排序方式: 共有125条查询结果,搜索用时 78 毫秒
121.
122.
Colton M. Miller Aaron J. Donner Emma E. Blank Andrew W. Egger Brianna M. Kellar Michael E. ?stergaard Punit P. Seth Edward N. Harris 《Nucleic acids research》2016,44(6):2782-2794
Phosphorothioate (PS)-modified antisense oligonucleotides (ASOs) have been extensively investigated over the past three decades as pharmacological and therapeutic agents. One second generation ASO, Kynamro™, was recently approved by the FDA for the treatment of homozygous familial hypercholesterolemia and over 35 second generation PS ASOs are at various stages of clinical development. In this report, we show that the Stabilin class of scavenger receptors, which were not previously thought to bind DNA, do bind and internalize PS ASOs. With the use of primary cells from mouse and rat livers and recombinant cell lines each expressing Stabilin-1 and each isoform of Stabilin-2 (315-HARE and 190-HARE), we have determined that PS ASOs bind with high affinity and these receptors are responsible for bulk, clathrin-mediated endocytosis within the cell. Binding is primarily dependent on salt-bridge formation and correct folding of the intact protein receptor. Increased internalization rates also enhanced ASO potency for reducing expression of the non-coding RNA Malat-1, in Stabilin-expressing cell lines. A more thorough understanding of mechanisms by which ASOs are internalized in cells and their intracellular trafficking pathways will aid in the design of next generation antisense agents with improved therapeutic properties. 相似文献
123.
124.
Brianna McDowell Pamela Burns Christopher A. Lepczyk 《Journal of applied animal welfare science : JAAWS》2013,16(4):321-339
One of the major goals of an animal welfare organization is to reduce the number of homeless, nonhuman animals in a community. In Hawaii, the Hawaiian Humane Society has provided numerous animal welfare services to work toward this goal, such as offering sterilizations and microchipping at reduced rates and facilitating animal adoptions and education. In addition, the Leash Law and the Cat Identification Program have increased animal welfare through increasing the responsibilities of companion animal caregivers (owners). The goal of this research was to assess if temporal changes in animal sheltering have occurred in Hawaii. The study assessed this by analyzing historical data on dogs (Canis familiaris) and cats (Felis catus) admitted, returned to owner, sterilized, euthanized, and adopted from the Humane Societies of Oahu, Hawaii, from 1993 to 2008. The study also analyzed dog and cat admittance and Honolulu population growth from 1975 to 2008. Sterilizations and pets returned to owners have increased significantly, whereas admittance and euthanasia rates have decreased significantly. Thus, although these data cannot conclusively state that there are fewer homeless animals in Hawaii, the results provide positive indicators of reducing homeless pets, especially when coupled with an increase in both the human population of Honolulu County and dog ownership. 相似文献
125.
Keith R. Hornberger Xin Chen Andrew P. Crew Andrew Kleinberg Lifu Ma Mark J. Mulvihill Jing Wang Victoria L. Wilde Mark Albertella Mark Bittner Andrew Cooke Salam Kadhim Jennifer Kahler Paul Maresca Earl May Peter Meyn Darlene Romashko Brianna Tokar Roy Turton 《Bioorganic & medicinal chemistry letters》2013,23(16):4511-4516
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer. 相似文献