全文获取类型
收费全文 | 1882篇 |
免费 | 144篇 |
国内免费 | 94篇 |
出版年
2023年 | 15篇 |
2022年 | 67篇 |
2021年 | 89篇 |
2020年 | 44篇 |
2019年 | 85篇 |
2018年 | 85篇 |
2017年 | 62篇 |
2016年 | 69篇 |
2015年 | 87篇 |
2014年 | 115篇 |
2013年 | 116篇 |
2012年 | 166篇 |
2011年 | 132篇 |
2010年 | 104篇 |
2009年 | 74篇 |
2008年 | 83篇 |
2007年 | 71篇 |
2006年 | 80篇 |
2005年 | 58篇 |
2004年 | 44篇 |
2003年 | 52篇 |
2002年 | 51篇 |
2001年 | 38篇 |
2000年 | 38篇 |
1999年 | 36篇 |
1998年 | 16篇 |
1997年 | 23篇 |
1996年 | 16篇 |
1995年 | 18篇 |
1994年 | 14篇 |
1993年 | 14篇 |
1992年 | 19篇 |
1991年 | 28篇 |
1990年 | 12篇 |
1989年 | 13篇 |
1988年 | 5篇 |
1987年 | 14篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1967年 | 3篇 |
排序方式: 共有2120条查询结果,搜索用时 15 毫秒
181.
Zou J Zhou L Du XX Ji Y Xu J Tian J Jiang W Zou Y Yu S Gan L Luo M Yang Q Cui Y Yang W Xia X Chen M Zhao X Shen Y Chen PY Worley PF Xiao B 《Developmental cell》2011,20(1):97-108
mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in?vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells?abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f,Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f,Nes-cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability. 相似文献
182.
The fluorescein diacetate (FDA) assay has been widely used to measure metabolic activity in phytoplankton. It was found that FDA fluorescence values did not decrease in some stressed cells, demonstrating that the applicability of the method needs to be assessed further in the context of growth‐influencing conditions. In the present study, changes of FDA fluorescence values were studied in bloom‐forming cyanobacterial Microcystis aeruginosa Kütz cells under stress conditions such as nitrogen (N) or phosphorus (P) deficiency, or darkness and low temperature (10°C), respectively. The results demonstrated that esterase activity decreased immediately in dark‐stressed cells, which correlated with the decline of biomass and photosynthetic activity. Under the other three stress conditions, however, especially at low temperature, the cells lost photosynthetic activity but had the highest esterase activity, which was five times higher than the control group. These findings contrast with the assay criteria that the expression of a stain should reflect the change of photosynthetic activity and that stressed cells should have a lower staining intensity than the control cells. According to these results, the esterase activity response was dependent on environmental factors. Furthermore, higher fluorescence intensity did not mean higher metabolic activity, but a discrepant value indicated a severe stress. 相似文献
183.
piRNA profiling during specific stages of mouse spermatogenesis 总被引:1,自引:0,他引:1
184.
Root hair development is orchestrated by nutritional factors and plant hormones. We investigated the action of ammonium (NH4+) and its interactions with methyl jasmonate (MeJA) and ethylene in Arabidopsis root hair growth. The formation of root hair branches was dramatically stimulated in media containing 1.25 to 20 mM NH4+ at pH values of 4.0 to 6.5. The NH4+-treated root hairs showed a very short tip growth stage and swells on the sides that indicated the emergence of branches.
MeJA (0.08 to 10 μM) worked in synergism with NH4+ to enhance hair branching. In contrast, ethylene had an antagonistic effect; the stimulation of hair branching by NH4+ was suppressed by the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) and was diminished in ethylene-overproducing
mutant eto1-1 seedlings. Moreover, the application of Ag+, an ethylene inhibitor, reduced the ACC-induced inhibition of NH4+-stimulated hair branching and restored NH4+-stimulated hair branching in eto1-1 seedlings. Thus, the actions of jasmonate and ethylene appear to be dependent on nutritional conditions such as available
nitrogen. 相似文献
185.
目的:观察IDl对大鼠胶质瘤细胞(c6细胞)侵袭转移能力的影响。方法:以C6细胞为研究对象,ID1 siRNA通过脂质体转染c6细胞,western blot检测C6细胞中ID1、P-NF—KBp65蛋白的表达、Elisa法检测细胞培养上清MMP.9的含量,Transwell小室观察成的转移侵袭能力。结果:干扰ID1后能显著降低C6细胞中P-NF-KBp65蛋白、细胞培养上清中MMP-9的含量(P〈0.01),降低C6细胞的转移侵袭能力(P〈0.01)。结论:干扰ID1能抑制C6细胞的转移侵袭,其机制可能与抑制C6细胞中P-NF-K Bp65蛋白、MMP-9的表达有关。 相似文献
186.
187.
Background
Cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation and angiotensin II (Ang II) in paraventricular nucleus (PVN) augments the CSAR in vagotomized (VT) and baroreceptor denervated (BD) rats with chronic heart failure (CHF). This study was designed to determine whether it is true in intact (INT) rats with CHF and to determine the effects of cardiac and baroreceptor afferents on the CSAR and sympathetic activity in CHF.Methodology/Principal Findings
Sham-operated (Sham) or coronary ligation-induced CHF rats were respectively subjected to BD+VT, VT, cardiac sympathetic denervation (CSD) or INT. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded, and the CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Either CSAR or the responses of RSNA, MAP and CSAR to Ang II in PVN were enhanced in CHF rats treated with BD+VT, VT or INT. Treatment with VT or BD+VT potentiated the CSAR and the CSAR responses to Ang II in both Sham and CHF rats. Treatment with CSD reversed the capsaicin-induced RSNA and MAP changes and the CSAR responses to Ang II in both Sham and CHF rats, and reduced the RSNA and MAP responses to Ang II only in CHF rats.Conclusions
The CSAR and the CSAR responses to Ang II in PVN are enhanced in intact CHF rats. Baroreceptor and vagal afferent activities inhibit CSAR and the CSAR responses to Ang II in intact Sham and CHF rats. 相似文献188.
Epothilones are a new class of microtubule stabilizing agents with promising preclinical and clinical activity. Their cellular target is β-tubulin and factors influencing intrinsic sensitivity to epothilones are not well understood. In this study, the functional significance of specific β-tubulin isotypes in intrinsic sensitivity to epothilone B was investigated using siRNA gene knockdown against βII-, βIII- or βIVb-tubulins in two independent non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and Calu-6. Drug-treated clonogenic assays showed that sensitivity to epothilone B was not altered following knockdown of βII-tubulin in both NSCLC cell lines. In contrast, knockdown of βIII-tubulin significantly increased sensitivity to epothilone B. Interestingly, βIVb-tubulin knockdowns were significantly less sensitive to epothilone B, compared to mock- and control siRNA cells. Cell cycle analysis of βIII-tubulin knockdown cells showed a higher percentage of cell death with epothilone B concentrations as low as 0.5 nM. In contrast, βIVb-tubulin knockdown cells displayed a decrease in epothilone B-induced G(2)-M cell cycle accumulation compared to control siRNA cells. Importantly, βIII-tubulin knockdowns displayed a significant dose-dependent increase in the percentage of apoptotic cells upon treatment with epothilone B, as detected using caspase 3/7 activity and Annexin-V staining. Higher concentrations of epothilone B were required to induce apoptosis in the βIVb-tubulin knockdowns compared to control siRNA, highlighting a potential mechanism underlying decreased sensitivity to this agent. This study demonstrates that specific β-tubulin isotypes can influence sensitivity to epothilone B and may influence differential sensitivity to this promising new agent. 相似文献
189.
Background
The Resonant Recognition Model (RRM) is a physico-mathematical model that interprets protein sequence linear information using digital signal processing methods. In this study the RRM concept was employed for structure-function analysis of myxoma virus (MV) proteins and the design of a short bioactive therapeutic peptide with MV-like antitumor/cytotoxic activity.Methodology/Principal Findings
The analogue RRM-MV was designed by RRM as a linear 18 aa 2.3 kDa peptide. The biological activity of this computationally designed peptide analogue against cancer and normal cell lines was investigated. The cellular cytotoxicity effects were confirmed by confocal immunofluorescence microscopy, by measuring the levels of cytoplasmic lactate dehydrogenase (LDH) and by Prestoblue cell viability assay for up to 72 hours in peptide treated and non-treated cell cultures. Our results revealed that RRM-MV induced a significant dose and time-dependent cytotoxic effect on murine and human cancer cell lines. Yet, when normal murine cell lines were similarly treated with RRM-MV, no cytotoxic effects were observed. Furthermore, the non-bioactive RRM designed peptide RRM-C produced negligible cytotoxic effects on these cancer and normal cell lines when used at similar concentrations. The presence/absence of phosphorylated Akt activity in B16F0 mouse melanoma cells was assessed to indicate the possible apoptosis signalling pathway that could be affected by the peptide treatment. So far, Akt activity did not seem to be significantly affected by RRM-MV as is the case for the original viral protein.Conclusions/Significance
Our findings indicate the successful application of the RRM concept to design a bioactive peptide analogue (RRM-MV) with cytotoxic effects on tumor cells only. This 2.345 kDa peptide analogue to a 49 kDa viral protein may be suitable to be developed as a potential cancer therapeutic. These results also open a new direction to the rational design of therapeutic agents for future cancer treatment. 相似文献190.