全文获取类型
收费全文 | 1527篇 |
免费 | 143篇 |
国内免费 | 3篇 |
专业分类
1673篇 |
出版年
2024年 | 1篇 |
2023年 | 5篇 |
2022年 | 11篇 |
2021年 | 22篇 |
2020年 | 10篇 |
2019年 | 17篇 |
2018年 | 32篇 |
2017年 | 18篇 |
2016年 | 23篇 |
2015年 | 63篇 |
2014年 | 79篇 |
2013年 | 77篇 |
2012年 | 116篇 |
2011年 | 113篇 |
2010年 | 73篇 |
2009年 | 87篇 |
2008年 | 99篇 |
2007年 | 109篇 |
2006年 | 106篇 |
2005年 | 105篇 |
2004年 | 105篇 |
2003年 | 111篇 |
2002年 | 95篇 |
2001年 | 13篇 |
2000年 | 12篇 |
1999年 | 13篇 |
1998年 | 19篇 |
1997年 | 21篇 |
1996年 | 20篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 9篇 |
1992年 | 14篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 6篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1974年 | 2篇 |
1973年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有1673条查询结果,搜索用时 9 毫秒
81.
Raghavan S Yang Z Mosley RT Schleif WA Gabryelski L Olsen DB Stahlhut M Kuo LC Emini EA Chapman KT Tata JR 《Bioorganic & medicinal chemistry letters》2002,12(20):2855-2858
A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2'. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol. 相似文献
82.
Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice 总被引:1,自引:0,他引:1
83.
Letavic MA Barberia JT Carty TJ Hardink JR Liras J Lopresti-Morrow LL Mitchell PG Noe MC Reeves LM Snow SL Stam EJ Sweeney FJ Vaughn ML Yu CH 《Bioorganic & medicinal chemistry letters》2003,13(19):3243-3246
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group. 相似文献
84.
Sun Q Tafesse L Islam K Zhou X Victory SF Zhang C Hachicha M Schmid LA Patel A Rotshteyn Y Valenzano KJ Kyle DJ 《Bioorganic & medicinal chemistry letters》2003,13(20):3611-3616
A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC(50)=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1). 相似文献
85.
Expression of SpC3, the sea urchin complement component,in response to lipopolysaccharide 总被引:6,自引:2,他引:4
The homologue of the vertebrate complement component C3 that is expressed in the coelomocytes of the purple sea urchin, Strongylocentrotus purpuratus, designated SpC3, was investigated for changes in response to immune challenge or injury. Immunoquiescent animals were used in this study because they have reduced or no detectable SpC3 in their coelomocytes or coelomic fluid (CF). Animals were injected with lipopolysaccharide (LPS) or sterile sea water (SSW, injury control). Changes in the amounts of SpC3 in coelomic fluid and in coelomocytes were then followed over time by Western blots and ELISA. Changes in mRNA from the SpC3 gene (Sp064) were also followed by RT-PCR. Although all animals responded to injury with increased levels of SpC3 in the coelomic fluid, those challenged with LPS had greater amounts of SpC3 in both CF and coelomocytes than those receiving SSW. In most of the animals receiving LPS, initial increases in SpC3 were observed within 1 h post-injection, while the earliest response in the animals receiving SSW was 6 h. The appearance of SpC3 in the coelomocytes was delayed compared to its appearance in CF, and was first detected several days after challenge. Changes in mRNA from the Sp064 gene paralleled the appearance of SpC3 in the coelomic fluid. Increases in the number of coelomocytes per milliliter of CF and in the percentage of coelomocytes that were SpC3+ also occurred after challenge with LPS or in response to injury, with a slightly greater increase in response to LPS. Although the changes in SpC3 were not as great as those identified previously for human C3 expressed in macrophages, the kinetics of the response are similar to that of acute-phase reactants in mammals. 相似文献
86.
Heather L. Rocchetta Lori L. Burrows Jennifer C. Pacan & Joseph S. Lam 《Molecular microbiology》1998,28(6):1103-1119
The Pseudomonas aeruginosa A-band lipopolysaccharide (LPS) molecule has an O-polysaccharide region composed of trisaccharide repeat units of α1 → 2, α1 → 3, α1 → 3 linked D -rhamnose (Rha). The A-band polysaccharide is assembled by the α-D -rhamnosyltransferases, WbpX, WbpY and WbpZ. WbpZ probably transfers the first Rha residue onto the A-band accepting molecule, while WbpY and WbpX subsequently transfer two α1 → 3 linked Rha residues and one α1 → 2 linked Rha respectively. The last two transferases are predicted to be processive, alternating in their activities to complete the A-band polymer. The genes coding for these transferases were identified at the 3′ end of the A-band biosynthetic cluster. Two additional genes, psecoA and uvrD, border the 3′ end of the cluster and are predicted to encode a co-enzyme A transferase and a DNA helicase II enzyme respectively. Chromosomal wbpX, wbpY and wbpZ mutants were generated, and Western immunoblot analysis demonstrates that these mutants are unable to synthesize A-band LPS, while B-band synthesis is unaffected. WbpL, a transferase encoded within the B-band biosynthetic cluster, was previously proposed to initiate B-band biosynthesis through the addition of Fuc2NAc (2-acetamido-2,6-dideoxy-D -galactose) to undecaprenol phosphate (Und-P). In this study, chromosomal wbpL mutants were generated that did not express A band or B band, indicating that WbpL initiates the synthesis of both LPS molecules. Cross-complementation experiments using WbpL and its homologue, Escherichia coli WecA, demonstrates that WbpL is bifunctional, initiating B-band synthesis with a Fuc2NAc residue and A-band synthesis with either a GlcNAc (N-acetylglucosamine) or GalNAc (N-acetylgalactosamine) residue. These data indicate that A-band polysaccharide assembly requires four glycosyltransferases, one of which is necessary for initiating both A-band and B-band LPS synthesis. 相似文献
87.
Cristina E. Tognon Heather E. Kirk Lori A. Passmore Ian P. Whitehead Channing J. Der Robert J. Kay 《Molecular and cellular biology》1998,18(12):6995-7008
As part of a cDNA library screen for clones that induce transformation of NIH 3T3 fibroblasts, we have isolated a cDNA encoding the murine homolog of the guanine nucleotide exchange factor RasGRP. A point mutation predicted to prevent interaction with Ras abolished the ability of murine RasGRP (mRasGRP) to transform fibroblasts and to activate mitogen-activated protein kinases (MAP kinases). MAP kinase activation via mRasGRP was enhanced by coexpression of H-, K-, and N-Ras and was partially suppressed by coexpression of dominant negative forms of H- and K-Ras. The C terminus of mRasGRP contains a pair of EF hands and a C1 domain which is very similar to the phorbol ester- and diacylglycerol-binding C1 domains of protein kinase Cs. The EF hands could be deleted without affecting the ability of mRasGRP to transform NIH 3T3 cells. In contrast, deletion of the C1 domain or an adjacent cluster of basic amino acids eliminated the transforming activity of mRasGRP. Transformation and MAP kinase activation via mRasGRP were restored if the deleted C1 domain was replaced either by a membrane-localizing prenylation signal or by a diacylglycerol- and phorbol ester-binding C1 domain of protein kinase C. The transforming activity of mRasGRP could be regulated by phorbol ester when serum concentrations were low, and this effect of phorbol ester was dependent on the C1 domain of mRasGRP. The C1 domain could also confer phorbol myristate acetate-regulated transforming activity on a prenylation-defective mutant of K-Ras. The C1 domain mediated the translocation of mRasGRP to cell membranes in response to either phorbol ester or serum stimulation. These results suggest that the primary mechanism of activation of mRasGRP in fibroblasts is through its recruitment to diacylglycerol-enriched membranes. mRasGRP is expressed in lymphoid tissues and the brain, as well as in some lymphoid cell lines. In these cells, RasGRP has the potential to serve as a direct link between receptors which stimulate diacylglycerol-generating phospholipase Cs and the activation of Ras. 相似文献
88.
Abnormal phospholipid composition impairs HDL biogenesis and maturation in mice lacking Abca1 总被引:3,自引:0,他引:3
Recent studies have demonstrated that the ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of phospholipids and cholesterol to apoprotein acceptors, leading to the synthesis of HDL. The purpose of this study was to determine the changes in the lipoprotein fractions in Abca1-deficient mice and study the mechanisms responsible for the low levels of HDL when ABCA1 is absent. Plasma phospholipid concentration was decreased by more than 75%, mostly due to a reduction of phosphatidylcholine (PC) in HDL. Abca1(-/-) HDL represents less than 2% of wild-type levels and is smaller and enriched in phospholipids (11.2-fold more than HDL from controls). Compared to wild-type littermates, Abca1(-/-) HDL had a 4-fold increase in PC, whereas lysophosphatidylcholine (LPC) (125-fold), sphingomyelin (SPH) (49-fold), and phosphatidylethanolamine (PE) (18-fold) showed even higher increases. As a consequence, the ratios of LPC/PC, SPH/PC, PE/PC, and phosphatidylinositol + phosphatidylserine (PI+PS)/PC were all much higher in HDL from Abca1(-/-), compared to wild-type HDL. Plasma phospholipid transfer protein (PLTP) and lecithin cholesterol acyltransferase (LCAT) activities were decreased by more than 80%, suggesting that the maturation of HDL is affected. To test this hypothesis, plasma from Abca1(-/-) mice was incubated with CHO cells that are known to express high levels of ABCA1 with the intent of restoring the flux of phospholipid and cholesterol onto apoAI. Compared to native plasma, no change in maturation of HDL was observed. In contrast, a 220% increase in the formation of mature HDL was observed when ABCA1 function and LCAT activities were restored. Taken together, these observations suggest that ABCA1 is necessary for the adequate lipidation of apoAI, which enables the interaction with LCAT and subsequent maturation. 相似文献
89.
Emily E. Puckett Thea V. Kristensen Clay M. Wilton Sara B. Lyda Karen V. Noyce Paula M. Holahan David M. Leslie Jr Jeff Beringer Jerrold L. Belant Don White Jr Lori S. Eggert 《Molecular ecology》2014,23(10):2414-2427
Bottlenecks, founder events, and genetic drift often result in decreased genetic diversity and increased population differentiation. These events may follow abundance declines due to natural or anthropogenic perturbations, where translocations may be an effective conservation strategy to increase population size. American black bears (Ursus americanus) were nearly extirpated from the Central Interior Highlands, USA by 1920. In an effort to restore bears, 254 individuals were translocated from Minnesota, USA, and Manitoba, Canada, into the Ouachita and Ozark Mountains from 1958 to 1968. Using 15 microsatellites and mitochondrial haplotypes, we observed contemporary genetic diversity and differentiation between the source and supplemented populations. We inferred four genetic clusters: Source, Ouachitas, Ozarks, and a cluster in Missouri where no individuals were translocated. Coalescent models using approximate Bayesian computation identified an admixture model as having the highest posterior probability (0.942) over models where the translocation was unsuccessful or acted as a founder event. Nuclear genetic diversity was highest in the source (AR = 9.11) and significantly lower in the translocated populations (AR = 7.07–7.34; P = 0.004). The Missouri cluster had the lowest genetic diversity (AR = 5.48) and served as a natural experiment showing the utility of translocations to increase genetic diversity following demographic bottlenecks. Differentiation was greater between the two admixed populations than either compared to the source, suggesting that genetic drift acted strongly over the eight generations since the translocation. The Ouachitas and Missouri were previously hypothesized to be remnant lineages. We observed a pretranslocation remnant signature in Missouri but not in the Ouachitas. 相似文献
90.
Mark J. Mitton-Fry Steven J. Brickner Judith C. Hamel Lori Brennan Jeffrey M. Casavant Michael Chen Tao Chen Xiaoyuan Ding James Driscoll Joel Hardink Thuy Hoang Erbing Hua Michael D. Huband Meghan Maloney Anthony Marfat Sandra P. McCurdy Dale McLeod Michael Plotkin Christopher Zook 《Bioorganic & medicinal chemistry letters》2013,23(10):2955-2961
A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed. 相似文献