全文获取类型
收费全文 | 8276篇 |
免费 | 709篇 |
国内免费 | 3篇 |
出版年
2023年 | 30篇 |
2022年 | 77篇 |
2021年 | 108篇 |
2020年 | 69篇 |
2019年 | 75篇 |
2018年 | 112篇 |
2017年 | 103篇 |
2016年 | 181篇 |
2015年 | 319篇 |
2014年 | 367篇 |
2013年 | 444篇 |
2012年 | 565篇 |
2011年 | 564篇 |
2010年 | 416篇 |
2009年 | 357篇 |
2008年 | 500篇 |
2007年 | 505篇 |
2006年 | 460篇 |
2005年 | 482篇 |
2004年 | 506篇 |
2003年 | 445篇 |
2002年 | 477篇 |
2001年 | 70篇 |
2000年 | 56篇 |
1999年 | 116篇 |
1998年 | 139篇 |
1997年 | 56篇 |
1996年 | 79篇 |
1995年 | 64篇 |
1994年 | 73篇 |
1993年 | 85篇 |
1992年 | 79篇 |
1991年 | 61篇 |
1990年 | 74篇 |
1989年 | 47篇 |
1988年 | 61篇 |
1987年 | 59篇 |
1986年 | 55篇 |
1985年 | 49篇 |
1984年 | 69篇 |
1983年 | 48篇 |
1982年 | 65篇 |
1981年 | 73篇 |
1980年 | 46篇 |
1979年 | 46篇 |
1978年 | 40篇 |
1977年 | 43篇 |
1976年 | 35篇 |
1975年 | 25篇 |
1974年 | 27篇 |
排序方式: 共有8988条查询结果,搜索用时 15 毫秒
861.
Black E Breed J Breeze AL Embrey K Garcia R Gero TW Godfrey L Kenny PW Morley AD Minshull CA Pannifer AD Read J Rees A Russell DJ Toader D Tucker J 《Bioorganic & medicinal chemistry letters》2005,15(10):2503-2507
Using structure-based design, a new class of inhibitors of protein tyrosine phosphatase-1B (PTP1B) has been identified, which incorporate the 1,2,5-thiadiazolidin-3-one-1,1-dioxide template. 相似文献
862.
Zheng G Dwoskin LP Deaciuc AG Crooks PA 《Bioorganic & medicinal chemistry letters》2005,15(20):4463-4466
A series of tropane derivatives has been synthesized as lobelane analogues and evaluated for their binding affinity at the vesicular monoamine transporter-2 (VMAT2), and at alpha4beta2* and alpha7* nicotinic acetylcholine receptors. The trop-2-ene analogues 4a and 4b exhibited good affinity and high selectivity for VMAT2. 相似文献
863.
Biftu T Feng D Ponpipom M Girotra N Liang GB Qian X Bugianesi R Simeone J Chang L Gurnett A Liberator P Dulski P Leavitt PS Crumley T Misura A Murphy T Rattray S Samaras S Tamas T Mathew J Brown C Thompson D Schmatz D Fisher M Wyvratt M 《Bioorganic & medicinal chemistry letters》2005,15(13):3296-3301
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial. 相似文献
864.
Papke RL Zheng G Horenstein NA Dwoskin LP Crooks PA 《Bioorganic & medicinal chemistry letters》2005,15(17):3874-3880
The alpha7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat alpha7 receptors expressed in Xenopus oocytes, with no significant activation of either alpha3beta4 or alpha4beta2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for alpha3beta4 and alpha4beta2 receptors, as well as for alpha7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified alpha7-selective agonists, suggests that they share a similar structural motif that may be applicable to other alpha7-selective agonists. 相似文献
865.
Fallahi A Kroll B Warner LR Oxford RJ Irwin KM Mercer LM Shadle SE Oxford JT 《Protein science : a publication of the Protein Society》2005,14(6):1526-1537
Fibrillar collagens are the principal structural molecules of connective tissues. The assembly of collagen fibrils is regulated by quantitatively minor fibrillar collagens, types V and XI. A unique amino-terminal propeptide domain of these collagens has been attributed this regulatory role. The structure of the amino terminal propeptide has yet to be determined. Low sequence similarity necessitated a secondary structure-based method to carry out homology modeling based upon the determined structure of LNS family members, named for a common structure in the laminin LG5 domain, the neurexin 1B domain and the sex hormone binding globulin. Distribution of amino acids within the model suggested glycosaminoglycan interaction and calcium binding. These activities were tested experimentally. Sequence analyses of existing genes for collagens indicate that 16 known collagen alpha chains may contain an LNS domain. A similar approach may prove useful for structure/function studies of similar domains in other collagens with similar domains. This will provide mechanistic details of the organization and assembly of the extracellular matrix and the underlying basis of structural integrity in connective tissues. The absolute requirement for collagen XI in skeletal growth is indicated by collagen XI deficiencies such as chondrodystrophies found in the cho/cho mouse and in humans with Stickler syndrome. 相似文献
866.
867.
In vitro neuronal recordings in the SCN have clearly documented shifts in the peak of unit activity following the application of serotonergic agents, and yet selectivity issues with these very tools have limited progress in establishing the precise receptor mechanisms. As an alternative strategy, mice were bred (C57BL/6J) lacking 1 serotonin receptor, the 5-HT(7), to serve as a null background for this subtype; earlier work had documented the involvement of 5-HT(7) receptors in the phase advances elicited by 8-OH-DPAT, a mixed 5-HT(1A/7) agonist, in SCN slices prepared from rat donors. Single-unit recordings in sequential electrode passes revealed peaks of activity that occurred at nearly the same time in the knockout (KO; ZT4.2 +/- 0.6) and wild-type animals (WT; ZT4.3 +/- 0.1), where ZT0 marks the beginning of the light phase in a 12:12 LD cycle. Bath application of 8-OH-DPAT produced a phase advance in neuronal firing (2.1 +/- 0.5 h) when applied 1 circadian cycle earlier at ZT6 (10 microM, 10 min), but surprisingly, the mean phase advance in slices prepared from KO mice (2.3 +/- 0.1 h) was no different. Coapplication of 8-OH-DPAT with WAY-100,635 (10 microM), a highly selective 5-HT(1A) antagonist, significantly reduced the phase advance, both in experiments with WT and KO mice, suggesting the greater importance of this serotonin sub-type independent of genetic modification. 5-HT itself (0.5 +/-M, 10 min) at ZT6 also yielded phase advances that were indistinguishable in slices prepared from WT and KO mice (1.8 +/- 0.4 h and 2.1 +/- 0.2 h, respectively) and that were also sensitive to WAY-100,635. Unlike the pattern with 8-OH-DPAT, however, 5-HT-induced phase advances, in both WT and KO mice, were blocked by ritanserin, in this paradigm useful as a 5-HT(5A/7) antagonist (in addition to its more typical role as a 5-HT2A/2C antagonist). Serotonin antagonists when administered alone were without effect in slices from WT mice but produced significant phase shifts when administered to those from KO animals. Taken together, these results highlight the importance of the species used in establishing receptor mechanism. More provocatively, they support the involvement of multiple serotonin receptors in shifting the phase of circadian rhythms at ZT6. 相似文献
868.
Ng HH Frantz CE Rausch L Fairchild DC Shimon J Riccio E Smith S Mirsalis JC 《Genomics》2005,86(6):657-667
The purpose of this study was to evaluate gene expression profiles in the liver and blood for prediction of infection severity from Listeria monocytogenes (LM). Mice were injected with medium broth (control) or a nonlethal or lethal dose of LM and sacrificed 6 h later. Gene expression changes were determined using Affymetrix MGU74Av2 GeneChips and confirmed by real-time polymerase chain reaction analysis. We identified discernable genes whose gene expression profiles can be used in pattern recognition to predict and classify samples in differently treated groups, with >or=90% accuracy in liver samples and 80% accuracy in blood at prediction; however, different genes were predictive in each tissue. Our results suggest that gene expression profiling in response to LM in mice may be able to distinguish samples in groups with varying severity of infection and provide information in finding molecular mechanisms and early biomarkers for subsequent conventional clinical endpoints. 相似文献
869.
In a recent study on the degradation of N,N-dibutylurea (DBU), a breakdown product of benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazole carbamate], the active ingredient in Benlate® fungicides, degradation half-lives of 1.4–46.5days were observed across several soils incubated at various combinations of soil moisture potential (–0.03 and –0.1MPa) and temperature (23, 33, and 44°C) for a single DBU application of 0.08 and 0.8 g g–1 (Lee et al. 2004). However, Benlate® can be applied as often as every 7days resulting in the repeated application of DBU likely to be present in the Benlate® over a growing season. In this study, the effect of seven repeated DBU applications on mineralization rate was investigated in two soils, which encompass the range in rates previously observed. For the slower degrading soil, repeated DBU application increased mineralization from 0.029 to 0.99day–1 at the 0.08 g g–1 rate, and 0.037 to 0.89day–1 at the 0.8 g g–1 rate. For the faster degrading soil, effects on mineralization of repeated DBU applications were small to negligible. For the latter soil, the effect on mineralization of applied DBU concentrations from 0.0008 to 80 g g–1 was also investigated. Mineralization rates decreased from 0.43 to 0.019day–1 with increasing DBU concentrations. However, the amount of DBU mineralized by day 70 was similar across concentrations and averaged 83% of applied. Microbial respiration was not affected by increasing DBU concentrations. These findings support the supposition that DBU is readily degraded by soil microorganisms, thus unlikely to accumulate in agricultural soils. 相似文献
870.
Retinoic acid signaling acts via Hox1 to establish the posterior limit of the pharynx in the chordate amphioxus 总被引:4,自引:0,他引:4
Schubert M Yu JK Holland ND Escriva H Laudet V Holland LZ 《Development (Cambridge, England)》2005,132(1):61-73
In the invertebrate chordate amphioxus, as in vertebrates, retinoic acid (RA) specifies position along the anterior/posterior axis with elevated RA signaling in the middle third of the endoderm setting the posterior limit of the pharynx. Here we show that AmphiHox1 is also expressed in the middle third of the developing amphioxus endoderm and is activated by RA signaling. Knockdown of AmphiHox1 function with an antisense morpholino oligonucleotide shows that AmphiHox1 mediates the role of RA signaling in setting the posterior limit of the pharynx by repressing expression of pharyngeal markers in the posterior foregut/midgut endoderm. The spatiotemporal expression of these endodermal genes in embryos treated with RA or the RA antagonist BMS009 indicates that Pax1/9, Pitx and Notch are probably more upstream than Otx and Nodal in the hierarchy of genes repressed by RA signaling. This work highlights the potential of amphioxus, a genomically simple, vertebrate-like invertebrate chordate, as a paradigm for understanding gene hierarchies similar to the more complex ones of vertebrates. 相似文献