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排序方式: 共有2481条查询结果,搜索用时 187 毫秒
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Jasmin Kuhn Philipp M. Klein Nader Al Danaf Joel Z. Nordin Sren Reinhard Dominik M. Loy Miriam Hhn Samir El Andaloussi Don C. Lamb Ernst Wagner Yoshitsugu Aoki Taavi Lehto Ulrich Lchelt 《Advanced functional materials》2019,29(48)
Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile. 相似文献
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Based on computer simulations, Kauffman (Physica D, 10, 145-156, 1984) made several generalizations about a random Boolean cellular automaton which he invented as a model of cellular metabolism. Here we give the first rigorous proofs of two of Kauffman's generalizations: a large fraction of vertices stabilize quickly, consequently the length of cycles in the automaton's behavior is small compared to that of a random mapping with the same number of states; and reversal of the states of a large fraction of the vertices does not affect the cycle to which the automaton moves. 相似文献
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Vijaya Gracias Alan F. Gasiecki Joel D. Moore Irini Akritopoulou-Zanze Stevan W. Djuric 《Tetrahedron letters》2006,47(50):8977-8980
A general method for the preparation of diaza-spirocycles is reported. This method used an olefin metathesis in order to construct the desired spirocyclic framework. Beginning with commercially available protected amino ketones, this strategy ultimately produced pharmacologically relevant diaza-scaffolds in an efficient and high-yielding process. 相似文献
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Chadwin D. Young Gennadi Bersuker Yuegang Zhao Jeff J. Peterson Joel Barnett George A. Brown Jang H. Sim Rino Choi Byoung Hun Lee Peter Zeitzoff 《Microelectronics Reliability》2005,45(5-6):806
Effects of constant voltage stress (CVS) on gate stacks consisting of an ALD HfO2 dielectric with various interfacial layers were studied with time dependent sensing measurements: DC I–V, pulse I–V, and charge pumping (CP) at different frequencies. The process of injected electron trapping/de-trapping on pre-existing defects in the bulk of the high-κ film was found to constitute the major contribution to the time dependence of the threshold voltage (Vt) shift during stress. The trap generation observed with the low frequency CP measurements is suggested to occur within the interfacial oxide layer or the interfacial layer/high-κ interface, with only a minor effect on Vt. 相似文献
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Joel Spencer 《Random Structures and Algorithms》1995,7(2):167-172
It is shown that under certain side conditions the natural random greedy algorithm almost always provides an asymptotically optimal packing of disjoint hyperedges from a hypergraph H. 相似文献
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