全文获取类型
收费全文 | 976篇 |
免费 | 77篇 |
出版年
2022年 | 7篇 |
2021年 | 16篇 |
2020年 | 10篇 |
2019年 | 9篇 |
2018年 | 26篇 |
2017年 | 18篇 |
2016年 | 27篇 |
2015年 | 32篇 |
2014年 | 40篇 |
2013年 | 71篇 |
2012年 | 65篇 |
2011年 | 72篇 |
2010年 | 28篇 |
2009年 | 36篇 |
2008年 | 62篇 |
2007年 | 59篇 |
2006年 | 42篇 |
2005年 | 50篇 |
2004年 | 35篇 |
2003年 | 29篇 |
2002年 | 46篇 |
2001年 | 26篇 |
2000年 | 37篇 |
1999年 | 24篇 |
1998年 | 8篇 |
1997年 | 10篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 9篇 |
1993年 | 5篇 |
1992年 | 18篇 |
1991年 | 18篇 |
1990年 | 7篇 |
1989年 | 6篇 |
1988年 | 11篇 |
1987年 | 10篇 |
1986年 | 6篇 |
1985年 | 8篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 7篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 7篇 |
1978年 | 5篇 |
1977年 | 3篇 |
1975年 | 4篇 |
1972年 | 3篇 |
1967年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有1053条查询结果,搜索用时 15 毫秒
131.
Activation and translocation of PKCdelta is necessary for VEGF-induced ERK activation through KDR in HEK293T cells 总被引:3,自引:0,他引:3
Kuriyama M Taniguchi T Shirai Y Sasaki A Yoshimura A Saito N 《Biochemical and biophysical research communications》2004,325(3):843-851
VEGF-KDR/Flk-1 signal utilizes the phospholipase C-gamma-protein kinase C (PKC)-Raf-MEK-ERK pathway as the major signaling pathway to induce gene expression and cPLA2 phosphorylation. However, the spatio-temporal activation of a specific PKC isoform induced by VEGF-KDR signal has not been clarified. We used HEK293T (human embryonic kidney) cells expressing transiently KDR to examine the activation mechanism of PKC. PKC specific inhibitors and human PKCdelta knock-down using siRNA method showed that PKCdelta played an important role in VEGF-KDR-induced ERK activation. Myristoylated alanine-rich C-kinase substrate (MARCKS) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC. Translocation of MARCKS-GFP induced by VEGF-KDR stimulus was blocked by rottlerin, a PKCdelta specific inhibitor, or human PKCdelta siRNA. VEGF-KDR stimulation did not induce ERK phosphorylation in human PKCdelta-knockdown HEK293T cells, but co-expression of rat PKCdelta-GFP recovered the ERK phosphorylation. Y311/332F mutant of rat PKCdelta-GFP which cannot be activated by tyrosine-phosphorylation but activated by DAG recovered the ERK phosphorylation, while C1B-deletion mutant of rat PKCdelta-GFP, which can be activated by tyrosine-phosphorylation but not by DAG, failed to recover the ERK phosphorylation in human PKCdelta-knockdown HEK293T cell. These results indicate that PKCdelta is involved in VEGF-KDR-induced ERK activation via C1B domain. 相似文献
132.
Superoxide production at phagosomal cup/phagosome through beta I protein kinase C during Fc gamma R-mediated phagocytosis in microglia 总被引:2,自引:0,他引:2
Ueyama T Lennartz MR Noda Y Kobayashi T Shirai Y Rikitake K Yamasaki T Hayashi S Sakai N Seguchi H Sawada M Sumimoto H Saito N 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(7):4582-4589
Protein kinase C (PKC) plays a prominent role in immune signaling. To elucidate the signal transduction in a respiratory burst and isoform-specific function of PKC during FcgammaR-mediated phagocytosis, we used live, digital fluorescence imaging of mouse microglial cells expressing GFP-tagged molecules. betaI PKC, epsilonPKC, and diacylglycerol kinase (DGK) beta dynamically and transiently accumulated around IgG-opsonized beads (BIgG). Moreover, the accumulation of p47(phox), an essential cytosolic component of NADPH oxidase and a substrate for betaI PKC, at the phagosomal cup/phagosome was apparent during BIgG ingestion. Superoxide (O(2)(-)) production was profoundly inhibited by G?6976, a cPKC inhibitor, and dramatically increased by the DGK inhibitor, R59949. Ultrastructural analysis revealed that BIgG induced O(2)(-) production at the phagosome but not at the intracellular granules. We conclude that activation/accumulation of betaI PKC is involved in O(2)(-) production, and that O(2)(-) production is primarily initiated at the phagosomal cup/phagosome. This study also suggests that DGKbeta plays a prominent role in regulation of O(2)(-) production during FcgammaR-mediated phagocytosis. 相似文献
133.
Takeuchi H Nakazawa T Okamoto T Shirai M Kimoto M Nishioka M Con SA Morimoto N Sugiura T 《Microbiology and immunology》2006,50(7):487-497
The cell division-related gene A (cdrA) of Helicobacter pylori is dispensable in vivo and unique in having a repressive role on cell division and long-term survival. To clarify its role, comparisons of the wildtype HPK5 and isogenic cdrA-disrupted mutant HPKT510 were examined by ultrastructural morphology, PBP profiles, and susceptibility to beta-lactam antibiotics during long-term cultivation. Ultrastructural analyses revealed that the shorter rods of HPKT510 had a slightly wider periplasmic space between the inner and the outer membrane than those of HPK5. Cell division of HPKT510 cells was complete even under high-salt conditions in which HPK5 cells became filamentous due to inhibition of division. The filamentous HPK5 cells constructed an inner membrane without a cell wall at the presumed division site. After 4 days of cultivation (the late stationary phase), most of the HPK5 cells turned into ghosts and aggregates, while some of the HPKT510 cells remained as curved rods, which coincided with the results of cell viability. HPKT510 cells became resistant to ampicillin killing compared to HPK5 cells, although their minimum inhibitory concentrations (MICs) and PBP profiles were not significantly different. These results suggest that the cdrA product represses cell division via inhibiting cell wall synthesis at division site. During infection in both mice and humans, inactivation of cdrA eventually gains biological aspects such as increased viability, long-term survival and tolerance to antibiotics and high-salt condition, which might enhance a persistent infection. 相似文献
134.
Morita H Yoshikawa H Takizawa T Shirai M Akahori F Yoshimura T 《Bioscience, biotechnology, and biochemistry》2006,70(12):2974-2981
Rat livers and microsomes were subjected to electron paramagnetic resonance (EPR) measurements at 77 K. The EPR spectra of the livers from the control group, carbon tetrachloride-, 3-methylcholanthrene-, and 3,3',4,4',5-pentachlorobiphenyl (PCB126)-treated rats exhibited an EPR spectrum at g=2.40, 2.24, and 1.93, which is characteristic of P450 in a resting state. The liver of the PCB126-treated rats showed an additional distinct EPR spectrum at g=2.49, 2.26, and 1.87 (g=2.49-species). The heme environmental structure of g=2.49-species was identified by crystal field analysis using three EPR g-values of the microsome treated with various chemicals. These results indicated that g=2.49-species is a hemeprotein with cysteine thiolate at the 5th coordination site, and a nitrogenous ligand at the 6th site. 相似文献
135.
Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: critical dimerization of inducible nitric-oxide synthase 总被引:1,自引:0,他引:1
Sakai K Suzuki H Oda H Akaike T Azuma Y Murakami T Sugi K Ito T Ichinose H Koyasu S Shirai M 《The Journal of biological chemistry》2006,281(26):17736-17742
Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85alpha regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-gamma stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction. 相似文献
136.
Shigematsu T Era S Mizuno Y Ninomiya K Kamegawa Y Morimura S Kida K 《Applied microbiology and biotechnology》2006,72(2):401-415
Abstract
We constructed a mesophilic anaerobic chemostat that was continuously
fed with synthetic wastewater containing propionate as the sole source
of carbon and energy. Steady-state conditions were achieved below the
critical dilution rate of 0.3 d
−1
with almost complete substrate degradation. The propionate-degrading
methanogenic communities in the chemostat at dilution rates of 0.01,
0.08, and 0.3 d
−1
were analyzed using molecular biological techniques. Fluorescence in
situ hybridization with archaeal and bacterial domain-specific probes
showed that archaeal cells predominated throughout the three dilution
rates. Archaeal-16S rRNA gene clone library analysis and quantitative
real-time polymerase chain reaction studies showed that hydrogenotrophic
methanogen rRNA genes closely related to
Methanoculleus
was detected at a dilution rate of 0.01 d
−1
, whereas rRNA genes closely related to the
Methanoculleus
and
Methanospirillum
genera were detected at dilution rates of 0.08 and 0.3 d
−1
. The aceticlastic methanogen,
Methanosaeta
, was detected throughout the three dilution rates. Bacterial-rRNA gene
clone library analysis and denaturing gradient gel electrophoresis
demonstrated that rRNA genes affiliated with the genus
Syntrophobacter
predominated at the low dilution rate, whereas rRNA genes affiliated
with the phylum
Firmicutes
predominated at the higher dilution rates. A significant number of rRNA
genes affiliated with the genus
Pelotomaculum
were detected at dilution rate of 0.3 d
−1
. The diversity of genes encoding acetate kinase agreed closely with the
results of the rRNA gene analysis. The dilution rates significantly
altered the archaeal and bacterial communities in the propionate-fed
chemostat. 相似文献
137.
138.
139.
140.
Hiroya Miyamoto Eri Katsuyama Yoshiteru Miyauchi Hiroko Hoshi Kana Miyamoto Yuiko Sato Tami Kobayashi Ryotaro Iwasaki Shigeyuki Yoshida Tomoaki Mori Hiroya Kanagawa Atsuhiro Fujie Wu Hao Hideo Morioka Morio Matsumoto Yoshiaki Toyama Takeshi Miyamoto 《The Journal of biological chemistry》2012,287(39):32479-32484