全文获取类型
收费全文 | 114606篇 |
免费 | 7293篇 |
国内免费 | 21篇 |
专业分类
121920篇 |
出版年
2023年 | 561篇 |
2022年 | 414篇 |
2021年 | 1001篇 |
2020年 | 928篇 |
2019年 | 937篇 |
2018年 | 2613篇 |
2017年 | 2315篇 |
2016年 | 3242篇 |
2015年 | 4832篇 |
2014年 | 4887篇 |
2013年 | 6604篇 |
2012年 | 8230篇 |
2011年 | 7892篇 |
2010年 | 4932篇 |
2009年 | 3532篇 |
2008年 | 6488篇 |
2007年 | 6533篇 |
2006年 | 6028篇 |
2005年 | 5686篇 |
2004年 | 5373篇 |
2003年 | 5014篇 |
2002年 | 4644篇 |
2001年 | 2488篇 |
2000年 | 2659篇 |
1999年 | 2119篇 |
1998年 | 808篇 |
1997年 | 623篇 |
1996年 | 545篇 |
1995年 | 554篇 |
1994年 | 575篇 |
1993年 | 440篇 |
1992年 | 1271篇 |
1991年 | 1194篇 |
1990年 | 1055篇 |
1989年 | 987篇 |
1988年 | 947篇 |
1987年 | 804篇 |
1986年 | 743篇 |
1985年 | 810篇 |
1984年 | 707篇 |
1983年 | 593篇 |
1982年 | 457篇 |
1981年 | 462篇 |
1979年 | 614篇 |
1978年 | 485篇 |
1977年 | 440篇 |
1976年 | 418篇 |
1975年 | 469篇 |
1974年 | 496篇 |
1973年 | 511篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
991.
Bcl-XL is a pro-survival member of the Bcl-2 family that can be found in the outer mitochondrial membrane and in soluble cytosolic homodimers. Bcl-XL can bind pro-apoptotic members of this family preventing them from activating the execution phase of apoptosis. Bcl-XL has been shown to homodimerize in different ways, although most binding and structural assays have been carried out in the absence of its carboxyl terminal transmembrane domain. We show here that this domain can by itself direct protein oligomerization, which could be related to its previously reported role in mitochondrial morphology alterations and apoptosis inhibition. 相似文献
992.
Our understanding of the evolution of the insulin signaling pathway (ISP) is still incomplete. One intriguing unanswered question is the explanation of the emergence of the glucostatic role of insulin in mammals. To find out whether this is due to the development of new sets of signaling transduction elements in these organisms, or to the establishment of new interactions between pre-existing proteins, we rebuilt putative orthologous ISPs in 17 eukaryotic organisms. Then, we computed the conservation of orthologous ISPs at different levels, from sequence similarity of orthologous proteins to co-evolution of interacting domains. We found that the emergence of glucostatic role in mammals can neither be explained by the development of new sets of signaling elements, nor by the establishment of new interactions between pre-existing proteins. The comparison of orthologous IRS molecules indicates that only in mammals have they acquired their complete functionality as efficient recruiters of effector sub-pathways. 相似文献
993.
Sérgio M. Santos Sadaki Yokota Shrivallabh P. Kamat José A. S. Cavaleiro Tomonori Motokawa Tomomi Kato Mayu Mochizuki Toshiyuki Fujiwara Yuki Fujii Yoshitaka Tanaka 《Pigment cell & melanoma research》2014,27(3):376-386
Tyrosinase, a melanosomal membrane protein containing copper, is a key enzyme for melanin synthesis in melanocytes. Inulavosin inhibits melanogenesis by enhancing a degradation of tyrosinase in lysosomes. However, the mechanism by which inulavosin redirects tyrosinase to lysosomes is yet unknown. The analyses of structure–activity relationship of inulavosin and its benzo‐derivatives reveal that the hydroxyl and the methyl groups play a critical role in their inhibitory activity. Intriguingly, the docking studies to tyrosinase suggest that the compounds showing inhibitory activity bind through hydrophobic interactions to the cavity of tyrosinase below which the copper‐binding sites are located. This cavity is proposed to be required for the association with a chaperon that assists in copper loading to tyrosinase in Streptomyces antibioticus. Inulavosin and its benzo‐derivatives may compete with the copper chaperon and result in a lysosomal mistargeting of apo‐tyrosinase that has a conformational defect. 相似文献
994.
In higher plants, the PII protein is a nuclear-encoded plastid protein that regulates the activity of a key enzyme of arginine biosynthesis. We have previously observed that Arabidopsis PII mutants are more sensitive to nitrite toxicity. Using intact chloroplasts isolated from Arabidopsis leaves and (15)N-labelled nitrite we show that a light-dependent nitrite uptake into chloroplasts is increased in PII knock-out mutants when compared to the wild-type. This leads to a higher incorporation of (15)N into ammonium and amino acids in the mutant chloroplasts. However, the uptake differences do not depend on GS/GOGAT activities. Our observations suggest that PII is involved in the regulation of nitrite uptake into higher plant chloroplasts. 相似文献
995.
Effects of mechanical stress on Anammox granules in a sequencing batch reactor (SBR) 总被引:1,自引:0,他引:1
The effect of shear stress on Anammox process was studied in a sequencing batch reactor (SBR). The reactor was operated during 218 days under different stirring speeds (60-250 rpm) in order to expose the system to different shear conditions and to study the stability of the Anammox granules referred to their biological activity and size. The nitrogen loading rate (NLR) fed to the SBR was kept around 0.3g N(L day)(-1). The nitrite (limiting substrate) removal percentage was 98% during most of the operational period. The specific Anammox activity of the biomass was practically constant and around 0.4 g N(g VSSday)(-1) and the average feret diameter of the formed granules was 0.64 mm. Obtained results indicated that stirring speeds up to 180 rpm have no negative effect on the performance of the Anammox process, whereas Anammox activity decreased to 40% when a rotating speed of 250 rpm was tested and the average diameter decreased in 45%, the concentration of solids in the effluent increased to 0.2g TSSL(-1) and nitrite was accumulated in the reactor up to 60 mg NL(-1). 相似文献
996.
Jeff A. O'Meara Christopher T. Lemke Cédrickx Godbout George Kukolj Lisette Lagacé Beno?t Moreau Diane Thibeault Peter W. White Montse Llinàs-Brunet 《The Journal of biological chemistry》2013,288(8):5673-5681
Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms. 相似文献
997.
998.
Ekaterini Blaveri Fiona Kelly Alessandra Mallei Kriss Harris Adam Taylor Juliet Reid Maria Razzoli Lucia Carboni Chiara Piubelli Laura Musazzi Girogio Racagni Aleksander Mathé Maurizio Popoli Enrico Domenici Stewart Bates 《PloS one》2010,5(9)
Background
The Flinders model is a validated genetic rat model of depression that exhibits a number of behavioural, neurochemical and pharmacological features consistent with those observed in human depression.Principal Findings
In this study we have used genome-wide microarray expression profiling of the hippocampus and prefrontal/frontal cortex of Flinders Depression Sensitive (FSL) and control Flinders Depression Resistant (FRL) lines to understand molecular basis for the differences between the two lines. We profiled two independent cohorts of Flinders animals derived from the same colony six months apart, each cohort statistically powered to allow independent as well as combined analysis. Using this approach, we were able to validate using real-time-PCR a core set of gene expression differences that showed statistical significance in each of the temporally distinct cohorts, representing consistently maintained features of the model. Small but statistically significant increases were confirmed for cholinergic (chrm2, chrna7) and serotonergic receptors (Htr1a, Htr2a) in FSL rats consistent with known neurochemical changes in the model. Much larger gene changes were validated in a number of novel genes as exemplified by TMEM176A, which showed 35-fold enrichment in the cortex and 30-fold enrichment in hippocampus of FRL animals relative to FSL.Conclusions
These data provide significant insights into the molecular differences underlying the Flinders model, and have potential relevance to broader depression research. 相似文献999.
Veera?KarkamoEmail author Anu?Kaistinen Anu?N?reaho Kati?Dillard Katri?Vainio-Siukola Gabriele?Vidgrén Niina?Tuoresm?ki Marjukka?Anttila 《Acta veterinaria Scandinavica》2014,56(1):84
Background
Leishmania spp. are zoonotic protozoans that infect humans and other mammals such as dogs. The most significant causative species in dogs is L. infantum. In dogs, leishmaniosis is a potentially progressive, chronic disease with varying clinical outcomes. Autochthonous cases of canine leishmaniosis have not previously been reported in the Nordic countries.Results
In this report we describe the first diagnosed autochthonous cases of canine leishmaniosis in Finland, in which transmission via a suitable arthropod vector was absent. Two Finnish boxers that had never been in endemic areas of Leishmania spp., had never received blood transfusions, nor were infested by ectoparasites were diagnosed with leishmaniosis. Another dog was found with elevated Leishmania antibodies. A fourth boxer dog that had been in Spain was considered to be the source of these infections. Transmission occurred through biting wounds and semen, however, transplacental infection in one of the dogs could not be ruled out.Two of the infected dogs developed a serious disease and were euthanized and sent for necropsy. The first one suffered from membranoproliferative glomerulonephritis and the second one had a chronic systemic disease. Leishmania sp. was detected from tissues by PCR and/or IHC in both dogs. The third infected dog was serologically positive for Leishmania sp. but remained free of clinical signs.Conclusions
This case report shows that imported Leishmania-infected dogs may pose a risk for domestic dogs, even without suitable local arthropod vectors.1000.
Autocrine activation of adenosine A1 receptors blocks D1A but not D1B dopamine receptor desensitization 总被引:1,自引:0,他引:1
Adenosine is known to modulate dopamine responses in several brain areas. Here, we show that tonic activation of adenosine receptors is able to impede desensitization of D1 dopamine receptors. As measured by cAMP accumulation in transfected COS-7 cells, long-term exposure to dopamine agonists promoted desensitization of D1B receptor but not that of D1A receptor. The inability of D1A receptor to desensitize was a result of the adenosine present in culture medium acting through activation of adenosine A1 receptors. Cell incubation with either adenosine deaminase, CGS-15943, a generic adenosine receptor antagonist, or the A1 antagonist DPCPX restored the long-term desensitization time-course of D1A receptors. In Ltk cells stably expressing A1 adenosine receptors and D1A dopamine receptors, pre-treatment of cells with R(-)-PIA, a full A1 receptor agonist, did not significantly inhibit the acute increase in cAMP levels induced by D1 receptor agonists, but blocked desensitization of D1A receptors. However, simultaneous activation of A1 and D1A receptors promoted a delayed D1A receptor desensitization. This suggests that functional interaction between A1 and D1A receptors may depend on the activation kinetics of components regulating D1 receptor responses, acting differentially on D1A and D1B receptors. 相似文献