全文获取类型
收费全文 | 1069篇 |
免费 | 65篇 |
出版年
2023年 | 7篇 |
2022年 | 10篇 |
2021年 | 16篇 |
2020年 | 10篇 |
2019年 | 13篇 |
2018年 | 17篇 |
2017年 | 15篇 |
2016年 | 26篇 |
2015年 | 53篇 |
2014年 | 34篇 |
2013年 | 67篇 |
2012年 | 71篇 |
2011年 | 60篇 |
2010年 | 35篇 |
2009年 | 41篇 |
2008年 | 69篇 |
2007年 | 61篇 |
2006年 | 55篇 |
2005年 | 62篇 |
2004年 | 50篇 |
2003年 | 36篇 |
2002年 | 37篇 |
2001年 | 18篇 |
2000年 | 26篇 |
1999年 | 19篇 |
1998年 | 7篇 |
1996年 | 4篇 |
1995年 | 9篇 |
1994年 | 4篇 |
1993年 | 11篇 |
1992年 | 19篇 |
1991年 | 14篇 |
1990年 | 12篇 |
1989年 | 9篇 |
1988年 | 10篇 |
1987年 | 9篇 |
1986年 | 6篇 |
1985年 | 10篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 10篇 |
1981年 | 5篇 |
1979年 | 7篇 |
1978年 | 8篇 |
1977年 | 8篇 |
1976年 | 10篇 |
1975年 | 6篇 |
1973年 | 6篇 |
1971年 | 5篇 |
1970年 | 9篇 |
排序方式: 共有1134条查询结果,搜索用时 15 毫秒
991.
992.
Four Na+/H+ antiporters, Mrp, TetA(L), NhaC, and MleN have so far been described in Bacillus subtilis 168. We identified an additional Na+/H+ antiporter, YvgP, from B. subtilis that exhibits homology to the cation: proton antiporter-1 (CPA-1) family. The yvgP-dependent complementation observed in a Na+(Ca2+)/H+ antiporter-defective Escherichia coli mutant (KNabc) suggested that YvgP effluxed Na+ and Li+. In addition, effects of yvgP expression on a K+ uptake-defective mutant of E. coli indicated that YvgP also supported K+ efflux. In a fluorescence-based assay of everted membrane vesicles prepared from E. coli KNabc transformants, YvgP-dependent Na+ (K+, Li+, Rb+)/H+ antiport activity was demonstrated. Na+ (K+, Li+)/H+ activity was higher at pH 8.5 than at pH 7.5. Mg2+, Ca2+ and Mn2+ did not serve as substrates but they inhibited YvgP antiport activities. Studies of yvgP expression in B. subtilis, using a reporter gene fusion, showed a significant constitutive level of expression that was highest in stationary phase,
increasing as stationary phase progressed. In addition, the expression level was significantly increased in the presence of
added K+ and Na+. 相似文献
993.
994.
995.
Shirata N Kudoh A Daikoku T Tatsumi Y Fujita M Kiyono T Sugaya Y Isomura H Ishizaki K Tsurumi T 《The Journal of biological chemistry》2005,280(34):30336-30341
Eukaryotic cells are equipped with machinery to monitor and repair damaged DNA. Herpes simplex virus (HSV) DNA replication occurs at discrete sites in nuclei, the replication compartment, where viral replication proteins cluster and synthesize a large amount of viral DNA. In the present study, HSV infection was found to elicit a cellular DNA damage response, with activation of the ataxia-telangiectasia-mutated (ATM) signal transduction pathway, as observed by autophosphorylation of ATM and phosphorylation of multiple downstream targets including Nbs1, Chk2, and p53, while infection with a UV-inactivated virus or with a replication-defective virus did not. Activated ATM and the DNA damage sensor MRN complex composed of Mre11, Rad50, and Nbs1 were recruited and retained at sites of viral DNA replication, probably recognizing newly synthesized viral DNAs as abnormal DNA structures. These events were not observed in ATM-deficient cells, indicating ATM dependence. In Nbs1-deficient cells, HSV infection induced an ATM DNA damage response that was delayed, suggesting a functional MRN complex requirement for efficient ATM activation. However, ATM silencing had no effect on viral replication in 293T cells. Our data open up an interesting question of how the virus is able to complete its replication, although host cells activate ATM checkpoint signaling in response to the HSV infection. 相似文献
996.
Kudoh A Fujita M Zhang L Shirata N Daikoku T Sugaya Y Isomura H Nishiyama Y Tsurumi T 《The Journal of biological chemistry》2005,280(9):8156-8163
When exposed to genotoxic stress, eukaryotic cells demonstrate a DNA damage response with delay or arrest of cell-cycle progression, providing time for DNA repair. Induction of the Epstein-Barr virus (EBV) lytic program elicited a cellular DNA damage response, with activation of the ataxia telangiectasia-mutated (ATM) signal transduction pathway. Activation of the ATM-Rad3-related (ATR) replication checkpoint pathway, in contrast, was minimal. The DNA damage sensor Mre11-Rad50-Nbs1 (MRN) complex and phosphorylated ATM were recruited and retained in viral replication compartments, recognizing newly synthesized viral DNAs as abnormal DNA structures. Phosphorylated p53 also became concentrated in replication compartments and physically interacted with viral BZLF1 protein. Despite the activation of ATM checkpoint signaling, p53-downstream signaling was blocked, with rather high S-phase CDK activity associated with progression of lytic infection. Therefore, although host cells activate ATM checkpoint signaling with response to the lytic viral DNA synthesis, the virus can skillfully evade this host checkpoint security system and actively promote an S-phase-like environment advantageous for viral lytic replication. 相似文献
997.
Manago Y Kanahori Y Shimada A Sato A Amano T Sato-Sano Y Setsuie R Sakurai M Aoki S Wang YL Osaka H Wada K Noda M 《Journal of neurochemistry》2005,92(5):1061-1072
Mammalian neuronal cells abundantly express a de-ubiquitinating isozyme, ubiquitin carboxy-terminal hydrolase L1 (UCH L1). Loss of UCH L1 function causes dying-back type of axonal degeneration. However, the function of UCH L1 in neuronal cells remains elusive. Here we show that overexpression of UCH L1 potentiated ATP-induced currents due to the activation of P2X receptors that are widely distributed in the brain and involved in various biological activities including neurosecretion. ATP-induced inward currents were measured in mock-, wild-type or mutant (C90S)-UCH L1-transfected PC12 cells under the conventional whole-cell patch clamp configuration. The amplitude of ATP-induced currents was significantly greater in both wild-type and C90S UCH L1-transfected cells, suggesting that hydrolase activity was not involved but increased level of mono-ubiquitin might play an important role. The increased currents were dependent on cAMP-dependent protein kinase (PKA) and Ca2+ and calmodulin-dependent protein kinase (CaMKII) but not protein kinase C. In addition, ATP-induced currents were likely to be modified via dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32) that is regulated by PKA and phosphatases. Our finding shows the first evidence that there is a relationship between UCH L1 and neurotransmitter receptor, suggesting that UCH L1 may play an important role in synaptic activity. 相似文献
998.
Kuwashima N Nishimura F Eguchi J Sato H Hatano M Tsugawa T Sakaida T Dusak JE Fellows-Mayle WK Papworth GD Watkins SC Gambotto A Pollack IF Storkus WJ Okada H 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(4):2730-2740
We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-alpha. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin-/-, IFN-gamma-/-, or FasL-/- mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-alpha and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways. 相似文献
999.
1000.
Kawakami A Hida A Yamasaki S Miyashita T Nakashima K Tanaka F Ida H Furuyama M Migita K Origuchi T Eguchi K 《Biochemical and biophysical research communications》2002,296(1):26-31
1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) is a synthetic inhibitor toward glucosyl transferase. Here, we showed the functional role of sphingolipids on CD54 expression of endothelial cells (ECs) by the use of PDMP. CD54 mRNA expression in human umbilical vein endothelial cells (HUVECs) was not changed by PDMP; however, PDMP treatment significantly enhanced the expression of membrane-bound CD54 (mCD54) on HUVECs. In contrast, the amount of soluble form of CD54 (sCD54) in the culture supernatants of HUVECs was diminished by PDMP. Similar results were obtained when HUVECs were incubated with metalloproteinase inhibitor, KB-R8301, or in the presence of C2-ceramide. The above effect of PDMP, KB-R8301, and C2-ceramide in HUVECs was commonly found in unstimulated, TNF-alpha-stimulated, and IL-1beta-stimulated HUVECs. These data provide the possibility that the shedding of mCD54 into sCD54 by metalloproteinase-like enzyme is inhibited by PDMP, in which PDMP-induced accumulation of ceramide may act as a second messenger. 相似文献