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排序方式: 共有223条查询结果,搜索用时 15 毫秒
21.
Jason W. Rausch Meijuan Tian Yuejin Li Lora Angelova Bernard S. Bagaya Kendall C. Krebs Feng Qian Chuanwu Zhu Eric J. Arts Stuart F. J. Le Grice Yong Gao 《PloS one》2015,10(4)
Converting single-stranded viral RNA into double stranded DNA for integration is an essential step in HIV-1 replication. Initial polymerization of minus-strand DNA is primed from a host derived tRNA, whereas subsequent plus-strand synthesis requires viral primers derived from the 3′ and central polypurine tracts (3′ and cPPTs). The 5′ and 3′ termini of these conserved RNA sequence elements are precisely cleaved by RT-associated RNase H to generate specific primers that are used to initiate plus-strand DNA synthesis. In this study, siRNA wad used to produce a replicative HIV-1 variant contained G(-1)A and T(-16)A substitutions within/adjacent to the 3′PPT sequence. Introducing either or both mutations into the 3′PPT region or only the G(-1)A substitution in the cPPT region of NL4-3 produced infectious virus with decreased fitness relative to the wild-type virus. In contrast, introducing the T(-16)A or both mutations into the cPPT rendered the virus(es) incapable of replication, most likely due to the F185L integrase mutation produced by this nucleotide substitution. Finally, the effects of G(-1)A and T(-16)A mutations on cleavage of the 3′PPT were examined using an in vitro RNase H cleavage assay. Substrate containing both mutations was mis-cleaved to a greater extent than either wild-type substrate or substrate containing the T(-16)A mutation alone, which is consistent with the observed effects of the equivalent nucleotide substitutions on the replication fitness of NL4-3 virus. In conclusion, siRNA targeting of the HIV-1 3′PPT region can substantially suppress virus replication, and this selective pressure can be used to generate infectious virus containing mutations within or near the HIV-1 PPT. Moreover, in-depth analysis of the resistance mutations demonstrates that although virus containing a G(-1)A mutation within the 3′PPT is capable of replication, this nucleotide substitution shifts the 3′-terminal cleavage site in the 3′PPT by one nucleotide (nt) and significantly reduces viral fitness. 相似文献
22.
John J.M. Wiener Alvah T. Wickboldt Danielle K. Wiener Alice Lee-Dutra James P. Edwards Lars Karlsson Steven Nguyen Siquan Sun Todd K. Jones Cheryl A. Grice 《Bioorganic & medicinal chemistry letters》2010,20(7):2375-2378
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution. 相似文献
23.
Chringma Sherpa Jason W. Rausch Stuart F.J. Le?Grice Marie-Louise Hammarskjold David Rekosh 《Nucleic acids research》2015,43(9):4676-4686
The HIV Rev protein forms a complex with a 351 nucleotide sequence present in unspliced and incompletely spliced human immunodeficiency virus (HIV) mRNAs, the Rev response element (RRE), to recruit the cellular nuclear export receptor Crm1 and Ran-GTP. This complex facilitates nucleo-cytoplasmic export of these mRNAs. The precise secondary structure of the HIV-1 RRE has been controversial, since studies have reported alternative structures comprising either four or five stem-loops. The published structures differ only in regions that lie outside of the primary Rev binding site. Using in-gel SHAPE, we have now determined that the wt NL4-3 RRE exists as a mixture of both structures. To assess functional differences between these RRE ‘conformers’, we created conformationally locked mutants by site-directed mutagenesis. Using subgenomic reporters, as well as HIV replication assays, we demonstrate that the five stem-loop form of the RRE promotes greater functional Rev/RRE activity compared to the four stem-loop counterpart. 相似文献
24.
McClure KJ Maher M Wu N Chaplan SR Eckert WA Lee DH Wickenden AD Hermann M Allison B Hawryluk N Breitenbucher JG Grice CA 《Bioorganic & medicinal chemistry letters》2011,21(18):5197-5201
The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein. 相似文献
25.
Savall BM Gomez L Chavez F Curtis M Meduna SP Kearney A Dunford P Cowden J Thurmond RL Grice C Edwards JP 《Bioorganic & medicinal chemistry letters》2011,21(21):6577-6581
This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model. 相似文献
26.
Bindewald E Wendeler M Legiewicz M Bona MK Wang Y Pritt MJ Le Grice SF Shapiro BA 《RNA (New York, N.Y.)》2011,17(9):1688-1696
Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) is a facile technique for quantitative analysis of RNA secondary structure. In general, low SHAPE signal values indicate Watson-Crick base-pairing, and high values indicate positions that are single-stranded within the RNA structure. However, the relationship of SHAPE signals to structural properties such as non-Watson-Crick base-pairing or stacking has thus far not been thoroughly investigated. Here, we present results of SHAPE experiments performed on several RNAs with published three-dimensional structures. This strategy allows us to analyze the results in terms of correlations between chemical reactivities and structural properties of the respective nucleotide, such as different types of base-pairing, stacking, and phosphate-backbone interactions. We find that the RNA SHAPE signal is strongly correlated with cis-Watson-Crick/Watson-Crick base-pairing and is to a remarkable degree not dependent on other structural properties with the exception of stacking. We subsequently generated probabilistic models that estimate the likelihood that a residue with a given SHAPE score participates in base-pairing. We show that several models that take SHAPE scores of adjacent residues into account perform better in predicting base-pairing compared with individual SHAPE scores. This underscores the context sensitivity of SHAPE and provides a framework for an improved interpretation of the response of RNA to chemical modification. 相似文献
27.
28.
Nancy P. Y. Chung Sabine K. J. Breun Arman Bashirova Joerg G. Baumann Thomas D. Martin Jaideep M. Karamchandani Jason W. Rausch Stuart F. J. Le Grice Li Wu Mary Carrington Vineet N. KewalRamani 《The Journal of biological chemistry》2010,285(3):2100-2112
In this study, we identify determinants in dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) necessary for human immunodeficiency virus, type 1 (HIV-1), transmission. Although human B cell lines expressing DC-SIGN efficiently capture and transmit HIV-1 to susceptible target cells, cells expressing the related molecule liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) do not. To understand the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions, we developed Raji B cell lines expressing different DC-SIGN/L-SIGN chimeras. Testing of the chimeras demonstrated that replacement of the DC-SIGN carbohydrate-recognition domain (CRD) with that of L-SIGN was sufficient to impair virus binding and prevent transmission. Conversely, the ability to bind and transmit HIV-1 was conferred to L-SIGN chimeras containing the DC-SIGN CRD. We identified Trp-258 in the DC-SIGN CRD to be essential for HIV-1 transmission. Although introduction of a K270W mutation at the same position in L-SIGN was insufficient for HIV-1 binding, an L-SIGN mutant molecule with K270W and a C-terminal DC-SIGN CRD subdomain transmitted HIV-1. These data suggest that DC-SIGN structural elements distinct from the oligosaccharide-binding site are required for HIV-1 glycoprotein selectivity. 相似文献
29.
Stuart E. Newson David I. Leech Chris M. Hewson Humphrey Q. P. Crick Phil V. Grice 《Journal of Ornithology》2010,151(1):211-218
Several woodland bird species have declined markedly in abundance in England over the past 40 years, whilst the grey squirrel
Sciurus carolinensis, a non-native nest predator, has increased. Given the timing, there has been concern that grey squirrels have driven these
declines, although there is little data to support this view. Using novel analytical methods and extensive national bird and
grey squirrel monitoring data, we examine whether there is evidence that woodland bird populations in England have been depressed
by grey squirrels and whether there is a relationship between nest failure and squirrel numbers. Our results indicate that
grey squirrels are very unlikely to have driven observed declines of woodland birds in recent years, although the number of
associations, positive as well as negative, between grey squirrels and woodland birds is greater than expected by chance.
For this reason, we cannot exclude the possibility that the populations of a small number of bird species, principally increasing
species, have been depressed to some degree at sites where a greater number of grey squirrels were present. Of these species,
perhaps the most convincing evidence is for Common Blackbird Turdus merula and Eurasian Collared Dove Streptopelia decaocto where nest record data also identified a positive relationship between nest failure at the egg stage and squirrel abundance. 相似文献
30.
Desma M. Grice Irina Vetter Helen M. Faddy Paraic A. Kenny Sarah J. Roberts-Thomson Gregory R. Monteith 《The Journal of biological chemistry》2010,285(48):37458-37466
Calcium signaling is a key regulator of pathways important in tumor progression, such as proliferation and apoptosis. Most studies assessing altered calcium homeostasis in cancer cells have focused on alterations mediated through changes in cytoplasmic free calcium levels. Here, we show that basal-like breast cancers are characterized by an alteration in the secretory pathway calcium ATPase 1 (SPCA1), a calcium pump localized to the Golgi. Inhibition of SPCA1 in MDA-MB-231 cells produced pronounced changes in cell proliferation and morphology in three-dimensional culture, without alterations in sensitivity to endoplasmic reticulum stress induction or changes in global calcium signaling. Instead, the effects of SPCA1 inhibition in MDA-MB-231 cells reside in altered regulation of calcium-dependent enzymes located in the secretory pathway, such as proprotein convertases. Inhibition of SPCA1 produced a pronounced alteration in the processing of insulin-like growth factor receptor (IGF1R), with significantly reduced levels of functional IGF1Rβ and accumulation of the inactive trans-Golgi network pro-IGF1R form. These studies identify for the first time a calcium transporter associated with the basal-like breast cancer subtype. The pronounced effects of SPCA1 inhibition on the processing of IGF1R in MDA-MB-231 cells independent of alterations in global calcium signaling also demonstrate that some calcium transporters can regulate the processing of proteins important in tumor progression without major alterations in cytosolic calcium signaling. Inhibitors of SPCA1 may offer an alternative strategy to direct inhibitors of IGF1R and attenuate the processing of other proprotein convertase substrates important in basal breast cancers. 相似文献