全文获取类型
收费全文 | 3716篇 |
免费 | 259篇 |
国内免费 | 2篇 |
出版年
2023年 | 15篇 |
2022年 | 41篇 |
2021年 | 76篇 |
2020年 | 63篇 |
2019年 | 68篇 |
2018年 | 60篇 |
2017年 | 58篇 |
2016年 | 105篇 |
2015年 | 164篇 |
2014年 | 189篇 |
2013年 | 243篇 |
2012年 | 308篇 |
2011年 | 300篇 |
2010年 | 174篇 |
2009年 | 144篇 |
2008年 | 244篇 |
2007年 | 200篇 |
2006年 | 193篇 |
2005年 | 189篇 |
2004年 | 165篇 |
2003年 | 138篇 |
2002年 | 131篇 |
2001年 | 74篇 |
2000年 | 58篇 |
1999年 | 61篇 |
1998年 | 34篇 |
1997年 | 33篇 |
1996年 | 11篇 |
1995年 | 26篇 |
1994年 | 16篇 |
1993年 | 19篇 |
1992年 | 27篇 |
1991年 | 34篇 |
1990年 | 22篇 |
1989年 | 21篇 |
1988年 | 31篇 |
1987年 | 14篇 |
1986年 | 8篇 |
1985年 | 13篇 |
1984年 | 16篇 |
1983年 | 11篇 |
1982年 | 16篇 |
1981年 | 12篇 |
1978年 | 8篇 |
1976年 | 7篇 |
1975年 | 14篇 |
1974年 | 9篇 |
1973年 | 8篇 |
1968年 | 15篇 |
1964年 | 7篇 |
排序方式: 共有3977条查询结果,搜索用时 187 毫秒
991.
Erika Cione Attilio Pingitore Francesco Genchi Giuseppe Genchi 《The international journal of biochemistry & cell biology》2010,42(1):106-112
The adenine nucleotide translocator (ANT) accomplishes the exchange of ATP from the mitochondrial matrix with cytoplasmic ADP. While investigating the biochemical mechanism of retinoic acid (RA) on the ANT via retinoylation, we have found and subsequently demonstrated a positive influence of Coenzyme A (CoA) on the transport of ATP across the membranes of rat liver mitochondria. CoA enhances ANT activity in a dose-dependent manner modifying the Vmax (673.3 ± 20.7 nmol ATP/mg protein/min versus 155.0 ± 1.9 nmol ATP/mg protein/min), the IC50 for the specific inhibitor carboxyatractyloside (CATR) (0.142 ± 0.012 μM versus 0.198 ± 0.011 μM) but not the Km (22.50 ± 0.52 μM versus 22.19 ± 0.98 μM). Data suggest a likely enzymatic involvement in the interaction between ANT and CoA. The effect of CoA is observed in mitochondria from several different tissues. 相似文献
992.
Notch signaling is critical to animal development, and its dysregulation leads to human maladies ranging from birth defects to cancer. Although endocytosis is currently thought to promote signal activation by delivering activated Notch to endosome‐localized γ‐secretase, the data are controversial and the mechanisms that control Notch endocytosis remain poorly defined. Here, we investigated the relationship between Notch internalization and signaling. siRNA‐mediated depletion studies reveal that Notch endocytosis is clathrin‐dependent and requires epsin1, the adaptor protein complex (AP2) and Nedd4. Moreover, we show that epsin1 interaction with Notch is ubiquitin‐dependent. Contrary to the current model, we show that internalization defects lead to elevated γ‐secretase‐mediated Notch processing and downstream signaling. These results indicate that signal activation occurs independently of Notch endocytosis and that γ‐secretase cleaves Notch at the plasma membrane. These observations support a model where endocytosis serves to downregulate Notch in signal‐receiving cells. 相似文献
993.
Shannon Kidd Lisa Caldwell Martin Dietrich Ismael Samudio Erika L Spaeth Keri Watson Yuexi Shi James Abbruzzese Marina Konopleva Michael Andreeff Frank C Marini 《Cytotherapy》2010,12(5):615-625
Background aimsBecause of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression.MethodsHuman pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-β were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase.ResultsMSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P = 0.032). The production of IFN-β within the tumor site by MSC–IFN-β further suppressed tumor growth (P = 0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFκB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC–IFN-β injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC–IFN-β alone (P = 0.041).ConclusionsThese results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-β for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents. 相似文献
994.
995.
Erika Kovacs Judit T��th Be��ta G. V��rtessy K��roly Liliom 《The Journal of biological chemistry》2010,285(3):1799-1808
Previously we have identified the lipid mediator sphingosylphosphorylcholine (SPC) as the first potentially endogenous inhibitor of the ubiquitous Ca2+ sensor calmodulin (CaM) (Kovacs, E., and Liliom, K. (2008) Biochem. J. 410, 427–437). Here we give mechanistic insight into CaM inhibition by SPC, based on fluorescence stopped-flow studies with the model CaM-binding domain melittin. We demonstrate that both the peptide and SPC micelles bind to CaM in a rapid and reversible manner with comparable affinities. Furthermore, we present kinetic evidence that both species compete for the same target site on CaM, and thus SPC can be considered as a competitive inhibitor of CaM-target peptide interactions. We also show that SPC disrupts the complex of CaM and the CaM-binding domain of ryanodine receptor type 1, inositol 1,4,5-trisphosphate receptor type 1, and the plasma membrane Ca2+ pump. By interfering with these interactions, thus inhibiting the negative feedback that CaM has on Ca2+ signaling, we hypothesize that SPC could lead to Ca2+ mobilization in vivo. Hence, we suggest that the action of the sphingolipid on CaM might explain the previously recognized phenomenon that SPC liberates Ca2+ from intracellular stores. Moreover, we demonstrate that unlike traditional synthetic CaM inhibitors, SPC disrupts the complex between not only the Ca2+-saturated but also the apo form of the protein and the target peptide, suggesting a completely novel regulation for target proteins that constitutively bind CaM, such as ryanodine receptors. 相似文献
996.
Lorena Rodríguez-Gallego Erika Meerhoff Juan M. Clemente Daniel Conde 《Hydrobiologia》2010,646(1):253-269
Hydrology is often the main determinant of water chemistry and structure of the aquatic communities in coastal lagoons, driven
by the interaction of freshwater load from the catchment and marine intrusions. However, submerged aquatic vegetation (SAV)
can have important local effects on both features, even during sporadically and short proliferations. A SAV summer proliferation
was observed during 2003 in a coastal lagoon in Uruguay (Laguna de Rocha), increasing macrophyte cover and biomass in the
less saline zones. SAV summer proliferations were first observed in summer 2001, with no records prior. The aim of this paper
is to describe the ephemeral proliferation of SAV in this shallow brackish lagoon and to analyze its effects on the abiotic
environment and on the zoobenthic community. Vegetated and unvegetated zones were sampled in the northern more limnic area
(9.1 mS cm−1 ± 4.8) and the southern brackish area (20.9 mS cm−1 ± 5.2). Water and sediment chemistry were analyzed by standard methods and benthos and plants were collected with an Ekman
grab. During SAV proliferation, suspended solids were five times lower inside macrophyte patches and water column total phosphorus
and nitrogen were three and two times lower, respectively. Zoobenthos abundance and richness were higher in vegetated patches.
However, no differences were found between sampling sites in the more brackish southern area and in the North after the SAV
proliferation ended. This indicates that SAV can influence water chemistry and benthos structure above a biomass threshold
of 100 g DW m−2. Although hydrology is the driving force regulating communities and water chemistry in these coastal lagoons, our results
showed that SAV can also be an important local factor above a certain biomass threshold. 相似文献
997.
Kosuke Miyauchi A Rachael Curran Yufei Long Naoyuki Kondo Aikichi Iwamoto Donald M Engelman Zene Matsuda 《Retrovirology》2010,7(1):1-12
Background
Each of the pathogenic human retroviruses (HIV-1/2 and HTLV-1) has a nonhuman primate counterpart, and the presence of these retroviruses in humans results from interspecies transmission. The passage of another simian retrovirus, simian foamy virus (SFV), from apes or monkeys to humans has been reported. Mandrillus sphinx, a monkey species living in central Africa, is naturally infected with SFV. We evaluated the natural history of the virus in a free-ranging colony of mandrills and investigated possible transmission of mandrill SFV to humans.Results
We studied 84 semi-free-ranging captive mandrills at the Primate Centre of the Centre International de Recherches Médicales de Franceville (Gabon) and 15 wild mandrills caught in various areas of the country. The presence of SFV was also evaluated in 20 people who worked closely with mandrills and other nonhuman primates. SFV infection was determined by specific serological (Western blot) and molecular (nested PCR of the integrase region in the polymerase gene) assays. Seropositivity for SFV was found in 70/84 (83%) captive and 9/15 (60%) wild-caught mandrills and in 2/20 (10%) humans. The 425-bp SFV integrase fragment was detected in peripheral blood DNA from 53 captive and 8 wild-caught mandrills and in two personnel. Sequence and phylogenetic studies demonstrated the presence of two distinct strains of mandrill SFV, one clade including SFVs from mandrills living in the northern part of Gabon and the second consisting of SFV from animals living in the south. One man who had been bitten 10 years earlier by a mandrill and another bitten 22 years earlier by a macaque were found to be SFV infected, both at the Primate Centre. The second man had a sequence close to SFVmac sequences. Comparative sequence analysis of the virus from the first man and from the mandrill showed nearly identical sequences, indicating genetic stability of SFV over time.Conclusion
Our results show a high prevalence of SFV infection in a semi-free-ranging colony of mandrills, with the presence of two different strains. We also showed transmission of SFV from a mandrill and a macaque to humans. 相似文献998.
Kaya T Ishizawa Hiroaki Kumano Atsushi Sato Hiroshi Sakura Yasuhiko Iwamoto 《BioPsychoSocial medicine》2010,4(1):1
Background
This study was performed to examine whether patients with type 2 diabetes have cognitive deficits associated with the prefrontal cortex (PFC). 相似文献999.
1000.