanistic studies of nitro-PAHs (polycyclic aromatic hydrocarbons) of interest might help elucidate which chemical characteristics are most important in eliciting toxic effects. 1-Nitropyrene (1-NP) is the predominant nitrated PAH emitted in diesel exhaust. 1-NP-exposed Hepa1c1c7 cells exhibited marked changes in cellular morphology, decreased proliferation and different forms of cell death. A dramatic increase in cytoplasmic vacuolization was observed already after 6 h of exposure and the cells started to round up at 12 h. The rate of cell proliferation was markedly reduced at 24 h and apoptotic as well as propidium iodide (PI)-positive cells appeared. Electron microscopic examination revealed thatmore » the vacuolization was partly due to mitochondria swelling. The caspase inhibitor Z-VAD-FMK inhibited only the apoptotic cell death and Nec-1 (an inhibitor of necroptosis) exhibited no inhibitory effects on either cell death or vacuolization. In contrast, cycloheximide markedly reduced both the number of apoptotic and PI-positive cells as well as the cytoplasmic vacuolization, suggesting that 1-NP induced paraptotic cell death. All the MAPKs; ERK1/2, p38 and JNK, appear to be involved in the death process since marked activation was observed upon 1-NP exposure, and their inhibitors partly reduced the induced cell death. The ERK1/2 inhibitor PD 98057 completely blocked the induced vacuolization, whereas the other MAPKs inhibitors only had minor effects on this process. These findings suggest that 1-NP may cause apoptosis and paraptosis. In contrast, the corresponding amine (1-aminopyrene) elicited only minor apoptotic and necrotic cell death, and cells with characteristics typical of paraptosis were absent.« less

  19. The thermal conductivity of 1-chloro-1,1-difluoroethane (HCFC-142b)

    NASA Astrophysics Data System (ADS)

    Sousa, A. T.; Fialho, P. S.; Nieto de Castro, C. A.; Tufeu, R.; Le Neindre, B.

    1992-05-01

    The thermal conductivity of 1-chloro-1,1-difluoroethane (HCFC-142b) has been measured in the temperature range 290 to 504 K and pressures up to 20 MPa with a concentric-cylinder apparatus operating in a steady-state mode. These temperature and pressure ranges cover all fluid states. The estimated accuracy of the method is about 2%. The density dependence of the thermal conductivity has been studied in the liquid region.

  20. Molecular Tracing of Hepatitis C Virus Genotype 1 Isolates in Iran: A NS5B Phylogenetic Analysis with Systematic Review.

    PubMed

    Hesamizadeh, Khashayar; Alavian, Seyed Moayed; Najafi Tireh Shabankareh, Azar; Sharafi, Heidar

    2016-12-01

    Hepatitis C virus (HCV) is characterized by a high degree of genetic heterogeneity and classified into 7 genotypes and different subtypes. It heterogeneously distributed through various risk groups and geographical regions. A well-established phylogenetic relationship can simplify the tracing of HCV hierarchical strata into geographical regions. The current study aimed to find genetic phylogeny of subtypes 1a and 1b of HCV isolates based on NS5B nucleotide sequences in Iran and other members of Eastern Mediterranean regional office of world health organization, as well as other Middle Eastern countries, with a systematic review of available published and unpublished studies. The phylogenetic analyses were performed based on the nucleotide sequences of NS5B gene of HCV genotype 1 (HCV-1), which were registered in the GenBank database. The literature review was performed in two steps: 1) searching studies evaluating the NS5B sequences of HCV-1, on PubMed, Scopus, and Web of Science, and 2) Searching sequences of unpublished studies registered in the GenBank database. In this study, 442 sequences from HCV-1a and 232 from HCV-1b underwent phylogenetic analysis. Phylogenetic analysis of all sequences revealed different clusters in the phylogenetic trees. The results showed that the proportion of HCV-1a and -1b isolates from Iranian patients probably originated from domestic sources. Moreover, the HCV-1b isolates from Iranian patients may have similarities with the European ones. In this study, phylogenetic reconstruction of HCV-1 sequences clearly indicated for molecular tracing and ancestral relationships of the HCV genotypes in Iran, and showed the likelihood of domestic origin for HCV-1a and various origin for HCV-1b.

  1. Classical ferroelectriclike behavior of highly ordered Pb (S c1 /2N b1 /2)O3 studied by dielectric and Brillouin scattering spectroscopy

    NASA Astrophysics Data System (ADS)

    Sivasubramanian, V.; Subramanian, V.; Kojima, S.

    2016-02-01

    The ferroelectric phase transition behavior in the highly ordered Pb (S c1 /2N b1 /2) O3 has been investigated by the dielectric and Brillouin spectroscopy. The dielectric permittivity ɛr exhibits a sharp maximum without any frequency dispersion at its Curie temperature Tc. In the temperature range far above Tc, it was noted that the dielectric permittivity exhibits a noticeable deviation from the Curie-Weiss law below the characteristic intermediate temperature T*=500 K , which is common to most of the Pb-based oxide perovskite relaxors. Upon cooling, the frequency of the longitudinal acoustic phonon mode exhibits a remarkable softening towards Tc. The relaxation time of the order parameter calculated using the Landau-Khalatnikov approach was determined to be more than one order of magnitude lower than that of the disordered Pb (S c1 /2N b1 /2)O3 and is very close to that observed in the paraelectric phase of the classical ferroelectric, BaTi O3 . The observed dielectric and relaxation features are qualitatively discussed in terms of the difference in the strength of the random electric fields.

  2. Genetic characterization of enterovirus strains identified in Hand, Foot and Mouth Disease (HFMD): Emergence of B1c, C1 subgenotypes, E2 sublineage of CVA16, EV71 and CVA6 strains in India.

    PubMed

    Ganorkar, Nital N; Patil, Pooja R; Tikute, Sanjay S; Gopalkrishna, Varanasi

    2017-10-01

    Hand, Foot and Mouth disease (HFMD) is a common childhood disease and caused due to Enterovirus-A (EV-A), EV-B and EV-C species worldwide. Cases of HFMD were reported from, Ahmedabad (Gujarat, 2012) and Pune (Maharashtra, 2013-2014) in India. The present study highlights the identification of EV strains (CVA16, CVA6, CVA4 and Echo12), characterization of subgenotypes of CVA16, CVA6 strains during 2012-14 and CVA16, CVA6, EV71 strains reported from the earlier study (2009-10) in HFMD cases from India. A total 158 clinical specimens collected from 64 HFMD cases (2012-2014) were included in the study. EV detection was carried out by 5'NCR based RT-PCR, molecular typing and subgenotyping was by VP1/2A junction or VP1, full VP1 gene amplification respectively followed by phylogenetic analysis. The present study reports 63.92% (101/158) EV positivity by RT-PCR. Ninety four of the 101 (93.06%) EV positive strains were amplified by VP1/2A junction or VP1 regions. Sequence analysis revealed the presence of CVA16 (61.7%), CVA6 (34.04%), CVA4 and Echo12 (4.3%). A total of 114 EV positive strains were genotyped using full and partial VP1 region. All CVA16 Indian strains (n=70) clustered with rarely reported B1c subgenotype, CVA6 (n=43) and EV71 (n=1) strains clustered with sub-lineage E2 and C1 subgenotypes respectively. In summary, the study reports genetic characterization of CVA16, CVA6, CVA4 and Echo12 strains in HFMD cases from India. Circulation of B1c subgenotype of CVA16, E2 sub-lineage of CVA6 and C1 subgenotype of EV 71 strains in HFMD cases were reported for the first time from India. This study helps to understand the genotype distribution, genetic diversity of EV strains associated with HFMD from Eastern, Western and Southern regions in India. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Analysis of a Cholera Toxin B Subunit (CTB) and Human Mucin 1 (MUC1) Conjugate Protein in a MUC1 Tolerant Mouse Model

    PubMed Central

    Pinkhasov, Julia; Alvarez, M. Lucrecia; Pathangey, Latha B.; Tinder, Teresa L.; Mason, Hugh S.; Walmsley, Amanda M.; Gendler, Sandra J.; Mukherjee, Pinku

    2011-01-01

    Since epithelial mucin 1 (MUC1) is associated with several adenocarcinomas at mucosal sites, it is pertinent to test the efficacy of a mucosally targeted vaccine formulation. The B subunit of the Vibrio cholerae cholera toxin (CTB) has great potential to act as a mucosal carrier for subunit vaccines. In the present study we evaluated whether a MUC1 tandem repeat (TR) peptide chemically linked to CTB would break self-antigen tolerance in the transgenic MUC1 tolerant mouse model (MUC1.Tg) through oral or parenteral immunizations. We report that oral immunization with the CTB-MUC1 conjugate along with mucosal adjuvant, unmethylated CpG oligodeoxynucleotide (ODN) and interleukin-12 (IL-12), did not break self-antigen tolerance in MUC1.Tg mice, but induced a strong humoral response in wild-type C57BL/6 mice. However, self-antigen tolerance in the MUC1.Tg mouse model was broken after parenteral immunizations with different doses of the CTB-MUC1 conjugate protein and with the adjuvant CpG ODN co-delivered with CTB-MUC1. Importantly, mice immunized systemically with CpG ODN alone and with CTB-MUC1 exhibited decreased tumor burden when challenged with a mammary gland tumor cell line that expresses human MUC1. PMID:20824430

  4. Analysis of a cholera toxin B subunit (CTB) and human mucin 1 (MUC1) conjugate protein in a MUC1-tolerant mouse model.

    PubMed

    Pinkhasov, Julia; Alvarez, M Lucrecia; Pathangey, Latha B; Tinder, Teresa L; Mason, Hugh S; Walmsley, Amanda M; Gendler, Sandra J; Mukherjee, Pinku

    2010-12-01

    Since epithelial mucin 1 (MUC1) is associated with several adenocarcinomas at the mucosal sites, it is pertinent to test the efficacy of a mucosally targeted vaccine formulation. The B subunit of the Vibrio cholerae cholera toxin (CTB) has great potential to act as a mucosal carrier for subunit vaccines. In the present study we evaluated whether a MUC1 tandem repeat (TR) peptide chemically linked to CTB would break self-antigen tolerance in the transgenic MUC1-tolerant mouse model (MUC1.Tg) through oral or parenteral immunizations. We report that oral immunization with the CTB-MUC1 conjugate along with mucosal adjuvant, unmethylated CpG oligodeoxynucleotide (ODN) and interleukin-12 (IL-12) did not break self-antigen tolerance in MUC1.Tg mice, but induced a strong humoral response in wild-type C57BL/6 mice. However, self-antigen tolerance in the MUC1.Tg mouse model was broken after parenteral immunizations with different doses of the CTB-MUC1 conjugate protein and with the adjuvant CpG ODN co-delivered with CTB-MUC1. Importantly, mice immunized systemically with CpG ODN alone and with CTB-MUC1 exhibited decreased tumor burden when challenged with a mammary gland tumor cell line that expresses human MUC1.

  5. 26 CFR 1.381(c)(4)-1 - Method of accounting.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 4 2012-04-01 2012-04-01 false Method of accounting. 1.381(c)(4)-1 Section 1... TAX (CONTINUED) INCOME TAXES (Continued) Insolvency Reorganizations § 1.381(c)(4)-1 Method of accounting. (a) Introduction—(1) Purpose. This section provides guidance regarding the method of accounting...

  6. Mechanism of Inhibition of Hsp90 Dimerization by Gyrase B Inhibitor Coumermycin A1 (C-A1) Revealed by Molecular Dynamics Simulations and Thermodynamic Calculations.

    PubMed

    Cele, Favourite N; Kumalo, Hezekiel; Soliman, Mahmoud E S

    2016-09-01

    Heat shock protein (Hsp) 90 an emerging and attracting target in the anti-HIV drug discovery process due to the key role it plays in the pathogenicity of HIV-1 virus. In this research study, long-range all-atom molecular dynamics simulations were engaged for the bound and the unbound proteins to enhance the understanding of the molecular mechanisms of the Hsp90 dimerization and inhibition. Results evidently showed that coumermycin A1 (C-A1), a recently discovered Hsp90 inhibitor, binds at the dimer's active site of the Hsp90 protein and leads to a substantial parting between dimeric opposed residues, which include Arg591.B, Lys594.A, Ser663.A, Thr653.B, Ala665.A, Thr649.B, Leu646.B and Asn669.A. Significant differences in magnitudes were observed in radius of gyration, root-mean-square deviation and root-mean-square fluctuation, which confirms a reasonably more flexible state in the apo conformation associated with it dimerization. In contrast, the bound conformer of Hsp90 showed less flexibility. This visibly highpoints the inhibition process resulting from the binding of the ligand. These findings were further validated by principal component analysis. We believe that the detailed dynamic analyses of Hsp90 presented in this study, would give an imperative insight and better understanding to the function and mechanisms of inhibition. Furthermore, information obtained from the binding mode of the inhibitor would be of great assistance in the design of more potent inhibitors against the HIV target Hsp90.

  7. Synthesis of fagopyritols A1 and B1 from D-chiro-inositol.

    PubMed

    Cid, M Belén; Alfonso, Francisco; Martín-Lomas, Manuel

    2004-09-13

    Fagopyritol A1 (3-O-alpha-d-galactopyranosyl-d-chiro-inositol) and fagopyritol B1 (2-O-alpha-d-galactopyranosyl-d-chiro-inositol) have been synthesized by glycosylation of the diequatorial diol 1,4,5,6-tetra-O-benzoyl-d-chiro-inositol, readily obtained from d-chiro-inositol, with 2,3,4,6-tetra-O-benzyl-d-galactopyranosyl trichloroacetimidate.

  8. Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

    PubMed Central

    Zhang, Jun; Jia, Lin; Lin, Weitao; Yip, Yim Ling; Lo, Kwok Wai; Lau, Victoria Ming Yi; Zhu, Dandan; Tsang, Chi Man; Zhou, Yuan; Deng, Wen; Lung, Hong Lok; Lung, Maria Li; Cheung, Lai Man

    2017-01-01

    ABSTRACT Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-κB is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-κB signaling to mediate aerobic glycolysis. NF-κB activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-κB activation and Glut-1 transcription. Interfering NF-κB signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-κB signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKKβ-mediated phosphorylation of TSC2 at Ser939. Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-κB/Glut-1 represents a novel therapeutic target against NPC. IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC

  9. A SEARCH FOR l-C{sub 3}H{sup +} AND l-C{sub 3}H IN Sgr B2(N), Sgr B2(OH), AND THE DARK CLOUD TMC-1

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

    McGuire, Brett A.; Carroll, P. Brandon; Loomis, Ryan A.

    2013-09-01

    Pety et al. recently reported the detection of several transitions of an unknown carrier in the Horsehead PDR and attribute them to l-C{sub 3}H{sup +}. Here, we have tested the predictive power of their fit by searching for, and identifying, the previously unobserved J = 1-0 and J = 2-1 transitions of the unknown carrier (B11244) toward Sgr B2(N) in data from the publicly available PRIMOS project. Also presented here are observations of the J = 6-5 and J = 7-6 transitions toward Sgr B2(N) and Sgr B2(OH) using the Barry E. Turner Legacy Survey and results from the Kaifumore » et al. survey of TMC-1. We calculate an excitation temperature and column density of B11244 of {approx}10 K and {approx}10{sup 13} cm{sup -2} in Sgr B2(N) and {approx}79 K with an upper limit of {<=}1.5 Multiplication-Sign 10{sup 13} cm{sup -2} in Sgr B2(OH) and find trace evidence for the cation's presence in TMC-1. Finally, we present spectra of the neutral species in both Sgr B2(N) and TMC-1, and comment on the robustness of the assignment of the detected signals to l-C{sub 3}H{sup +}.« less

  10. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... levels can be high if diabetes is not well controlled. Why Are Hemoglobin A1c Tests Done? When a child has diabetes, hemoglobin A1c levels are followed to see how well medicines are working. If a child with diabetes ...

  11. Chemical segregation in the young protostars Barnard 1b-N and S. Evidence of pseudo-disk rotation in Barnard 1b-S

    NASA Astrophysics Data System (ADS)

    Fuente, A.; Gerin, M.; Pety, J.; Commerçon, B.; Agúndez, M.; Cernicharo, J.; Marcelino, N.; Roueff, E.; Lis, D. C.; Wootten, H. A.

    2017-10-01

    The extremely young Class 0 object B1b-S and the first hydrostatic core (FSHC) candidate, B1b-N, provide a unique opportunity to study the chemical changes produced in the elusive transition from the prestellar core to the protostellar phase. We present 40″ × 70″ images of Barnard 1b in the 13CO 1 → 0, C18O 1 → 0, NH2D 11,1a→ 10,1s, and SO 32→ 21 lines obtained with the NOEMA interferometer. The observed chemical segregation allows us to unveil the physical structure of this young protostellar system down to scales of 500 au. The two protostellar objects are embedded in an elongated condensation, with a velocity gradient of 0.2-0.4 m s-1 au-1 in the east-west direction, reminiscent of an axial collapse. The NH2D data reveal cold and dense pseudo-disks (R 500 - 1000 au) around each protostar. Moreover, we observe evidence of pseudo-disk rotation around B1b-S. We do not see any signature of the bipolar outflows associated with B1b-N and B1b-S, which were previously detected in H2CO and CH3OH, in any of the imaged species. The non-detection of SO constrains the SO/CH3OH abundance ratio in the high-velocity gas. Based on observations carried out with the IRAM Northern Extended Millimeter Array (NOEMA). IRAM is supported by INSU/ CNRS (France), MPG (Germany), and IGN (Spain).The reduced datacube is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/606/L3

  12. A1C test

    MedlinePlus

    ... every 3 or 6 months is recommended. Normal Results The following are the results when A1C is ... meaning of your specific test results. What Abnormal Results Mean An abnormal result means that you have ...

  13. Preliminary X-ray crystallographic analysis of glutathione transferase zeta 1 (GSTZ1a-1a)

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

    Boone, Christopher D.; Zhong, Guo; Smeltz, Marci

    2014-01-21

    Crystals of glutathione transferase zeta 1 were grown and shown to diffract X-rays to 3.1 Å resolution. They belonged to space group P1, with unit-cell parameters a = 42.0, b = 49.6, c = 54.6 Å, α = 82.9, β = 69.9, γ = 73.4°.

  14. Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

    PubMed Central

    Miyagawa, Taku; Honda, Makoto; Kawashima, Minae; Shimada, Mihoko; Tanaka, Susumu; Honda, Yutaka; Tokunaga, Katsushi

    2009-01-01

    Background SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy. Principal Findings EHS was significantly associated with SNP rs5770917 (Pallele = 3.6×10−3; OR = 1.56; 95% c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P positivity = 9.2×10−11; OR = 3.97; 95% c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS. Conclusion CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy. PMID:19404393

  15. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18 U...

  16. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18 U...

  17. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18 U...

  18. 18 CFR 1b.20 - Request for confidential treatment.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 1 2014-04-01 2014-04-01 false Request for confidential treatment. 1b.20 Section 1b.20 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY... disclosure requirements of the Freedom of Information Act (5 U.S.C. 552), is information referred to in 18 U...

  19. Vav1-phospholipase C1 (Vav1-PLC-γ1) pathway initiated by T cell antigen receptor (TCRγδ) activation is required to overcome inhibition by ubiquitin ligase Cbl-b during γδT cell cytotoxicity.

    PubMed

    Yin, Shanshan; Zhang, Jianmin; Mao, Yujia; Hu, Yu; Cui, Lianxian; Kang, Ning; He, Wei

    2013-09-13

    T cell antigen receptor γδ (TCRγδ) and natural killer group 2, member D (NKG2D) are two crucial receptors for γδT cell cytotoxicity. Compelling evidences suggest that γδT cell cytotoxicity is TCRγδ-dependent and can be co-stimulated by NKG2D. However, the molecular mechanism of underlying TCRγδ-dependent activation of γδT cells remains unclear. In this study we demonstrated that TCRγδ but not NKG2D engagement induced lytic granule polarization and promoted γδT cell cytotoxicity. TCRγδ activation alone was sufficient to trigger Vav1-dependent phospholipase C1 signaling, resulting in lytic granule polarization and effective killing, whereas NKG2D engagement alone failed to trigger cytotoxicity-related signaling to overcome the inhibitory effect of Cbl-b; therefore, NKG2D engagement alone could not induce effective killing. However, NKG2D ligation augmented the activation of γδT cell cytotoxicity through the Vav1-phospholipase C1 pathway. Vav1 overexpression or Cbl-b knockdown not only enhanced TCRγδ activation-initiated killing but also enabled NKG2D activation alone to induce γδT cell cytotoxicity. Taken together, our results suggest that the activation of γδT cell cytotoxicity requires a strong activation signal to overcome the inhibitory effect of Cbl-b. Our finding provides new insights into the molecular mechanisms underlying the initiation of γδT cell cytotoxicity and likely implications for optimizing γδT cell-based cancer immunotherapy.

  20. The thermal conductivity of 1-chloro-1,1-difluoroethane (HCFC-142b)

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

    Sousa, A.T.; Fialho, P.S.; Nieto de Castro, C.A.

    1992-05-01

    The thermal conductivity of 1-chloro-1,1-difluoroethane (HCFC-142b) has been measured in the temperature range 290 to 504 K and pressures up to 20 MPa with a concentric-cylinder apparatus operating in a steady-state mode. These temperature and pressure ranges cover all fluid states. The estimated accuracy of the method is about 2%. The density dependence of the thermal conductivity has been studied in the liquid region. 19 refs., 5 figs., 4 tabs.

  1. CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma.

    PubMed

    Souzeau, Emmanuelle; Hayes, Melanie; Ruddle, Jonathan B; Elder, James E; Staffieri, Sandra E; Kearns, Lisa S; Mackey, David A; Zhou, Tiger; Ridge, Bronwyn; Burdon, Kathryn P; Dubowsky, Andrew; Craig, Jamie E

    2015-01-01

    To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma. In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA). No deletions or duplications were found in any of the cases. This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility.

  2. Word Frequency Analysis MOS: 17C. Skill Levels 1 & 2.

    DTIC Science & Technology

    1981-05-01

    AP 1 BURNED 14 BUR ST 1 B UR STS I BURY - 4 BUSHES q BI.T 4A BUTT 12 AUTTON 4 RUTTPLATE P ROVEFR * 1’P? AV I ARI 148 C 1 C-PATIEN 7 C-1 I C-ts 2 C-2 2...I BRAEING I mvFAKS I RAT4 I ARFATHF 1 BREATHS I RPInGFS I1 BRIEF I1 RtrIC.NSS I PROWN I AliI AINIIs 1 Bu ILt. I IIIINKERS I BURNED I AP1KV I at 1 C...PREPARING 1PRESCR IBE I PRECRIBED Porr.RAN II ~NTFO PRIOR 1 PROCEDUREIN( I PaCPFRTY 1P21IO I PUA FADSIN I RAtE AIE I REACHING I READRE 1 R ED O R

  3. 26 CFR 1.381(c)(25)-1 - Deficiency dividend of a qualified investment entity.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Deficiency dividend of a qualified investment entity. 1.381(c)(25)-1 Section 1.381(c)(25)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(25...

  4. Docking and QSAR comparative studies of polycyclic aromatic hydrocarbons and other procarcinogen interactions with cytochromes P450 1A1 and 1B1.

    PubMed

    Gonzalez, J; Marchand-Geneste, N; Giraudel, J L; Shimada, T

    2012-01-01

    To obtain chemical clues on the process of bioactivation by cytochromes P450 1A1 and 1B1, some QSAR studies were carried out based on cellular experiments of the metabolic activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic compounds by those enzymes. Firstly, the 3D structures of cytochromes 1A1 and 1B1 were built using homology modelling with a cytochrome 1A2 template. Using these structures, 32 ligands including heterocyclic aromatic compounds, polycyclic aromatic hydrocarbons and corresponding diols, were docked with LigandFit and CDOCKER algorithms. Binding mode analysis highlighted the importance of hydrophobic interactions and the hydrogen bonding network between cytochrome amino acids and docked molecules. Finally, for each enzyme, multilinear regression and artificial neural network QSAR models were developed and compared. These statistical models highlighted the importance of electronic, structural and energetic descriptors in metabolic activation process, and could be used for virtual screening of ligand databases. In the case of P450 1A1, the best model was obtained with artificial neural network analysis and gave an r (2) of 0.66 and an external prediction [Formula: see text] of 0.73. Concerning P450 1B1, artificial neural network analysis gave a much more robust model, associated with an r (2) value of 0.73 and an external prediction [Formula: see text] of 0.59.

  5. 7 CFR 1c.109 - IRB review of research.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 1 2011-01-01 2011-01-01 false IRB review of research. 1c.109 Section 1c.109... research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that...

  6. 7 CFR 1c.109 - IRB review of research.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 1 2012-01-01 2012-01-01 false IRB review of research. 1c.109 Section 1c.109... research. (a) An IRB shall review and have authority to approve, require modifications in (to secure approval), or disapprove all research activities covered by this policy. (b) An IRB shall require that...

  7. Heat Shock Protein B1-Deficient Mice Display Impaired Wound Healing

    PubMed Central

    McNamee, Kay; Przybycien, Paulina M.; Lu, Xin; Williams, Richard O.; Bou-Gharios, George; Saklatvala, Jeremy; Dean, Jonathan L. E.

    2013-01-01

    There is large literature describing in vitro experiments on heat shock protein (hsp)B1 but understanding of its function in vivo is limited to studies in mice overexpressing human hspB1 protein. Experiments in cells have shown that hspB1 has chaperone activity, a cytoprotective role, regulates inflammatory gene expression, and drives cell proliferation. To investigate the function of the protein in vivo we generated hspB1-deficient mice. HspB1-deficient fibroblasts display increased expression of the pro-inflammatory cytokine, interleukin-6, compared to wild-type cells, but reduced proliferation. HspB1-deficient fibroblasts exhibit reduced entry into S phase and increased expression of cyclin-dependent kinase inhibitors p27kip1 and p21waf1. The expression of hspB1 protein and mRNA is also controlled by the cell cycle. To investigate the physiological function of hspB1 in regulating inflammation and cell proliferation we used an excisional cutaneous wound healing model. There was a significant impairment in the rate of healing of wounds in hspB1-deficient mice, characterised by reduced re-epithelialisation and collagen deposition but also increased inflammation. HspB1 deficiency augments neutrophil infiltration in wounds, driven by increased chemokine (C-X-C motif) ligand 1 expression. This appears to be a general mechanism as similar results were obtained in the air-pouch and peritonitis models of acute inflammation. PMID:24143227

  8. Locoregional treatment and overall survival of men with T1a,b,cN0M0 breast cancer: A population-based study.

    PubMed

    Leone, José Pablo; Leone, Julieta; Zwenger, Ariel Osvaldo; Iturbe, Julián; Leone, Bernardo Amadeo; Vallejo, Carlos Teodoro

    2017-01-01

    Male breast cancer (MaBC) is an understudied disease; information about locoregional treatment and outcomes in patients with early stage is unknown. We aimed to analyse patient characteristics, locoregional treatment and overall survival (OS) of T1a,b,cN0M0 male breast cancer. We evaluated men with T1a,b,cN0M0 breast cancer reported to Surveillance, Epidemiology, and End Results program from 1988 to 2012. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. We included 1263 patients. Median age was 66 years (range 27-103). Median follow-up was 62 months (range 1-294). OS at 5 and 10 years were 85.1% and 66.5%, respectively. Distribution according to tumour sub-stage was: T1a 6.5%, T1b 20.7% and T1c 72.8%. Mastectomy was performed in >74% of patients of each tumour size group and overall 44.1% had >5 lymph nodes examined (LNE). Univariate analysis showed that patients with T1c, no surgery and 0 LNE had worse prognosis. In multivariate analysis, older age (hazard ratio [HR] 11.09), grade 3/4 tumours (HR 1.7), no surgery (HR 3.3), 0 LNE (HR 5.1) and unmarried patients (HR 1.7) had significantly shorter OS. There were no differences in OS between breast conservation versus mastectomy and 1-5 LNE versus > 5 LNE. Men with early breast cancer have a favourable OS. However, older age, higher grade, no breast surgery, no LNE and unmarried status emerged as poor prognostic characteristics. Efforts to decrease the high rates of mastectomy and extensive LNE should be taken given similar OS observed with breast conservation and 1-5 LNE, respectively. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in...

  10. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in...

  11. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in...

  12. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in...

  13. 20 CFR 655.700 - What statutory provisions govern the employment of H-1B, H-1B1, and E-3 nonimmigrants and how do...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... employment of H-1B, H-1B1, and E-3 nonimmigrants and how do employers apply for H-1B, H-1B1, and E-3 visas... Requirements for Employers Seeking To Employ Nonimmigrants on H-1b Visas in Specialty Occupations and as Fashion Models, and Requirements for Employers Seeking To Employ Nonimmigrants on H-1b1 and E-3 Visas in...

  14. 26 CFR 1.381(c)(13)-1 - Involuntary conversions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Involuntary conversions. 1.381(c)(13)-1 Section...) INCOME TAX (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(13)-1 Involuntary conversions... involuntary conversions. This rule shall apply even though the property similar or related in service or use...

  15. 26 CFR 1.381(c)(13)-1 - Involuntary conversions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 4 2011-04-01 2011-04-01 false Involuntary conversions. 1.381(c)(13)-1 Section...) INCOME TAX (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(13)-1 Involuntary conversions... involuntary conversions. This rule shall apply even though the property similar or related in service or use...

  16. 26 CFR 1.381(c)(4)-1 - Method of accounting.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 4 2010-04-01 2010-04-01 false Method of accounting. 1.381(c)(4)-1 Section 1... TAX (CONTINUED) INCOME TAXES Insolvency Reorganizations § 1.381(c)(4)-1 Method of accounting. (a... section 381(a) applies, an acquiring corporation shall use the same method of accounting used by the...

  17. Bacterially activated B-cells drive T cell differentiation towards Tr1 through PD-1/PD-L1 expression.

    PubMed

    Said, Sawsan Sudqi; Barut, Guliz Tuba; Mansur, Nesteren; Korkmaz, Asli; Sayi-Yazgan, Ayca

    2018-04-01

    Regulatory B cells (Bregs) play a crucial role in immunological tolerance primarily through the production of IL-10 in many diseases including autoimmune disorders, allergy, infectious diseases, and cancer. To date, various Breg subsets with overlapping phenotypes have been identified. However, the roles of Bregs in Helicobacter infection are largely unknown. In the present study, we investigate the phenotype and function of Helicobacter -stimulated B cells. Our results demonstrate that Helicobacter felis -stimulated IL-10- producing B cells (Hf stim - IL-10 + B) are composed of B10 and Transitional 2 Marginal Zone Precursor (T2-MZP) cells with expression of CD9, Tim-1, and programmed death 1 (PD-1). On the other hand, Helicobacter felis -stimulated IL-10- nonproducing B (Hf stim - IL-10 - B) cells are mainly marginal zone (MZ) B cells that express PD-L1 and secrete TGF-β, IL-6, and TNF-α, and IgM and IgG2b. Furthermore, we show that both Hf stim - IL-10 + B cells and Hf stim - IL-10 - B cells induce CD49b + LAG-3 + Tr1 cells. Here, we describe a novel mechanism for PD-1/PD-L1- driven B cell-dependent Tr1 cell differentiation. Finally, we explore the capability of Hf stim - IL-10 - B cells to induce Th17 cell differentiation, which we find to be dependent on TGF-β. Taken together, the current study demonstrates that Hf stim - B cells induce Tr1 cells through the PD-1/PD-L1 axis and Th17 cells by secreting TGF-β. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Hepatitis C virus core protein induces hepatic steatosis via Sirt1-dependent pathway.

    PubMed

    Zhang, Chuanhai; Wang, Jingjing; Zhang, Hanlin; Liu, Shunai; Lee, Hyuek Jong; Jin, Wanzhu; Cheng, Jun

    2018-05-01

    Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied. Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression. Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Policy. 1b.2 Section 1b.2 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.2 Policy. (a) All policies and programs of... environment for present and future generations. (b) Each USDA agency is responsible for compliance with this...

  20. 7 CFR 1b.2 - Policy.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Policy. 1b.2 Section 1b.2 Agriculture Office of the Secretary of Agriculture NATIONAL ENVIRONMENTAL POLICY ACT § 1b.2 Policy. (a) All policies and programs of... environment for present and future generations. (b) Each USDA agency is responsible for compliance with this...