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71.
72.
M R Stillings S Freeman P L Myers M J Readhead A P Welbourn M J Rance D C Atkinson 《Journal of medicinal chemistry》1985,28(2):225-233
During an investigation of the antiinflammatory properties of a number of tetracyclic derivatives of 6,8-dichlorodibenz[b,f]oxepin-10(11H)-one, the ring-expanded 1,3-dichloro-5H-dibenz[b,g]-1,4-oxazocine (9) was prepared and found to be considerable pharmacological interest. It was subsequently found that the corresponding ring-opened amino acid 66, a close analogue of the antiinflammatory agent fenclofenac, also possessed significant antiinflammatory activity, superior both to the dibenzoxazocine and to fenclofenac. These findings prompted extensive synthetic programs in both areas, and a number of derivatives in the amino acid series showed potencies considerably in excess of the standard compound. These phenylacetic acids, however, were significantly more ulcerogenic than fenclofenac whereas the corresponding dibenzoxazocines showed few signs of ulcerogenicity at doses up to 1 g/kg. 相似文献
73.
Thymocyte positive and negative selection are dependent on avidity-driven TCR-mediated recognition events in the thymus. High-avidity recognition events result in negative selection, while low-avidity recognition events result in positive selection. However, it has not been established how thymocytes maturation stages affect their responses to TCR signals of different avidities. We gained insight into this question when we reduced thymocyte selection to an in vitro system, in which full maturation of developmentally synchronized immature double-positive thymocytes was induced on a cloned line of thymic epithelial cells. Our analysis of the kinetics of thymocyte development supports a multi-phasic model of thymic selection. In it, thymocyte maturation stages as well as interaction avidity control the outcome TCR stimulation. Positive selection is initiated during a primary recognition event that proceeds independently of the TCR avidity. During a secondary recognition event the final fate of thymocyte, full maturation versus negative selection, is determined by TCR avidity. 相似文献
74.
目的研究神经干细胞(NSCs)移植对大鼠脊髓损伤(SCI)后红核神经元的作用。方法5-溴脱氧尿嘧啶核苷(BrdU)法标记处于对数生长期的NSCs,采用电控脊髓损伤打击装置制作大鼠脊髓损伤模型。实验分为3组:NSCs组、SCI组和假手术组(Sham组)。SCI后3 d进行NSCs移植,用免疫组化法观察移植细胞的存活及迁移情况,用辣根过氧化物酶(HRP)逆行示踪技术标记红核神经元,并用四甲基联苯胺(TMB)呈色反应显示红核脊髓束神经元的存活情况,用行为学(BBB)评分法观察大鼠瘫痪肢体的恢复情况。结果在损伤脊髓区域可检测到BrdU标记的阳性NSCs,中脑HRP标记红核神经元数目明显多于SCI组(P<0.01),BBB评分亦明显高于SCI组(P<0.01)。结论体外培养的胚胎大鼠NSCs在移植到脊髓损伤区域后可存活和迁移,对SCI后中脑红核神经元具有保护作用,从而促进了大鼠肢体功能的恢复。 相似文献
75.
RJ Mann NE Nasr JK Sinfield E Paci D Donnelly 《British journal of pharmacology》2010,160(8):1973-1984
BACKGROUND AND PURPOSE
Exendin-4 (exenatide, Ex4) is a high-affinity peptide agonist at the glucagon-like peptide-1 receptor (GLP-1R), which has been approved as a treatment for type 2 diabetes. Part of the drug/hormone binding site was described in the crystal structures of both GLP-1 and Ex4 bound to the isolated N-terminal domain (NTD) of GLP-1R. However, these structures do not account for the large difference in affinity between GLP-1 and Ex4 at this isolated domain, or for the published role of the C-terminal extension of Ex4. Our aim was to clarify the pharmacology of GLP-1R in the context of these new structural data.EXPERIMENTAL APPROACH
The affinities of GLP-1, Ex4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Molecular dynamics coupled with in silico mutagenesis were used to model and interpret the data.KEY RESULTS
The membrane-tethered NTD of hGLP-1R displayed similar affinity for GLP-1 and Ex4 in sharp contrast to previous studies using the soluble isolated domain. The selectivity at rGLP-1R for Ex4(9–39) over Ex4(9–30) was due to Ser-32 in the ligand. While this selectivity was not observed at hGLP-1R, it was regained when Glu-68 of hGLP-1R was mutated to Asp.CONCLUSIONS AND IMPLICATIONS
GLP-1 and Ex4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of Ex4 and Asp-68 of rGLP-1R, which is not formed with Glu-68 of hGLP-1R, is responsible for the improved affinity of Ex4 at the rat receptor. 相似文献76.
AIM: The study evaluated, in active elderly women, the accuracy and bias of anthropometry and bioelectrical impedance analysis (BIA) for lower-limb and whole-body tissue composition measures using dual-energy X-ray absorptiometry (DXA) as the criterion method. METHODS: Nineteen individuals (66.1 +/- 4.2 years) participated in the study. Whole-body fat mass (FM) and fat-free mass (FFM) were measured by anthropometry, BIA and DXA. Lower-limb volume (LLV) and lower-limb FFM (LLFFM) were assessed by anthropometry and DXA. RESULTS: LLV and LLFFM were significantly overestimated by anthropometry vs. DXA (p < 0.05 and p < 0.001, respectively) but significant relationships were observed [coefficient of determination (R(2)) > 0.25, p < 0.05]. No significant difference was observed between FM(A) (where (A) stands for anthropometry) vs. FM(DXA) and FFM(A) vs. FFM(DXA) and significant relationships were observed [R(2) = 0.93, p < 0.001, coefficient of variation (CV) = 7.3%; and R(2) = 0.85, p < 0.001, CV = 4.4%, respectively]. No significant difference was observed between FM(BIA) and FM(DXA) and a significant relationship was observed (R(2) = 0.80, p < 0.001, CV = 11.6%). FFM was significantly underestimated by BIA vs. DXA (p < 0.01). CONCLUSIONS: In active elderly women, (i) compared with DXA, anthropometry overestimates LLV and LLFFM; (ii) anthropometry can be an accurate method for assessing whole-body composition; and (iii) despite a non-significant bias for the FM measurement, the BIA tends to overestimate FM and underestimate FFM. 相似文献
77.
78.
Rance G Kearns LS Tan J Gravina A Rosenfeld L Henley L Carew P Graydon K O'Hare F Mackey DA 《Journal of neurology》2012,259(3):542-550
The aims of this study are to investigate whether auditory dysfunction is part of the spectrum of neurological abnormalities
associated with Leber’s hereditary optic neuropathy (LHON) and to determine the perceptual consequences of auditory neuropathy
(AN) in affected listeners. Forty-eight subjects confirmed by genetic testing as having one of four mitochondrial mutations
associated with LHON (mt11778, mtDNA14484, mtDNA14482 and mtDNA3460) participated. Thirty-two of these had lost vision, and
16 were asymptomatic at the point of data collection. While the majority of individuals showed normal sound detection, >25%
(of both symptomatic and asymptomatic participants) showed electrophysiological evidence of AN with either absent or severely
delayed auditory brainstem potentials. Abnormalities were observed for each of the mutations, but subjects with the mtDNA11778
type were the most affected. Auditory perception was also abnormal in both symptomatic and asymptomatic subjects, with >20%
of cases showing impaired detection of auditory temporal (timing) cues and >30% showing abnormal speech perception both in
quiet and in the presence of background noise. The findings of this study indicate that a relatively high proportion of individuals
with the LHON genetic profile may suffer functional hearing difficulties due to neural abnormality in the central auditory
pathways. 相似文献
79.
Campbell PJ Pleasance ED Stephens PJ Dicks E Rance R Goodhead I Follows GA Green AR Futreal PA Stratton MR 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(35):13081-13086
During the clonal expansion of cancer from an ancestral cell with an initiating oncogenic mutation to symptomatic neoplasm, the occurrence of somatic mutations (both driver and passenger) can be used to track the on-going evolution of the neoplasm. All subclones within a cancer are phylogenetically related, with the prevalence of each subclone determined by its evolutionary fitness and the timing of its origin relative to other subclones. Recently developed massively parallel sequencing platforms promise the ability to detect rare subclones of genetic variants without a priori knowledge of the mutations involved. We used ultra-deep pyrosequencing to investigate intraclonal diversification at the Ig heavy chain locus in 22 patients with B-cell chronic lymphocytic leukemia. Analysis of a non-polymorphic control locus revealed artifactual insertions and deletions resulting from sequencing errors and base substitutions caused by polymerase misincorporation during PCR amplification. We developed an algorithm to differentiate genuine haplotypes of somatic hypermutations from such artifacts. This proved capable of detecting multiple rare subclones with frequencies as low as 1 in 5000 copies and allowed the characterization of phylogenetic interrelationships among subclones within each patient. This study demonstrates the potential for ultra-deep resequencing to recapitulate the dynamics of clonal evolution in cancer cell populations. 相似文献
80.
n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood 总被引:2,自引:0,他引:2
Whalley LJ Deary IJ Starr JM Wahle KW Rance KA Bourne VJ Fox HC 《The American journal of clinical nutrition》2008,87(2):449-454
BACKGROUND: Evidence for an inverse relation between dietary intake of n-3 polyunsaturated fatty acids (PUFAs) and age-related cognitive decline is inconsistent. This inconsistency may arise because the relation is present only in the absence of the apolipoprotein E epsilon4 (APOE epsilon4) allele. OBJECTIVE: We aimed to determine the contribution of erythrocyte n-3 PUFA content to cognitive aging in the presence or absence of the APOE epsilon4 allele. DESIGN: We followed up 120 volunteers, born in 1936, at approximate ages of 64, 66, and 68 y. Their intelligence quotient at 11 y old was available. At first follow-up, we determined APOE genotype and measured the PUFA composition of erythrocyte membranes. Six cognitive tests were administered at all follow-ups. We related cognitive performance at approximately 64 y old and cognitive changes from approximately 64 to approximately 68 y old to erythrocyte n-3 PUFA composition on recruitment and to APOE epsilon4 allele status. RESULTS: Total n-3 PUFA and docosohexaenoic acid concentrations were associated with benefits for cognition at approximately 64 y old and from approximately 64 to approximately 68 y old. After adjustment for sex, APOE epsilon4 status, and intelligence quotient at 11 y old, the effects associated with total n-3 PUFA remained significant. Cognitive benefits were associated with higher erythrocyte n-3 PUFA content but were significant only in the absence of the APOE epsilon4 allele. CONCLUSIONS: These data are evidence of a gene x environment interaction for cognitive aging. They are relevant to the analysis of trials of n-3 PUFA supplements in cognitive aging and dementia prevention, and they support heterogeneity in cognitive aging and, possibly, in Alzheimer disease. 相似文献