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排序方式: 共有718条查询结果,搜索用时 15 毫秒
81.
Robinson TP Hubbard RB Ehlers TJ Arbiser JL Goldsmith DJ Bowen JP 《Bioorganic & medicinal chemistry》2005,13(12):4007-4013
Curcumin, a natural product isolated from the spice turmeric, has been shown to exhibit a wide range of pharmacological activities including certain anti-cancer properties. It has been specifically shown to be an effective inhibitor of angiogenesis both in vitro and in vivo. Using curcumin as a lead compound for anti-angiogenic analog design, a series of structurally related compounds utilizing a substituted chalcone backbone have been synthesized and tested via an established SVR cell proliferation assay. The results have yielded a wide range of compounds that equal or exceed curcumin's ability to inhibit endothelial cell growth in vitro. Due to both their commercial availability and their fairly straightforward synthetic preparation, these low molecular weight compounds are attractive leads for developing future angiogenic inhibitors. 相似文献
82.
Kirk D. Robarge Shirley A. Brunton Georgette M. Castanedo Yong Cui Michael S. Dina Richard Goldsmith Stephen E. Gould Oivin Guichert Janet L. Gunzner Jason Halladay Wei Jia Cyrus Khojasteh Michael F.T. Koehler Karen Kotkow Hank La Rebecca L. LaLonde Kevin Lau Leslie Lee Derek Marshall James C. Marsters Minli Xie 《Bioorganic & medicinal chemistry letters》2009,19(19):5576-5581
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. 相似文献
83.
K. L. Buchanan M. R. Evans M. L. Roberts L. Rowe A. R. Goldsmith 《Journal of avian biology》2010,41(4):445-451
Badges of status function in many birds within a social context to establish dominance hierarchies and reduce antagonistic encounters. In order to maintain the honesty of the signalling system, such badges must be costly to produce or to maintain. The chest bib of the house sparrow functions as a badge of status and changes in size are known to be controlled by testosterone levels. We sought to test the relative importance of testosterone as opposed to bib size in determining dominance within a group of male house sparrows. We did this by manipulating testosterone levels independently during both breeding and post‐breeding seasons in experimental birds and examining the effect of testosterone titre, as well as corticosterone titre relative to bib size on dominance levels. Dominance hierarchies within the groups were tested during both the breeding and post‐breeding phases. We compared the results of these tests with dominance among intact (unmanipulated) birds. Results suggested that the breeding season dominance levels were largely determined by testosterone levels as well as bib size, whereas the post‐breeding dominance levels were determined by post‐breeding testosterone titre and previous breeding season dominance level. Within unmanipulated birds, basal corticosterone levels were significantly, negatively correlated with dominance level, but only during the breeding season. The influence of breeding season dominance on post‐breeding dominance suggests social history is important in determining dominance interactions as well as current testosterone levels and bib size. 相似文献
84.
Khare SD Kipnis Y Greisen P Takeuchi R Ashani Y Goldsmith M Song Y Gallaher JL Silman I Leader H Sussman JL Stoddard BL Tawfik DS Baker D 《Nature chemical biology》2012,8(3):294-300
The ability to redesign enzymes to catalyze noncognate chemical transformations would have wide-ranging applications. We developed a computational method for repurposing the reactivity of metalloenzyme active site functional groups to catalyze new reactions. Using this method, we engineered a zinc-containing mouse adenosine deaminase to catalyze the hydrolysis of a model organophosphate with a catalytic efficiency (k(cat)/K(m)) of ~10(4) M(-1) s(-1) after directed evolution. In the high-resolution crystal structure of the enzyme, all but one of the designed residues adopt the designed conformation. The designed enzyme efficiently catalyzes the hydrolysis of the R(P) isomer of a coumarinyl analog of the nerve agent cyclosarin, and it shows marked substrate selectivity for coumarinyl leaving groups. Computational redesign of native enzyme active sites complements directed evolution methods and offers a general approach for exploring their untapped catalytic potential for new reactivities. 相似文献
85.
86.
Dissociation of the CD4 downregulation and viral infectivity enhancement functions of human immunodeficiency virus type 1 Nef. 总被引:2,自引:14,他引:2 下载免费PDF全文
M A Goldsmith M T Warmerdam R E Atchison M D Miller W C Greene 《Journal of virology》1995,69(7):4112-4121
Recent evidence indicates that the nef gene of human immunodeficiency virus type 1 augments rather than inhibits viral replication in both cell culture and in vivo models. In addition, nef alters various normal cellular processes, including the display of CD4 on the cell surface. However, it remains unknown whether the enhancement of infectivity and the downregulation of CD4 represent linked or independent biologic properties of this single protein. In the present studies, mutational analyses were performed to define structure-function relationships within the Nef protein that mediate these effects. To assess the functional consequences of these mutations, sensitive and reliable assays were developed to quantitate the viral infectivity enhancement and CD4 downregulation functions of Nef. The results indicate that membrane-targeting sequences at the N terminus of Nef are important for both functions of Nef, while certain other conserved regions are dispensable for both functions. A conserved proline-X-X repeat segment in the central core of the protein, which is reminiscent of an SH3-binding domain, is critical for the enhancement of infectivity function but is dispensable for CD4 downregulation. However, the downregulation of CD4 by Nef appears to involve a two-step process requiring the initial dissociation of p56lck from CD4 to permit engagement of the endocytic apparatus by CD4. Together, these findings demonstrate that the infectivity enhancement and CD4 downregulation activities of human immunodeficiency virus type 1 Nef can be dissociated. Thus, these processes may be independent of one another in the viral replication cycle. 相似文献
87.
88.
Ori Eytan Fanny Morice-Picard Ofer Sarig Khaled Ezzedine Ofer Isakov Qiaoli Li Akemi Ishida-Yamamoto Noam Shomron Tomer Goldsmith Dana Fuchs-Telem Noam Adir Jouni Uitto Seth?J. Orlow Alain Taieb Eli Sprecher 《American journal of human genetics》2013,93(4):752-757
The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases. 相似文献
89.
John E. Moore Yasunori Maeda Jiru Xu B. Cherie Millar Peter H. Herold V. M. J. Browne-Lauwers Colin E. Goldsmith Anne Loughrey Paul J. Rooney J. Stuart Elborn Motoo Matsuda 《World journal of microbiology & biotechnology》2008,24(7):1227-1232
To employ 16S rDNA PCR and automated sequencing techniques to identify a collection of bacterial veterinary pathogens from
avian, equine, canine and ovine sources, that have proven difficult to identify, employing conventional cultural techniques.
Universal or “broad-range” eubacterial PCR was performed on a collection of 46 difficult-to-identify bacterial isolates originating
from clinical veterinary specimens. 16S rDNA PCR was performed using two sets of universal primers to successfully generate
a composite amplicon of 1,068 bp, which was sequenced to obtain each isolate’s identity. Sequence analysis was able to identify
all isolates examined with relative ease. Where the use of molecular identification methods is justified, such as in outbreak
control or bioterrorism in animal health, employment of partial 16S rDNA PCR and sequencing employing universal or “broad-range”
16S rDNA, provides a valuable and reliable method of identification of such pathogens. 相似文献
90.