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11.
David C. Pryde Martin Corless David R. Fenwick Helen J. Mason Blanda C. Stammen Peter T. Stephenson David Ellis David Bachelor David Gordon Christopher G. Barber Anthony Wood Donald S. Middleton David C. Blakemore Gemma C. Parsons Rachel Eastwood Michelle Y. Platts Keith Statham Kerry A. Paradowski Catherine Burt Wolfgang Klute 《Bioorganic & medicinal chemistry letters》2009,19(4):1084-1088
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential. 相似文献
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The increase in systemic blood pressure after an obstructive apnea is due, in part, to sympathetically mediated vasoconstriction. We questioned whether upper airway (UA) receptors could contribute reflexly to this vasoconstriction. Four unanesthetized dogs were studied during wakefulness and non-rapid-eye-movement (NREM) sleep. The dogs breathed via a fenestrated tracheostomy tube sealed around the tracheal stoma. The snout was sealed with an airtight mask, thereby isolating the UA when the fenestration was closed and exposing the UA to negative inspiratory intrathoracic pressure when it was open. The blood pressure response to three UA perturbations was studied: 1) square-wave negative pressures sufficient to cause UA collapse with the fenestration closed during a mechanical hyperventilation-induced central apnea; 2) tracheal occlusion with the fenestration open vs. closed; and 3) high-frequency pressure oscillations (HFPO) with the fenestration closed. During NREM sleep, 1) blood pressure response to tracheal occlusion was similar with the fenestration open or closed; 2) collapsing the UA with negative pressures failed to alter blood pressure during a central apnea; and 3) application of HFPO to the UA during eupnea and resistive-loaded breaths increased heart rate and blood pressure. However, these changes were likely to be secondary to the effects of HFPO-induced reflex changes on prolonging expiratory time. These findings suggest that activation of UA pressure-sensitive receptors does not contribute directly to the pressor response associated with sleep-disordered breathing events. 相似文献
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Mei-Shang Ho MD. MPH Yi-Chien Mau Chih-Feng Lu Shiang-Fen Huang Li-Ching Hsu Sheue-Rong Lin Hsu-Mei Hsu 《Journal of biomedical science》1998,5(5):355-362
Hepatitis B virus (HBV) variants that possessed missense mutation within the neutralization epitope of the major S antigen as defined by amino acid residues (aa#) 124–147, termed the a determinant variants, were identified through a population-based serosurvey of 2,305 children of the vaccinated birth cohorts born after 1986. Data on the 678 nucleotides encoding the S antigen of HBV were available for 75 HBV strains that were collected from 63 vaccinated children and 12 unvaccinated or incompletely vaccinated children, and 21 HBV strains from 25 unvaccinated adults. Among the diverse patterns of one to three amino acid substitutions within the a determinant, 145-Arg occurred most frequently (5/14); other variants were: 126-Ala, 127-Thr, 126-Ser/131-Asn/133-Thr, 129-His, 129-Arg, 123-Asn/131-Ile, 133-Leu, 141-Glu, and 141-Arg/144-Ala. Only one of these variants occurred in the 16 hepatitis B surface antigen (HBsAg)-carrier children born to HBsAg-negative mothers, whereas 12 of these variants occurred in the 20 (50%) children born to HBsAg-positive mothers. In addition, early administration of HBV vaccine within the noenatal period increased the likelihood of the emergence of these variants to 64.7% (11/17). Five of the 21 (23.8%) unvaccinated HBsAg-carrier adults harbored the a determinant variants possessing mutations within aa# 125–136, i.e. the putative first loop formed by the cysteine disulfide bonds. Vaccinated children were likely to harbor HBV variants possessing mutations involving altered charge of side chains and/or its hydrophobicity of amino acid residues within the putative second loop between aa#140 and 146. Our data suggest that emergence of these HBV S gene mutants in the phase of HBV vaccination program would be most common among populations in whom perinatal/vertical transmission of HBV is most common, i.e. southeast Asian and the Taiwanese. 相似文献
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This review covers discoveries made over the past 30–35 years that were important to our understanding of the synthetic pathway required for initiation of the antennae or branches on complex N-glycans and O-glycans. The review deals primarily with the author's contributions but the relevant work of other laboratories is also discussed. The focus of the review is almost entirely on the glycosyltransferases involved in the process. The following topics are discussed. (1) The localization of the synthesis of complex N-glycan antennae to the Golgi apparatus. (2) The evolutionary boundary at the stage in N-glycan processing where there is a change from oligomannose to complex N-glycans; this switch correlates with the appearance of multicellular organisms. (3) The discovery of the three enzymes which play a key role in this switch, N-acetylglucosaminyltransferases I and II and mannosidase II. (4) The yellow brick road which leads from oligomannose to highly branched complex N-glycans with emphasis on the enzymes involved in the process and the factors which control the routes of synthesis. (5) A short discussion of the characteristics of the enzymes involved and of the genes that encode them. (6) The role of complex N-glycans in mammalian and Caenorhabditis elegans development. (7) The crystal structure of N-acetylglucosaminyltransferase I. (8) The discovery of the enzymes which synthesize O-glycan cores 1, 2, 3 and 4 and their elongation. 相似文献
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Bean plants grown in a controlled temperature glasshouse athigh temperatures (33/28, 30/25, or 27/22 °C) during theperiod of seed development and maturation matured early andproduced small seeds. The seeds were of lower vigour than thosegrown at 21/16 or 18/13 °C. The detrimental effect of highmaturation temperatures was observed even on plants bearingwell-developed seeds (yellow, fleshy-pod stage). Seeds maturedat high temperatures were also more susceptible to deteriorationwith delay in harvest, and to mechanical damage. Heavy wateringof plants with seed ready to harvest caused a reduction in seedvigour. For optimum quality bean seed, it appears essentialthat the seed develops and matures at cool temperatures, ina dry environment. 相似文献
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Cheng Qian MD Danqi Chang MD Hang Li MD Yanggan Wang 《Journal of cellular biochemistry》2019,120(5):7771-7777
Heart failure (HF) remains a common complication after acute ST-segment elevation myocardial infarction (STEMI). Here, we aim to identify critical genes related to the developed HF in patients with STEMI using bioinformatics analysis. The microarray data of GSE59867, including peripheral blood samples from nine patients with post-infarct HF and eight patients without post-infarct HF, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HF and non-HF groups were screened by LIMMA package. Functional enrichment analyses of DEGs were conducted, followed by construction of a protein-protein interaction (PPI) network. The dynamic messenger RNA (mRNA) level of the hub genes during the follow-up was analyzed to further elucidate their role in HF development. A total of 58 upregulated and 75 downregulated DEGs were screen out. They were mainly enriched in biological processes about inflammatory response, extracellular matrix organization, response to cAMP, immune response, and positive regulation of cytosolic calcium ion concentration. Pathway analysis revealed that the DEGs were also involved in hematopoietic cell lineage, pathways in cancer, and extracellular matrix-receptor interaction. In the PPI network consisting of 58 nodes and 72 interactions, CXCL8 (degree = 15), THBS1 (degree = 8), FOS (degree = 7), and ITGA2B (degree = 6) were identified as the hub genes. In the comparison of patients with and without post-infarct HF, the mRNA level of these hub genes were all higher within 30 days but reached similar at 6 months after STEMI. In conclusion, CXCL8, THBS1, FOS, and ITGA2B may play important roles in the development of HF after acute STEMI. 相似文献
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Gabriella Fóris MD PhD George A. Medgyesi Mátyás Hauck 《Molecular and cellular biochemistry》1986,69(2):127-137
Summary Met-enkephalin (ME) exerts a bimodal effect on functional activities of rat peritoneal macrophages (PM); in a range of low concentration (10-9-10-7 M) antibody dependent cellular cytotoxicity (ADCC)was markedly stimulated with a simultaneous decrease of Fc receptor (FcR) mediated phagocytosis while the opposite was observed at 10-6-10-5 M concentrations.Studying the possible underlying mechanism(s) the followings were recorded: (1) ME in all applied concentrations induced an early Na+ influx which was followed by a Ca2+ efflux in the range of low concentrations. In the range of high concentrations Na+ influx was accompanied by a Ca2+ influx. (2) ME at 10-8 M concentration induced a rise in cGMP level with a plateau in the 60–120th min of incubation. This effect was prevented by 10-5 M of naloxone. At 10-6 M concentration a transient rise of cAMP level was recorded which was not affected by naloxone. (3) Verapamil in 10-6 M abolished both the Ca2+ influx and the rise in cAMP level induced by 10-6-10-5 M ME but not the rise in cGMP level induced by lower ME concentrations. (4) cAMP elevation by high ME concentrations was abolished by enkephalinase inhibitory puromycin. (5) PM-enkephalinase as assessed by the cleavage of fluorogenic substrate L-alanine beta naphthylamide (ABNA), was inhibited by 10-6-10-5 M of ME. This inhibition was abolished by verapamil, but not affected by naloxone. In the range of low concentrations ME appears to act on specific delta opioid receptors and its action is positively coupled to guanylate cyclase. In relatively higher concentrations ME-action is not mediated by specific delta opioid receptors and it appears to involve Ca2+ influx, adenylate cyclase activation as well as the processing of hormone by PM-enkephalinase. 相似文献
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