全文获取类型
收费全文 | 3303篇 |
免费 | 193篇 |
出版年
2024年 | 2篇 |
2023年 | 19篇 |
2022年 | 43篇 |
2021年 | 95篇 |
2020年 | 42篇 |
2019年 | 75篇 |
2018年 | 111篇 |
2017年 | 116篇 |
2016年 | 166篇 |
2015年 | 171篇 |
2014年 | 221篇 |
2013年 | 246篇 |
2012年 | 294篇 |
2011年 | 307篇 |
2010年 | 199篇 |
2009年 | 116篇 |
2008年 | 222篇 |
2007年 | 192篇 |
2006年 | 157篇 |
2005年 | 181篇 |
2004年 | 117篇 |
2003年 | 129篇 |
2002年 | 85篇 |
2001年 | 15篇 |
2000年 | 11篇 |
1999年 | 15篇 |
1998年 | 17篇 |
1997年 | 15篇 |
1996年 | 5篇 |
1995年 | 14篇 |
1994年 | 12篇 |
1993年 | 11篇 |
1992年 | 10篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 6篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1954年 | 2篇 |
1948年 | 1篇 |
1945年 | 1篇 |
排序方式: 共有3496条查询结果,搜索用时 15 毫秒
961.
Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization 总被引:5,自引:0,他引:5
Pfeiffer M Kirscht S Stumm R Koch T Wu D Laugsch M Schröder H Höllt V Schulz S 《The Journal of biological chemistry》2003,278(51):51630-51637
The micro-opioid receptor (MOR1) and the substance P receptor (NK1) coexist and functionally interact in nociceptive brain regions; however, a molecular basis for this interaction has not been established. Using coimmunoprecipitation and bioluminescence resonance energy transfer (BRET), we show that MOR1 and NK1 can form heterodimers in HEK 293 cells coexpressing the two receptors. Although NK1-MOR1 heterodimerization did not substantially change the ligand binding and signaling properties of these receptors, it dramatically altered their internalization and resensitization profile. Exposure of the NK1-MOR1 heterodimer to the MOR1-selective ligand [D-Ala2,Me-Phe4,Gly5-ol]enkephalin (DAMGO) promoted cross-phosphorylation and cointernalization of the NK1 receptor. Conversely, exposure of the NK1-MOR1 heterodimer to the NK1-selective ligand substance P (SP) promoted cross-phosphorylation and cointernalization of the MOR1 receptor. In cells expressing MOR1 alone, beta-arrestin directs the receptors to clathrin-coated pits, but does not internalize with the receptor. In cells expressing NK1 alone, beta-arrestin internalizes with the receptor into endosomes. Interestingly, in cells coexpressing MOR1 and NK1 both DAMGO and SP induced the recruitment of beta-arrestin to the plasma membrane and cointernalization of NK1-MOR1 heterodimers with beta-arrestin into the same endosomal compartment. Consequently, resensitization of MOR1-dependent receptor functions was severely delayed in coexpressing cells as compared with cells expressing MOR1 alone. Together, our findings indicate that MOR1 by virtue of its physical interaction with NK1 is sequestered via an endocytotic pathway with delayed recycling and resensitization kinetics. 相似文献
962.
Gozdz A Habas A Jaworski J Zielinska M Albrecht J Chlystun M Jalili A Hetman M 《The Journal of biological chemistry》2003,278(44):43663-43671
Neurons are exposed to damaging stimuli that can trigger cell death and subsequently cause serious neurological disorders. Therefore, it is important to define defense mechanisms that can be activated in response to damage to reduce neuronal loss. Here we report that cisplatin (CPDD), a neurotoxic anticancer drug that damages DNA, triggered apoptosis and activated the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in cultured rat cortical neurons. Inhibition of ERK1/2 activation using either pharmacological inhibitors or a dominant-negative mutant of the ERK1/2 activator, mitogen-activated protein kinase kinase 1, increased the toxicity of CPDD. Interestingly, N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonists reduced the ERK1/2 activation and exacerbated apoptosis in CPDD-treated neurons. Pre-treatment with CPDD increased ERK1/2 activation triggered by exogenous NMDA, suggesting that CPDD augmented NMDAR responsiveness. CPDD-enhanced response of NMDAR and CPDD-mediated ERK1/2 activation were both decreased by inhibition of poly(ADP-ribose) polymerase (PARP). Interestingly, PARP activation did not produce ATP depletion, suggesting involvement of a non-energetic mechanism in NMDAR regulation by PARP. Finally, CPDD toxicity was reduced by brain-derived neurotrophic factor, and this protection required ERK1/2. In summary, our data identify a novel compensatory circuit in central nervous system neurons that couples the DNA injury, through PARP and NMDAR, to the defensive ERK1/2 activation. 相似文献
963.
Over a decade ago, the gene STT3 was identified in a staurosporine and temperature sensitivity screen of yeast. Subsequently the product of this gene was shown to be a subunit of the endoplasmic reticulum-localized oligosaccharyl transferase (OT) complex. Although stt3 mutants are known to be staurosporine-sensitive, we found that mutants of other OT subunits (except ost4 Delta) are staurosporine-resistant, which indicates that this phenotype of stt3 mutants is not simply a consequence of their defect in glycosylation, as previously speculated. Staurosporine sensitivity was found to be an allele-specific phenotype restricted to cells harboring mutations in highly conserved residues in the N-terminal domain of the STT3 protein. Cells bearing mutations in one of the cytosolic-oriented loops (amino acids 158-168) in the N terminus of Stt3p were found to be specifically susceptible to staurosporine. Staurosporine is a specific inhibitor of Pkc1p, and a genetic link had previously been suggested between PKC1 and STT3. It is known that overexpression of PKC1 suppresses the staurosporine sensitivity of the stt3 mutants in an allele-specific manner, which is typical of mutants of Pkc1p cascade. It has been shown that the pkc1 null mutant exhibits lowered OT activity. Our results combined with these previous observations indicate that the N-terminal domain of Stt3p may interact with members of the Pkc1p cascade and consequently mutations in this domain result in staurosporine sensitivity. We further speculate that the Pkc1p regulates OT activity through the N-terminal domain of Stt3p, the C-terminal domain of which possesses the recognition and/or catalytic site of the OT complex. 相似文献
964.
Intratumor CpG-oligodeoxynucleotide injection induces protective antitumor T cell immunity 总被引:8,自引:0,他引:8
Lonsdorf AS Kuekrek H Stern BV Boehm BO Lehmann PV Tary-Lehmann M 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(8):3941-3946
Tumor cells are typically poorly immunogenic. The same mechanisms that evolved to avoid the induction of immune responses against self tissues, and, hence, autoimmune disease, also have to be overcome for immune therapy of cancer. Toll-like receptor-activating microbial products such as CpG motif containing DNA are among the primary stimuli that the immune system uses to distinguish between infectious nonself (that is to be attacked) and noninfectious self (that must not be attacked). We tested in a murine RMA lymphoma/C57BL/6 model whether providing the infectious nonself context in a tumor-by injecting CpG-oligodeoxynucleotides directly into the tumor-would elicit a protective antitumor response. Complete remission of established solid tumors was achieved in immune competent mice, but not in T cell/B cell-deficient RAG-1 knockout mice. Intratumor injection of CpG-oligodeoxynucleotides was shown to induce a tumor-specific CD4(+) and CD8(+) T cell response of the type 1 effector class, and T cells adoptively transferred the protection to RAG-1 knockout mice. The data show that intratumor injection of CpG-oligodeoxynucleotides is a promising strategy for rendering tumors immunogenic. 相似文献
965.
966.
967.
Deneka M Neeft M van der Sluijs P 《Critical reviews in biochemistry and molecular biology》2003,38(2):121-142
Membrane flow through the cell is a highly dynamic process in which intracellular compartments communicate via tubulo-vesicular structures shuttling cargo molecules to their destinations. Transport carriers are formed at a donor compartment and navigate through the cytoplasm to the target organelle, on which they subsequently dock and fuse. Many of these events are regulated by the cooperative action of monomeric rab GTPases and their effector proteins. Research in recent years resulted in the identification of many rab effectors, providing first glimpses how the GTPase switch of individual rab proteins is utilized in discrete transport steps. 相似文献
968.
Nadina?NevesEmail author Magdalena?Segura-Nieto María?A.?Blanco Margelys?Sánchez Alfredo?González Justo?L.?González Ramiro?Castillo 《In vitro cellular & developmental biology. Plant》2003,39(3):343-345
Summary With the aim to determine a possible relationship between somatic embryogenesis and some metabolic contents in embryogenic
and non-embryogenic calluses of sugarcane (Saccharum sp. var CP-5243), the present study was carried out. Embryogenic callus has more soluble proteins, free proline, proteolytic
activity, soluble sugars, and invertase, and lower putreseine/(spermidine + spermine) than non-embryogenic tissue. Non-embryogenic
callus has a higher peroxidase and gallic acid level, lower dry matter/fresh matter ratio, and more gross fat compared with
embryogenic callus. 相似文献
969.
Myosin motors and not actin comets are mediators of the actin-based Golgi-to-endoplasmic reticulum protein transport 下载免费PDF全文
Durán JM Valderrama F Castel S Magdalena J Tomás M Hosoya H Renau-Piqueras J Malhotra V Egea G 《Molecular biology of the cell》2003,14(2):445-459
We have previously reported that actin filaments are involved in protein transport from the Golgi complex to the endoplasmic reticulum. Herein, we examined whether myosin motors or actin comets mediate this transport. To address this issue we have used, on one hand, a combination of specific inhibitors such as 2,3-butanedione monoxime (BDM) and 1-[5-isoquinoline sulfonyl]-2-methyl piperazine (ML7), which inhibit myosin and the phosphorylation of myosin II by the myosin light chain kinase, respectively; and a mutant of the nonmuscle myosin II regulatory light chain, which cannot be phosphorylated (MRLC2(AA)). On the other hand, actin comet tails were induced by the overexpression of phosphatidylinositol phosphate 5-kinase. Cells treated with BDM/ML7 or those that express the MRLC2(AA) mutant revealed a significant reduction in the brefeldin A (BFA)-induced fusion of Golgi enzymes with the endoplasmic reticulum (ER). This delay was not caused by an alteration in the formation of the BFA-induced tubules from the Golgi complex. In addition, the Shiga toxin fragment B transport from the Golgi complex to the ER was also altered. This impairment in the retrograde protein transport was not due to depletion of intracellular calcium stores or to the activation of Rho kinase. Neither the reassembly of the Golgi complex after BFA removal nor VSV-G transport from ER to the Golgi was altered in cells treated with BDM/ML7 or expressing MRLC2(AA). Finally, transport carriers containing Shiga toxin did not move into the cytosol at the tips of comet tails of polymerizing actin. Collectively, the results indicate that 1) myosin motors move to transport carriers from the Golgi complex to the ER along actin filaments; 2) nonmuscle myosin II mediates in this process; and 3) actin comets are not involved in retrograde transport. 相似文献
970.
We analyzed the role of the C677T polymorphism of the 5,10-methylenetetrahydrofolate and the A66G polymorphism of the methionine synthase reductase genes as risk factors for occurrence of spina bifida. The studied population included 106 mothers and 104 children from affected families, and a control group of 100 adults. We found statistically significant differences between the occurrence of the homozygosity in these polymorphisms in the groups of mothers and children with thoracolumbal defects (C677T polymorphism) and lumbosacral defects (A66G polymorphism). We postulate that these polymorphisms should be regarded as independent risk factors for spina bifida. 相似文献