全文获取类型
收费全文 | 7449篇 |
免费 | 1043篇 |
出版年
2023年 | 39篇 |
2022年 | 89篇 |
2021年 | 175篇 |
2020年 | 108篇 |
2019年 | 141篇 |
2018年 | 157篇 |
2017年 | 120篇 |
2016年 | 230篇 |
2015年 | 375篇 |
2014年 | 428篇 |
2013年 | 463篇 |
2012年 | 664篇 |
2011年 | 646篇 |
2010年 | 434篇 |
2009年 | 356篇 |
2008年 | 455篇 |
2007年 | 507篇 |
2006年 | 509篇 |
2005年 | 522篇 |
2004年 | 463篇 |
2003年 | 377篇 |
2002年 | 411篇 |
2001年 | 52篇 |
2000年 | 35篇 |
1999年 | 65篇 |
1998年 | 73篇 |
1997年 | 51篇 |
1996年 | 45篇 |
1995年 | 41篇 |
1994年 | 40篇 |
1993年 | 40篇 |
1992年 | 44篇 |
1991年 | 22篇 |
1990年 | 24篇 |
1989年 | 25篇 |
1988年 | 17篇 |
1987年 | 27篇 |
1986年 | 24篇 |
1985年 | 18篇 |
1984年 | 18篇 |
1983年 | 11篇 |
1982年 | 19篇 |
1981年 | 17篇 |
1980年 | 20篇 |
1979年 | 15篇 |
1978年 | 12篇 |
1977年 | 9篇 |
1976年 | 11篇 |
1975年 | 8篇 |
1974年 | 9篇 |
排序方式: 共有8492条查询结果,搜索用时 46 毫秒
981.
Schaefer TL Skelton MR Herring NR Gudelsky GA Vorhees CV Williams MT 《Journal of neurochemistry》2008,104(6):1674-1685
Rats treated with (±)-3,4-methylenedioxymethamphetamine (MDMA) or (+)-methamphetamine (MA) neonatally exhibit long-lasting learning impairments (i.e., after treatment on postnatal days (P)11–15 or P11–20). Although both drugs are substituted amphetamines, they each produce a unique profile of cognitive deficits (i.e., spatial vs. path integration learning and severity of deficits) which may be the result of differential early neurochemical changes. We previously showed that MA and MDMA increase corticosterone (CORT) and MDMA reduces levels of serotonin (5-HT) 24 h after treatment on P11, however, learning deficits are seen after 5 or 10 days of drug treatment, not just 1 day. Accordingly, in the present experiment, rats were treated with MA or MDMA starting on P11 for 5 or 10 days (P11–15 or P11–20) and tissues collected on P16, P21, or P30. Five-day MA administration dramatically increased CORT on P16, whereas MDMA did not. Both drugs decreased hippocampal 5-HT on P16 and P21, although MDMA produced larger reductions. Ten-day treatment with either drug increased dopamine utilization in the neostriatum on P21, whereas 5-day treatment had no effect. No CORT or brain 5-HT or dopamine changes were found with either drug on P30. Although the monoamine changes are transient, they may alter developing neural circuits sufficiently to permanently disrupt later learning and memory abilities. 相似文献
982.
Hennigs JK Burhenne N Stähler F Winnig M Walter B Meyerhof W Schmale H 《Journal of neurochemistry》2008,106(5):2249-2262
In a search for sweet taste receptor interacting proteins, we have identified the calcium- and integrin-binding protein 1 (CIB1) as specific binding partner of the intracellular carboxyterminal domain of the rat sweet taste receptor subunit Tas1r2. In heterologous human embryonic kidney 293 (HEK293) cells, the G protein chimeras Gα16gust44 and Gα15i3 link the sweet taste receptor dimer TAS1R2/TAS1R3 to an inositol 1,4,5-trisphosphate (InsP3 )-dependent Ca2+ release pathway. To demonstrate the influence of CIB1 on the cytosolic Ca2+ concentration, we used sweet and umami compounds as well as other InsP3 -generating ligands in FURA-2-based Ca2+ assays in wild-type HEK293 cells and HEK293 cells expressing functional human sweet and umami taste receptor dimers. Stable and transient depletion of CIB1 by short-hairpin RNA increased the Ca2+ response of HEK293 cells to the InsP3 -generating ligands ATP, UTP and carbachol. Over-expression of CIB1 had the opposite effect as shown for the sweet ligand saccharin, the umami receptor ligand monosodium glutamate and UTP. The CIB1 effect was dependent on the thapsigargin-sensitive Ca2+ store of the endoplasmic reticulum (ER) and independent of extracellular Ca2+ . The function of CIB1 on InsP3 -evoked Ca2+ release from the ER is most likely mediated by its interaction with the InsP3 receptor. Thus, CIB1 seems to be an inhibitor of InsP3 -dependent Ca2+ release in vivo . 相似文献
983.
Li Z Zharikova A Bastian J Esperon L Hebert N Mathes C Rowland NE Peris J 《Journal of neurochemistry》2008,106(1):170-181
Capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF) provides 15-s temporal resolution of amino acid levels in microdialysate, which, for the first time, allows almost real time measurement of changes during episodes of behavior. We trained Sprague-Dawley rats to self-administer either 10% ethanol-containing gelatin or non-alcoholic gelatin in a typical operant chamber. After rats reached stable daily levels of responding, microdialysis probes were inserted into nucleus accumbens and samples were collected before, during and after operant sessions with on-line analysis via CE-LIF. During the first 15 min of the operant session, there was a significant increase in taurine that correlated with the amount of ethanol consumed ( R 2 = 0.81) but no change in rats responding for plain gel. There were large, consistent increases in glycine in both the ethanol and plain gel groups which correlated with the amount of gel consumed. A smaller increase was observed in rats with free non-operant access to plain gel compared to the increase seen with the same amount of gel consumed under operant conditions. When rats were given a time out after each delivery of gel in the operant protocol, the greatest increase of glycine was obtained with the longest time out period. Thus, increases in glycine in nucleus accumbens appear to be related to anticipation of reinforcement. 相似文献
984.
985.
Kedzierska K Thomas PG Venturi V Davenport MP Doherty PC Turner SJ La Gruta NL 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(4):2556-2562
Virus-immune CD8(+) TCR repertoires specific for particular peptide-MHC class I complexes may be substantially shared between (public), or unique to, individuals (private). Because public TCRs can show reduced TdT-mediated N-region additions, we analyzed how TdT shapes the heavily public (to D(b)NP(366)) and essentially private (to D(b)PA(224)) CTL repertoires generated following influenza A virus infection of C57BL/6 (B6, H2(b)) mice. The D(b)NP(366)-specific CTL response was virtually clonal in TdT(-/-) B6 animals, with one of the three public clonotypes prominent in the wild-type (wt) response consistently dominating the TdT(-/-) set. Furthermore, this massive narrowing of TCR selection for D(b)NP(366) reduced the magnitude of D(b)NP(366)-specific CTL response in the virus-infected lung. Conversely, the D(b)PA(224)-specific responses remained comparable in both magnitude and TCR diversity within individual TdT(-/-) and wt mice. However, the extent of TCR diversity across the total population was significantly reduced, with the consequence that the normally private wt D(b)PA(224)-specific repertoire was now substantially public across the TdT(-/-) mouse population. The key finding is thus that the role of TdT in ensuring enhanced diversity and the selection of private TCR repertoires promotes optimal CD8(+) T cell immunity, both within individuals and across the species as a whole. 相似文献
986.
Neutropenia with impaired immune response to Streptococcus pneumoniae in ceramide kinase-deficient mice 总被引:1,自引:0,他引:1
Graf C Zemann B Rovina P Urtz N Schanzer A Reuschel R Mechtcheriakova D Müller M Fischer E Reichel C Huber S Dawson J Meingassner JG Billich A Niwa S Badegruber R Van Veldhoven PP Kinzel B Baumruker T Bornancin F 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3457-3466
In mammals, ceramide kinase (CerK)-mediated phosphorylation of ceramide is the only known pathway to ceramide-1-phosphate (C1P), a recently identified signaling sphingolipid metabolite. To help delineate the roles of CerK and C1P, we knocked out the gene of CerK in BALB/c mice by homologous recombination. All in vitro as well as cell-based assays indicated that CerK activity is completely abolished in Cerk-/- mice. Labeling with radioactive orthophosphate showed a profound reduction in the levels of de novo C1P formed in Cerk-/- macrophages. Consistently, mass spectrometry analysis revealed a major contribution of CerK to the formation of C16-C1P. However, the significant residual C1P levels in Cerk-/- animals indicate that alternative routes to C1P exist. Furthermore, serum levels of proapoptotic ceramide in these animals were significantly increased while levels of dihydroceramide as the biosynthetic precursor were reduced. Previous literature pointed to a role of CerK or C1P in innate immune cell function. Using a variety of mechanistic and disease models, as well as primary cells, we found that macrophage- and mast cell-dependent readouts are barely affected in the absence of CerK. However, the number of neutrophils was strikingly reduced in blood and spleen of Cerk-/- animals. When tested in a model of fulminant pneumonia, Cerk-/- animals developed a more severe disease, lending support to a defect in neutrophil homeostasis following CerK ablation. These results identify ceramide kinase as a key regulator of C1P, dihydroceramide and ceramide levels, with important implications for neutrophil homeostasis and innate immunity regulation. 相似文献
987.
Shumilina E Lam RS Wölbing F Matzner N Zemtsova IM Sobiesiak M Mahmud H Sausbier U Biedermann T Ruth P Sausbier M Lang F 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(12):8040-8047
Mast cell stimulation by Ag is followed by the opening of Ca(2+)-activated K(+) channels, which participate in the orchestration of mast cell degranulation. The present study has been performed to explore the involvement of the Ca(2+)-activated K(+) channel K(Ca)3.1 in mast cell function. To this end mast cells have been isolated and cultured from the bone marrow (bone marrow-derived mast cells (BMMCs)) of K(Ca)3.1 knockout mice (K(Ca)3.1(-/-)) and their wild-type littermates (K(Ca)3.1(+/+)). Mast cell number as well as in vitro BMMC growth and CD117, CD34, and FcepsilonRI expression were similar in both genotypes, but regulatory cell volume decrease was impaired in K(Ca)3.1(-/-) BMMCs. Treatment of the cells with Ag, endothelin-1, or the Ca(2+) ionophore ionomycin was followed by stimulation of Ca(2+)-activated K(+) channels and cell membrane hyperpolarization in K(Ca)3.1(+/+), but not in K(Ca)3.1(-/-) BMMCs. Upon Ag stimulation, Ca(2+) entry but not Ca(2+) release from intracellular stores was markedly impaired in K(Ca)3.1(-/-) BMMCs. Similarly, Ca(2+) entry upon endothelin-1 stimulation was significantly reduced in K(Ca)3.1(-/-) cells. Ag-induced release of beta-hexosaminidase, an indicator of mast cell degranulation, was significantly smaller in K(Ca)3.1(-/-) BMMCs compared with K(Ca)3.1(+/+) BMMCs. Moreover, histamine release upon stimulation of BMMCs with endothelin-1 was reduced in K(Ca)3.1(-/-) cells. The in vivo Ag-induced decline in body temperature revealed that IgE-dependent anaphylaxis was again significantly (by approximately 50%) blunted in K(Ca)3.1(-/-) mice. In conclusion, K(Ca)3.1 is required for Ca(2+)-activated K(+) channel activity and Ca(2+)-dependent processes such as endothelin-1- or Ag-induced degranulation of mast cells, and may thus play a critical role in anaphylactic reactions. 相似文献
988.
Posevitz V Arndt B Krieger T Warnecke N Schraven B Simeoni L 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(3):1634-1642
The transmembrane adaptor protein SIT is a negative regulator of TCR-mediated signaling. However, little is known about the functional role of SIT in mature T cells. In this study, we show that mice deficient for SIT display a decreased number of naive CD8(+) T cells and a progressive accumulation of memory-like (CD44(high)) CD8(+) T lymphocytes that resemble cells undergoing homeostatic proliferation. Indeed, when transferred into lymphopenic hosts, SIT(-/-) naive CD8(+) T cells undergo enhanced homeostatic proliferation and express a higher level of CD44 in comparison to wild-type T cells. By using class-I-restricted TCR transgenic models with different ligand affinity/avidity, we show that lymphopenia-induced homeostatic proliferation is more pronounced in cells carrying low-affinity TCRs. Strikingly, the loss of SIT induces homeostatic proliferation of HY TCR transgenic cells, which are normally unable to proliferate in lymphopenic mice. Collectively, these data demonstrate that SIT negatively regulates T cell homeostasis. Finally, we show that SIT-deficient T cells develop a mechanism analogous to sensory adaptation as they up-regulate CD5, down-regulate the coreceptor, and display impaired TCR-mediated ZAP-70 activation. 相似文献
989.
Papillomavirus E6 proteins are adapters that change the function of cellular regulatory proteins. The bovine papillomavirus type 1 E6 (BE6) binds to LXXLL peptide sequences termed LD motifs (consensus sequence LDXLLXXL) on the cellular protein paxillin that is a substrate of Src and focal adhesion kinases. Anchorage-independent transformation induced by BE6 required both paxillin and BE6-binding LD motifs on paxillin but was independent of the major tyrosine phosphorylation sites of paxillin. The essential role of paxillin in transformation by BE6 highlights the role of paxillin in the transduction of cellular signals that result in anchorage-independent cell proliferation. 相似文献
990.
Yap MW Lindemann D Stanke N Reh J Westphal D Hanenberg H Ohkura S Stoye JP 《Journal of virology》2008,82(11):5429-5439
Foamy viruses (FVs) are unconventional retroviruses with a replication strategy that is significantly different from orthoretroviruses and bears some homology to that of hepadnaviruses. Although some cellular proteins, such as APOBEC3, have been reported to block FVs, no restriction by Trim5alpha has been described to date. The sensitivity of three FV isolates of human-chimpanzee or prototypic (PFV), macaque (SFVmac), and feline (FFV) origin to a variety of primate Trim5alphas was therefore tested. PFV and SFVmac were restricted by Trim5alphas from most New World monkeys, but not from other primates, whereas FFV-based vectors were restricted by Trim5alphas from the great apes gorilla and orangutan. Trim5alphas from Old World monkeys did not restrict any FV isolate tested. Capuchin Trim5alpha was unique, as it restricted SFVmac and FFV but not PFV. Trim5alpha specificity for FVs was determined by the B30.2 domain, interestingly involving, in some instances, the same residues of the variable regions previously implicated as major determinants for human immunodeficiency virus type 1 restriction. FVs with chimeric Gags were made to map the viral determinants of sensitivity to restriction. The N-terminal half of the Gag molecule was found to contain the regions that control susceptibility. This region most likely corresponds to the capsid of conventional retroviruses. Due to their unique replication strategy, FVs should provide a valuable new system to examine the mechanism of retroviral restriction by Trim5alpha. 相似文献