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31.
Ami E Nakahara K Sato A Nguyen JT Hidaka K Hamada Y Nakatani S Kimura T Hayashi Y Kiso Y 《Bioorganic & medicinal chemistry letters》2007,17(15):4213-4217
We designed several HIV protease inhibitors with various d-cysteine derivatives as P(2)/P(3) moieties based on the structure of clinical drug candidate, KNI-764. Herein, we report their synthesis, HIV protease inhibitory activity, HIV IIIB cell inhibitory activity, cellular toxicity, and inhibitory activity against drug-resistant HIV strains. KNI-1931 showed distinct selectivity against HIV proteases and high potency against drug-resistant strains, surpassing those of Ritonavir and Nelfinavir. 相似文献
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Background
The lymphatic system complements the blood circulatory system in absorption and transport of nutrients, and in the maintenance of homeostasis. Angiopoietins 1 and 2 (Ang1 and Ang2) are regulators of both angiogenesis and lymphangiogenesis through the Tek/Tie-2 receptor tyrosine kinase. The response of endothelial cells to stimulation with either Ang1 or Ang2 is thought to be dependent upon the origin of the endothelial cells. In this study, we examined the effects of the angiopoietins on lymphatic, venous and arterial primary endothelial cells (bmLEC, bmVEC and bmAEC, respectively), which were isolated and cultured from bovine mesenteric vessels.Results
BmLEC, bmVEC and bmAEC cell populations all express Tie-2 and were shown to express the appropriate cellular markers Prox-1, VEGFR3, and Neuropilin-1 that define the particular origin of each preparation. We showed that while bmLECs responded slightly more readily to angiopoietin-2 (Ang2) stimulation, bmVECs and bmAECs were more sensitive to Ang1 stimulation. Furthermore, exposure of bmLECs to Ang2 induced marginally higher levels of proliferation and survival than did exposure to Ang1. However, exposure to Ang1 resulted in higher levels of migration in bmLECs than did to Ang2.Conclusion
Our results suggest that although both Ang1 and Ang2 can activate the Tie-2 receptor in bmLECs, Ang1 and Ang2 may have distinct roles in mesenteric lymphatic endothelial cells. 相似文献34.
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36.
Moore V Kanu A Byron O Campbell G Danson MJ Hough DW Crennell SJ 《Extremophiles : life under extreme conditions》2011,15(3):327-336
Using citrate synthase from the hyperthermophile Pyrococcus furiosus (PfCS) as our test molecule, we show through guanidine hydrochloride-induced unfolding that the dimer separates into folded,
but inactive, monomers before individual subunit unfolding takes place. Given that forces across the dimer interface are vital
for thermostability, a robust computational method was derived that uses the University of Houston Brownian Dynamics (UHBD)
program to calculate both the hydrophobic and electrostatic contribution to the dimerisation energy at 100°C. The results
from computational and experimental determination of the lowered stability of interface mutants were correlated, being both
of the same order of magnitude and placing the mutant proteins in the same order of stability. This computational method,
optimised for hyperthermophilic molecules and tested in the laboratory, after further testing on other examples, could be
of widespread use in the prediction of thermostabilising mutations in other oligomeric proteins for which dissociation is
the first step in unfolding. 相似文献
37.
Leonard H Glasson E Nassar N Whitehouse A Bebbington A Bourke J Jacoby P Dixon G Malacova E Bower C Stanley F 《PloS one》2011,6(3):e17875
Background
Research findings investigating the sociodemographics of autism spectrum disorder (ASD) have been inconsistent and rarely considered the presence of intellectual disability (ID).Methods
We used population data on Western Australian singletons born from 1984 to 1999 (n = 398,353) to examine the sociodemographic characteristics of children diagnosed with ASD with or without ID, or ID without ASD compared with non-affected children.Results
The profiles for the four categories examined, mild-moderate ID, severe ID, ASD without ID and ASD with ID varied considerably and we often identified a gradient effect where the risk factors for mild-moderate ID and ASD without ID were at opposite extremes while those for ASD with ID were intermediary. This was demonstrated clearly with increased odds of ASD without ID amongst older mothers aged 35 years and over (odds ratio (OR) = 1.69 [CI: 1.18, 2.43]), first born infants (OR = 2.78; [CI: 1.67, 4.54]), male infants (OR = 6.57 [CI: 4.87, 8.87]) and increasing socioeconomic advantage. In contrast, mild-moderate ID was associated with younger mothers aged less than 20 years (OR = 1.88 [CI: 1.57, 2.25]), paternal age greater than 40 years (OR = 1.59 [CI: 1.36, 1.86]), Australian-born and Aboriginal mothers (OR = 1.60 [CI: 1.41, 1.82]), increasing birth order and increasing social disadvantage (OR = 2.56 [CI: 2.27, 2.97]). Mothers of infants residing in regional or remote areas had consistently lower risk of ASD or ID and may be linked to reduced access to services or under-ascertainment rather than a protective effect of location.Conclusions
The different risk profiles observed between groups may be related to aetiological differences or ascertainment factors or both. Untangling these pathways is challenging but an urgent public health priority in view of the supposed autism epidemic. 相似文献38.
39.
Latres E Amini AR Amini AA Griffiths J Martin FJ Wei Y Lin HC Yancopoulos GD Glass DJ 《The Journal of biological chemistry》2005,280(4):2737-2744
40.
Sakuraba Y Sezutsu H Takahasi KR Tsuchihashi K Ichikawa R Fujimoto N Kaneko S Nakai Y Uchiyama M Goda N Motoi R Ikeda A Karashima Y Inoue M Kaneda H Masuya H Minowa O Noguchi H Toyoda A Sakaki Y Wakana S Noda T Shiroishi T Gondo Y 《Biochemical and biophysical research communications》2005,336(2):609-616
The large-scale mouse mutagenesis with ENU has provided forward-genetic resources for functional genomics. The frozen sperm archive of ENU-mutagenized generation-1 (G1) mice could also provide a "mutant mouse library" that allows us to conduct reverse genetics in any particular target genes. We have archived frozen sperm as well as genomic DNA from 9224 G1 mice. By genome-wide screening of 63 target loci covering a sum of 197 Mbp of the mouse genome, a total of 148 ENU-induced mutations have been directly identified. The sites of mutations were primarily identified by temperature gradient capillary electrophoresis method followed by direct sequencing. The molecular characterization revealed that all the identified mutations were point mutations and mostly independent events except a few cases of redundant mutations. The base-substitution spectra in this study were different from those of the phenotype-based mutagenesis. The ENU-based gene-driven mutagenesis in the mouse now becomes feasible and practical. 相似文献