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121.
Lamont Lindstrom 《Anthropological Forum》1999,9(1):99-105
Mambu: A Melanesian millennium, by Kenelm Burridge. Princeton University Press, Princeton NJ, 1995 [reprinting of original 1960 edition with new preface]. 296pp., appendices, index. ISBN 0–691–00166–9 (paperback). 相似文献
122.
Linda M. Lucero Maegan M. Weltzin J. Brek Eaton John F. Cooper Jon M. Lindstrom Ronald J. Lukas Paul Whiteaker 《The Journal of biological chemistry》2016,291(5):2444-2459
Two α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) isoforms exist with (α4)2(β2)3 and (α4)3(β2)2 subunit stoichiometries and high versus low agonist sensitivities (HS and LS), respectively. Both isoforms contain a pair of α4(+)/(−)β2 agonist-binding sites. The LS isoform also contains a unique α4(+)/(−)α4 site with lower agonist affinity than the α4(+)/(−)β2 sites. However, the relative roles of the conserved α4(+)/(−)β2 agonist-binding sites in and between the isoforms have not been studied. We used a fully linked subunit concatemeric nAChR approach to express pure populations of HS or LS isoform α4β2*-nAChR. This approach also allowed us to mutate individual subunit interfaces, or combinations thereof, on each isoform background. We used this approach to systematically mutate a triplet of β2 subunit (−)-face E-loop residues to their non-conserved α4 subunit counterparts or vice versa (β2HQT and α4VFL, respectively). Mutant-nAChR constructs (and unmodified controls) were expressed in Xenopus oocytes. Acetylcholine concentration-response curves and maximum function were measured using two-electrode voltage clamp electrophysiology. Surface expression was measured with 125I-mAb 295 binding and was used to define function/nAChR. If the α4(+)/(−)β2 sites contribute equally to function, making identical β2HQT substitutions at either site should produce similar functional outcomes. Instead, highly differential outcomes within the HS isoform, and between the two isoforms, were observed. In contrast, α4VFL mutation effects were very similar in all positions of both isoforms. Our results indicate that the identity of subunits neighboring the otherwise equivalent α4(+)/(−)β2 agonist sites modifies their contributions to nAChR activation and that E-loop residues are an important contributor to this neighbor effect. 相似文献
123.
Pre-steady state partitioning analysis of the HhaI DNA methyltransferase directly demonstrates the catalytic competence of the enzyme.DNA complex and the lack of catalytic competence of the enzyme.S-adenosyl-L-methionine (AdoMet) complex. The enzyme.AdoMet complex does form, albeit with a 50-fold decrease in affinity compared with the ternary enzyme.AdoMet.DNA complex. These findings reconcile the distinct binding orientations previously observed within the binary enzyme.AdoMet and ternary enzyme. S-adenosyl-L-homocysteine.DNA crystal structures. The affinity of the enzyme for DNA is increased 900-fold in the presence of its cofactor, and the preference for hemimethylated DNA is increased to 12-fold over unmethylated DNA. We suggest that this preference is partially due to the energetic cost of retaining a cavity in place of the 5-methyl moiety in the ternary complex with the unmethylated DNA, as revealed by the corresponding crystal structures. The hemi- and unmethylated substrates alter the fates and lifetimes of discrete enzyme.substrate intermediates during the catalytic cycle. Hemimethylated substrates partition toward product formation versus dissociation significantly more than unmethylated substrates. The mammalian DNA cytosine-C-5 methyltransferase Dnmt1 shows an even more pronounced partitioning toward product formation. 相似文献
124.
Malygin EG Lindstrom WM Schlagman SL Hattman S Reich NO 《Nucleic acids research》2000,28(21):4207-4211
The DNA methyltransferase of bacteriophage T4 (T4 Dam MTase) recognizes the palindromic sequence GATC, and catalyzes transfer of the methyl group from S:-adenosyl-L-methionine (AdoMet) to the N(6)-position of adenine [generating N(6)-methyladenine and S:-adenosyl-L-homocysteine (AdoHcy)]. Pre-steady state kinetic analysis revealed that the methylation rate constant k(meth) for unmethylated and hemimethylated substrates (0.56 and 0.47 s(-1), respectively) was at least 20-fold larger than the overall reaction rate constant k(cat) (0.023 s(-1)). This indicates that the release of products is the rate-limiting step in the reaction. Destabilization of the target-base pair did not alter the methylation rate, indicating that the rate of target nucleoside flipping does not limit k(meth). Preformed T4 Dam MTase-DNA complexes are less efficient than preformed T4 Dam MTase-AdoMet complexes in the first round of catalysis. Thus, this data is consistent with a preferred route of reaction for T4 Dam MTase in which AdoMet is bound first; this preferred reaction route is not observed with the DNA-[C5-cytosine]-MTases. 相似文献
125.
Fisher MJ Giese U Harms CS Kinnick MD Lindstrom TD McCowan JR Mest HJ Morin JM Mullaney JT Paal M Rapp A Rühter G Ruterbories KJ Sall DJ Scarborough RM Schotten T Stenzel W Towner RD Um SL Utterback BG Wyss VL Jakubowski JA 《Bioorganic & medicinal chemistry letters》2000,10(4):385-389
6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration. 相似文献
126.
Henderson AP Bleasdale C Delaney K Lindstrom AB Rappaport SM Waidyanatha S Watson WP Golding BT 《Bioorganic chemistry》2005,33(5):363-373
Glutathione induces the rapid isomerization of (Z,Z)-muconaldehyde to (E,E)-muconaldehyde via (E,Z)-muconaldehyde, probably via reversible Michael addition of the thiol to one of the enal moieties of the muconaldehyde. Reactions of (E,E)-muconaldehyde with glutathione (in the presence and absence of equine glutathione S-transferase), phenylmethanethiol, N-acetyl-l-cysteine, and N-acetyl-l-cysteine methyl ester were investigated using mass spectrometric techniques. In each case, evidence was obtained for the formation of Michael adducts, e.g., reaction between (E,E)-muconaldehyde and glutathione gave 4-glutathionyl-hex-2-enedial and 3,4-bis-glutathionyl-hexanedial. These experiments suggest that (Z,Z)-muconaldehyde, a putative metabolite of benzene, could lead to the long established urinary metabolite of benzene, (E,E)-muconic acid, via glutathione-mediated isomerization to (E,E)-muconaldehyde. 相似文献
127.
Responsiveness of human retinoblastoma and neuroblastoma models to a non-calcemic 19-nor Vitamin D analog 总被引:3,自引:0,他引:3
Albert DM Plum LA Yang W Marcet M Lindstrom MJ Clagett-Dame M DeLuca HF 《The Journal of steroid biochemistry and molecular biology》2005,97(1-2):165-172
OBJECTIVES: To investigate the effectiveness of 2-methylene-19-nor-(20S)-1alpha-hydroxybishomopregnacalciferol (2MbisP) in inhibiting the growth of retinoblastoma (RB) and neuroblastoma (NB). METHODS: For the RB study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model and the transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 2MbisP or vehicle for 5 weeks. For the NB study, the xenograft athymic mouse/human neuroblastoma cell (SK-N-AS) model was treated with 2MbisP or vehicle for 5 weeks. Tumor size and toxicity were assessed. RESULTS: In the xenograft models of RB and NB, 2MbisP caused statistically significant inhibition of tumor growth. Tumor growth inhibition was also observed in the transgenic RB mice, but did not achieve statistical significance. In all the groups, no biologically significant toxic effects were observed using the following variables: serum calcium levels, degree of kidney calcification, changes in body weight or survival. CONCLUSIONS: In athymic mice, 2MbisP was effective in inhibiting RB and NB growth compared with controls. A lesser effect was seen in the transgenic RB model. 2MbisP did not cause hypercalcemia or a significant increase in mortality. CLINICAL RELEVANCE: 2MbisP should be considered for use in clinical trials of RB and NB. 相似文献
128.
129.
Dickerson EB Akhtar N Steinberg H Wang ZY Lindstrom MJ Padilla ML Auerbach R Helfand SC 《Molecular cancer research : MCR》2004,2(12):663-673
We engineered a fusion protein, mrIL-12vp [mouse recombinant interleukin (IL)-12 linked to vascular peptide], linking the vascular homing peptide CDCRGDCFC (RGD-4C), a ligand for alphavbeta3 integrin, to mrIL-12 to target IL-12 directly to tumor neovasculature. The fusion protein stimulated IFN-gamma production in vitro and in vivo, indicating its biological activity was consistent with mrIL-12. Immunofluorescence techniques showed mrIL-12vp specifically bound to alphavbeta3 integrin-positive cells but not to alphavbeta3 integrin-negative cells. In corneal angiogenesis assays using BALB/c mice treated with either 0.5 microg/mouse/d of mrIL-12vp or mrIL-12 delivered by subcutaneous continuous infusion, mrIL-12vp inhibited corneal neovascularization by 67% compared with only a slight reduction (13%) in angiogenesis in the mrIL-12-treated animals (P = 0.008). IL-12 receptor knockout mice given mrIL-12vp showed a marked decrease in the area of corneal neovascularization compared with mice treated with mrIL-12. These results indicate that mrIL-12vp inhibits angiogenesis through IL-12-dependent and IL-12-independent mechanisms, and its augmented antiangiogenic activity may be due to suppression of endothelial cell signaling pathways by the RGD-4C portion of the fusion protein. Mice injected with NXS2 neuroblastoma cells and treated with mrIL-12vp showed significant suppression of tumor growth compared with mice treated with mrIL-12 (P = 0.03). Mice did not show signs of IL-12 toxicity when treated with mrIL-12vp, although hepatic necrosis was present in mrIL-12-treated mice. Localization of IL-12 to neovasculature significantly enhances the antiangiogenic effect, augments antitumor activity, and decreases toxicity of IL-12, offering a promising strategy for expanding development of IL-12 for treatment of cancer patients. 相似文献
130.