全文获取类型
收费全文 | 15345篇 |
免费 | 1416篇 |
国内免费 | 6篇 |
专业分类
16767篇 |
出版年
2023年 | 41篇 |
2022年 | 90篇 |
2021年 | 171篇 |
2020年 | 125篇 |
2019年 | 133篇 |
2018年 | 172篇 |
2017年 | 180篇 |
2016年 | 350篇 |
2015年 | 569篇 |
2014年 | 648篇 |
2013年 | 763篇 |
2012年 | 1097篇 |
2011年 | 1168篇 |
2010年 | 766篇 |
2009年 | 692篇 |
2008年 | 922篇 |
2007年 | 1023篇 |
2006年 | 867篇 |
2005年 | 878篇 |
2004年 | 919篇 |
2003年 | 860篇 |
2002年 | 826篇 |
2001年 | 168篇 |
2000年 | 121篇 |
1999年 | 220篇 |
1998年 | 256篇 |
1997年 | 166篇 |
1996年 | 169篇 |
1995年 | 157篇 |
1994年 | 159篇 |
1993年 | 151篇 |
1992年 | 143篇 |
1991年 | 100篇 |
1990年 | 114篇 |
1989年 | 100篇 |
1988年 | 110篇 |
1987年 | 92篇 |
1986年 | 92篇 |
1985年 | 93篇 |
1984年 | 127篇 |
1983年 | 92篇 |
1982年 | 119篇 |
1981年 | 113篇 |
1980年 | 98篇 |
1979年 | 55篇 |
1978年 | 67篇 |
1977年 | 64篇 |
1976年 | 64篇 |
1975年 | 46篇 |
1974年 | 57篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Role of carboxylate residues adjacent to the conserved core Walker B motifs in the catalytic cycle of multidrug resistance protein 1 (ABCC1) 总被引:4,自引:0,他引:4
Payen LF Gao M Westlake CJ Cole SP Deeley RG 《The Journal of biological chemistry》2003,278(40):38537-38547
MRP1 belongs to subfamily "C" of the ABC transporter superfamily. The nucleotide-binding domains (NBDs) of the C family members are relatively divergent compared with many ABC proteins. They also differ in their ability to bind and hydrolyze ATP. In MRP1, NBD1 binds ATP with high affinity, whereas NBD2 is hydrolytically more active. Furthermore, ATP binding and/or hydrolysis by NBD2 of MRP1, but not NBD1, is required for MRP1 to shift from a high to low affinity substrate binding state. Little is known of the structural basis for these functional differences. One minor structural difference between NBDs is the presence of Asp COOH-terminal to the conserved core Walker B motif in NBD1, rather than the more commonly found Glu present in NBD2. We show that the presence of Asp or Glu following the Walker B motif profoundly affects the ability of the NBDs to bind, hydrolyze, and release nucleotide. An Asp to Glu mutation in NBD1 enhances its hydrolytic capacity and affinity for ADP but markedly decreases transport activity. In contrast, mutations that eliminate the negative charge of the Asp side chain have little effect. The decrease in transport caused by the Asp to Glu mutation in NBD1 is associated with an inability of MRP1 to shift from high to low affinity substrate binding states. In contrast, mutation of Glu to Asp markedly increases the affinity of NBD2 for ATP while decreasing its ability to hydrolyze ATP and to release ADP. This mutation eliminates transport activity but potentiates the conversion from a high to low affinity binding state in the presence of nucleotide. These observations are discussed in the context of catalytic models proposed for MRP1 and other ABC drug transport proteins. 相似文献
992.
993.
Song K Cornelius SC Reiss M Danielpour D 《The Journal of biological chemistry》2003,278(40):38342-38351
994.
Zhong H Wade SM Woolf PJ Linderman JJ Traynor JR Neubig RR 《The Journal of biological chemistry》2003,278(9):7278-7284
Regulators of G protein signaling (RGS) are GTPase-accelerating proteins (GAPs), which can inhibit heterotrimeric G protein pathways. In this study, we provide experimental and theoretical evidence that high concentrations of receptors (as at a synapse) can lead to saturation of GDP-GTP exchange making GTP hydrolysis rate-limiting. This results in local depletion of inactive heterotrimeric G-GDP, which is reversed by RGS GAP activity. Thus, RGS enhances receptor-mediated G protein activation even as it deactivates the G protein. Evidence supporting this model includes a GTP-dependent enhancement of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding to G(i) by RGS. The RGS domain of RGS4 is sufficient for this, not requiring the NH(2)- or COOH-terminal extensions. Furthermore, a kinetic model including only the GAP activity of RGS replicates the GTP-dependent enhancement of GTPgammaS binding observed experimentally. Finally in a Monte Carlo model, this mechanism results in a dramatic "spatial focusing" of active G protein. Near the receptor, G protein activity is maintained even with RGS due to the ability of RGS to reduce depletion of local Galpha-GDP levels permitting rapid recoupling to receptor and maintained G protein activation near the receptor. In contrast, distant signals are suppressed by the RGS, since Galpha-GDP is not depleted there. Thus, a novel RGS-mediated "kinetic scaffolding" mechanism is proposed which narrows the spatial range of active G protein around a cluster of receptors limiting the spill-over of G protein signals to more distant effector molecules, thus enhancing the specificity of G(i) protein signals. 相似文献
995.
Amyloid beta protein (Abeta) is the primary constituent of plaque seen in Alzheimer's disease. Abeta is proposed to play an etiological role in Alzheimer's disease and to be a cause of the decrease in the level of acetylcholine in the hippocampus. The SAMP8 strain of mouse develops age-related increases in Abeta and deficits in learning and memory by 12 months of age. We examined in 12 month old SAMP8 mice the effects of giving antibody to Abeta by septal or intracerebroventricular (ICV) injection on acetylcholine levels in the hippocampus. Antibody to Abeta increased acetylcholine in the hippocampus over 100% after ICV injection and over 200% after septal injection. Injection of rabbit serum, antibody directed towards mouse IgG, or a blocking antibody directed towards human interleukin-1beta were without effect. These results suggest that antagonism of Abeta increases acetylcholine concentrations in the hippocampus, an area important for learning and memory. 相似文献
996.
Continued discovery of ligands for G protein-coupled receptors 总被引:1,自引:0,他引:1
G protein-coupled receptors are under intense scrutiny as potential targets of drug research, which stems mostly from the sheer size and diversity of this receptor family as well as the recognized high levels of specificity and sensitivity attainable by drugs targeting these receptors. The continued discovery of genes encoding G protein-coupled receptors has provided an extensive reserve of potential therapeutic targets. However, testing experimental therapeutic agents at these receptors requires a high degree of receptor characterization, beginning with the identity of an endogenous ligand. Often, low levels of sequence identity of a newly identified receptor to previously characterized receptors preclude the prompt identification of a ligand. In such cases, innovative techniques commonly referred to as reverse pharmacology have been employed to ascertain the ligand's identity for these "orphan" receptors. To date over 30 endogenous ligands, both novel and previously known, have been paired with orphan G protein-coupled receptors. Here, we briefly summarize the recent identification of neuropeptides W and B and carboxylic acid anions for their respective receptors GPR7, GPR8 and GPR40, GPR41, GPR43. 相似文献
997.
The effects of acute administration of nicotine on target biting (defensive) and resident-intruder (offensive) attack of male mice were assessed. In the target biting procedure confined mice received tail shock on a fixed time, 2-min schedule. Under baseline conditions, biting attack directed toward an inanimate target occurred at three distinct rates. A high target biting rate (13.5 +/- 3.8 bites/15 sec) followed shock delivery, an intermediate biting rate (9.6 +/- 4.1 bites/15 sec) occurred during the inter-shock interval, and a low biting rate (1.0 +/- 0.5 bites/15 sec) occurred during a tone stimulus which signalled the impending shock. Nicotine (administered IP, 15 min presession) reduced post-shock and inter-shock interval target biting in a dose-dependent manner (ED50 values estimated at 0.13 and 0.14 mg/kg, respectively) but exerted more variable effects on target biting during the tone. In the resident-intruder paradigm the same mice were exposed to an intruder introduced into its home cage for a 10-min test session. Under baseline conditions, residents directed 20 +/- 3.2 biting attacks toward the intruder during the session with an average latency of 89 +/- 40 sec to the first attack. Nicotine caused a dose-dependent decrease in this attack behavior (ED50 values estimated to be 0.48 and 0.49 mg/kg, respectively). These observations are interpreted to indicate that nicotine has an increased potency at reducing "defensive" aggression. 相似文献
998.
999.
Two antineoplastic agents, chlornaphazine (CN) and chlorambucil (CHL), were tested for the induction of dominant lethal mutations in male mice. Both compounds are nitrogen mustard derivatives and have been shown to be genotoxic in a variety of organisms. CN was administered intraperitoneally to DBA/2J male mice at a dosage of 0, 500, 1000, or 1500 mg/kg body weight (bw). Immediately following treatment, each male was mated at 4-day intervals to two virgin C57BL/6J females. CHL was administered intraperitoneally to C3H/HeJ and DBA/2J males at a dosage of 0, 2.5, or 5.0 mg/kg bw. These males were mated at weekly intervals to two virgin T-stock females. CN and CHL clearly induced dominant lethal mutations. CN induced dominant lethal effects in all post-meiotic germ-cell stages of treated DBA males, with a clear dose-response relationship. The results with CHL-treated DBA males indicated that all post-meiotic germ-cell stages, except late-spermatids, were affected by CHL treatment, while in C3H males, CHL induced dominant lethal effects in all post-meiotic germ-cell stages. A dose-response relationship was also observed with CHL in C3H male mice. In the present experiments, regardless of the agent or the mouse strain used, spermatids appeared to be the germ-cell stage most sensitive to dominant lethal induction. 相似文献
1000.
Barron DM Chatterjee SK Ravindra R Roof R Baloglu E Kingston DG Bane S 《Analytical biochemistry》2003,315(1):49-56
With the advent of combinatorial chemistry and the extensive libraries of potential drugs produced from it, there is a growing need for rapid sensitive, high-throughput screening for drug potency. Microtubules are important targets for anticancer agents, and new antimicrotubule compounds are of continued interest in drug development. The in vitro potency of antimicrotubule drugs may be evaluated by measuring the extent of tubulin assembly. The extent of polymerization is proportional to the turbidity of the solution, which usually has been measured as apparent absorption. The turbidity method has inherent problems that hinder its adaptation to a high-throughput format, such as a requirement for high protein concentrations and a high coefficient of variation. We present here a high-throughput assay for antimicrotubule activity in which fluorescence is used to monitor microtubule assembly. Both assembly-inhibiting and assembly-promoting compounds can be evaluated. The assay is rapid and easy to perform, and the data are reliable, with good accuracy and reproducibility. 相似文献