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501.
Polla MO Tottie L Nordén C Linschoten M Müsil D Trumpp-Kallmeyer S Aukrust IR Ringom R Holm KH Neset SM Sandberg M Thurmond J Yu P Hategan G Anderson H 《Bioorganic & medicinal chemistry》2004,12(5):1151-1175
A series of 3-mercapto-propionic acid derivatives that function as reversible inhibitors of carboxypeptidase U have been prepared. We present a successful design strategy using cyclic, low basicity guanidine mimetics resulting in potent, selective and bioavailable inhibitors of carboxypeptidase U (TAFIa). 相似文献
502.
Malberg H Bauernschmitt R Meyerfeldt U Schirdewan A Wessel N 《Indian pacing and electrophysiology journal》2004,4(4):162-175
New methods for the analysis of arrhythmias and their hemodynamic consequences have been applied in risk stratification, in particular to patients after myocardial infarction. This study investigates the suitability of short-term heart rate turbulence (HRT) analysis in comparison to heart rate and blood pressure variability as well as baroreceptor sensitivity analyses to characterise the regulatory differences between patients with dilated cardiomyopathy (DCM) and healthy controls. In this study, 30 minutes data of non-invasive continuous blood pressure and ECGs of 37 DCM patients and 167 controls measured under standard resting conditions were analysed. The results show highly significant differences between DCM patients and controls in heart rate and blood pressure variability as well as in baroreceptor sensitivity parameters. Applying a combined heart rate-blood pressure trigger, ventricular premature beats were detected in 24.3% (9) of the DCM patients and 11.3% (19) of the controls. This fact demonstrates the limited applicability of short-term HRT analyses. However, the HRT parameters showed significant differences in this subgroup with ventricular premature beats (turbulence onset: DCM: 1.80+/-2.72, controls: - 4.34+/-3.10, p<0.001; turbulence slope: DCM: 6.75+/-5.50, controls: 21.30+/-17.72, p=0.021). Considering all (including HRT) parameters in the subgroup with ventricular beats, a discrimination rate between DCM patients and controls of 88.0% was obtained (max. 6 parameters). The corresponding value obtained for the total group was 86.3% (without HRT parameters). Comparable classification rates and high correlations between heart rate turbulence and variability and baroreflex parameters point to a more universal applicability of the latter methods. 相似文献
503.
A three-dimensional structure comparison between the dimeric regulatory serine-binding domain of Escherichia coli D-3-phosphoglycerate dehydrogenase [Schuller, D. J., Grant, G. A., and Banaszak, L. J. (1995) Nat. Struct. Biol. 2, 69-76] and the regulatory domain of E. coli threonine deaminase [Gallagher, D. T., Gilliland, G. L., Xiao, G., Zondlo, J., Fisher, K. E., Chinchilla, D. , and Eisenstein, E. (1998) Structure 6, 465-475] led us to make the hypothesis that threonine deaminase could have two binding sites per monomer. To test this hypothesis about the corresponding plant enzyme, site-directed mutagenesis was carried out on the recombinant Arabidopsis thaliana threonine deaminase. Kinetic and binding experiments demonstrated for the first time that each regulatory domain of the monomers of A. thaliana threonine deaminase possesses two different effector-binding sites constituted in part by Y449 and Y543. Our results demonstrate that Y449 belongs to a high-affinity binding site whose interaction with a first isoleucine induces conformational modifications yielding a conformer displaying a higher activity and with enhanced ability to bind a second isoleucine on a lower-affinity binding site containing Y543. Isoleucine interaction with this latter binding site is responsible for conformational modifications leading to final inhibition of the enzyme. Y449 interacts with both regulators, isoleucine and valine. However, interaction of valine with the high-affinity binding site induces different conformational modifications leading to reversal of isoleucine binding and reversal of inhibition. 相似文献
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According to the view of differentiation-related alterations in the glycosylation pattern of neurones, recent studies have shown development dependent expression patterns of lactoseries carbohydrate epitopes, CD15 and HNK-1, on olfactory receptor neurones in rats and chicks. In order to evaluate a general role for these epitopes during development of vertebrate olfactory receptor neurones, this investigation focuses on the situation in the mouse, bovine and Xenopus olfactory epithelium. In all three species CD15 expression was found on a subpopulation of morphologically mature receptor cells starting at the time of initial synaptogenesis. Whereas for bovine and Xenopus the timetable of HNK-1 expression is similar to that described for the chick, suggesting involvement in pathfinding, in the mouse HNK-1 is found on immature cells when mature CD15 positive receptor cells could already be discerned. By our results a role for CD15 during establishment of synaptic contacts and for HNK-1 during their formation is suggested. 相似文献
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ABSTRACT: BACKGROUND: Recent studies in human have highlighted the importance of the monocyte chemotactic proteins (MCP) in leukocyte trafficking and their effects in inflammatory processes, tumor progression, and HIV-1 infection. In European rabbit (Oryctolagus cuniculus) one of the prime MCP targets, the chemokine receptor CCR5 underwent a unique structural alteration. Until now, no homologue of MCP-2/CCL8a, MCP-3/CCL7 or MCP-4/CCL13 genes have been reported for this species. This is interesting, because at least the first two genes are expressed in most, if not all, mammals studied, and appear to be implicated in a variety of important chemokine ligand-receptor interactions. By assessing the Rabbit Whole Genome Sequence (WGS) data we have searched for orthologs of the mammalian genes of the MCP-Eotaxin cluster. RESULTS: We have localized the orthologs of these chemokine genes in the genome of European rabbit and compared them to those of leporid genera which do (i.e. Oryctolagus and Bunolagus) or do not share the CCR5 alteration with European rabbit (i.e. Lepus and Sylvilagus). Of the Rabbit orthologs of the CCL8, CCL7, and CCL13 genes only the last two were potentially functional, although showing some structural anomalies at the protein level. The ortholog of MCP-2/CCL8 appeared to be pseudogenized by deleterious nucleotide substitutions affecting exon1 and exon2. By analyzing both genomic and cDNA products, these studies were extended to wild specimens of four genera of the Leporidae family: Oryctolagus, Bunolagus, Lepus, and Sylvilagus. It appeared that the anomalies of the MCP-3/CCL7 and MCP-4/CCL13 proteins are shared among the different species of leporids. In contrast, whereas MCP-2/CCL8 was pseudogenized in every studied specimen of the Oryctolagus - Bunolagus lineage, this gene was intact in species of the Lepus - Sylvilagus lineage, and was, at least in Lepus, correctly transcribed. CONCLUSION: The biological function of a gene was often revealed in situations of dysfunction or gene loss. Infections with Myxoma virus (MYXV) tend to be fatal in European rabbit (genus Oryctolagus), while being harmless in Hares (genus Lepus) and benign in Cottontail rabbit (genus Sylvilagus), the natural hosts of the virus. This communication should stimulate research on a possible role of MCP-2/CCL8 in poxvirus related pathogenicity. 相似文献
509.
Gellynck E Andressen KW Lintermans B Haegeman G Levy FO Vanhoenacker P Van Craenenbroeck K 《The FEBS journal》2012,279(11):1994-2003
The 5-hydroxytryptamine (5-HT)(7(a)) receptor is a G-protein-coupled receptor critically involved in human psychiatric and neurological disorders. In the present study, we evaluate the presence and the functional role of N-glycosylation of the human 5-HT(7) receptor. Western blot analysis of HEK293T cells transiently expressing the 5-HT(7(a)) receptor in the presence of tunicamycin gave rise to a band shift, indicating the existence of an N-glycosylated form of the 5-HT(7(a)) receptor. To further investigate this, we mutated the two predicted N-glycosylation sites (N5Q and N66Q) and compared the molecular mass of the immunoreactive bands with those of the wild-type receptor, indicating that both asparagines were N-glycosylated. The mutant receptors had the same binding affinity for [(3) H]5-CT and the same potency and efficacy with regard to 5-HT-induced activation of adenylyl cyclase. However, there was a reduction in maximal ligand binding for the single and double mutants compared to the wild-type receptor. Next, membrane labelling and immunocytochemical studies demonstrated that the N-glycosylation mutants were expressed at the cell surface. We conclude that N-glycosylation is not important for cell surface expression of the 5-HT(7) receptor. 相似文献
510.