全文获取类型
收费全文 | 2173篇 |
免费 | 175篇 |
国内免费 | 201篇 |
出版年
2024年 | 4篇 |
2023年 | 30篇 |
2022年 | 71篇 |
2021年 | 112篇 |
2020年 | 70篇 |
2019年 | 112篇 |
2018年 | 103篇 |
2017年 | 74篇 |
2016年 | 90篇 |
2015年 | 142篇 |
2014年 | 145篇 |
2013年 | 135篇 |
2012年 | 210篇 |
2011年 | 173篇 |
2010年 | 103篇 |
2009年 | 83篇 |
2008年 | 109篇 |
2007年 | 87篇 |
2006年 | 77篇 |
2005年 | 75篇 |
2004年 | 40篇 |
2003年 | 48篇 |
2002年 | 55篇 |
2001年 | 38篇 |
2000年 | 33篇 |
1999年 | 49篇 |
1998年 | 19篇 |
1997年 | 31篇 |
1996年 | 20篇 |
1995年 | 29篇 |
1994年 | 30篇 |
1993年 | 16篇 |
1992年 | 35篇 |
1991年 | 22篇 |
1990年 | 19篇 |
1989年 | 14篇 |
1988年 | 11篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 7篇 |
1984年 | 11篇 |
1983年 | 6篇 |
1982年 | 1篇 |
1981年 | 2篇 |
排序方式: 共有2549条查询结果,搜索用时 15 毫秒
91.
Molecular dynamics simulations were performed to elucidate the interactions of CDK2 and CDK5 complexes with three inhibitors: R-roscovitine, S-roscovitine, and indirubin-3′-oxime. The preference of the two complexes for R-roscovitine over the S enantiomer, as reported by the experiment, was also found by the simulations. More importantly, the simulations showed that the cause of the stronger affinity for the R enantiomer is the presence of an important hydrogen bond between R-roscovitine and the kinases not found with S-roscovitine. The simulations also showed two amino acid mutations in the active site of CDK5/R-roscovitine that favor binding-enhanced electrostatic contributions, making the inhibitor more effective for CDK5 than for CDK2. This suggests that the effectiveness of roscovitine-like inhibitors can be improved by enhancing their electrostatic interaction with the kinases. Finally, molecular mechanics–Possion–Boltzmann/surface area calculations of the CDK5/indirubin-3′-oxime system in both water-excluded and water-included environments gave significantly different electrostatic contributions to the binding. The simulations detected the displacement of a water molecule in the active site of the water-included CDK/indirubin-3′-oxime system. This resulted in a more conserved binding pattern than the water-excluded structure. Hence, in the design of new indirubin-like inhibitors, it is important to include the water molecule in the analysis.
Figure Hydrogen bonding networks at the active sites of both CDK5/R-roscotivine
(light grey) and CDK2/R-roscovitine (black). 相似文献
92.
Li Yuanbin Liu Haifen Zeng Zhaohui Lin Hui Chen Xin Yuan Xianglian Qiu Jizhe Fu Fengchun Chen Zhuang Kuang Jianjun 《Journal of molecular histology》2022,53(4):763-772
Journal of Molecular Histology - We investigate the protective effect of ginsenoside Rb3 on skin flap microvasculature following ischemia-reperfusion (I/R) injury and its regulatory mechanism. We... 相似文献
93.
94.
深入了解荒漠短命植物的化学计量特征,有助于更好地理解生境土壤因子与植物生存策略的关系。以古尔班通古特沙漠广泛分布的尖喙牻牛儿苗(Erodium oxyrrhynchum)、假狼紫草(Nonea caspica)、琉苞菊(Hyalea pulchella)、飘带果(Lactuca undulata)为植物材料,测定不同深度(0~5、5~10、10~15 cm)的土壤理化性质,野外原位多时段采样比较分析4种植物化学计量特征与土壤因子的动态变化及其耦合关系。结果表明:①4种短命植物碳(C)、氮(N)、磷(P)含量普遍较低,化学计量特征存在物种间差异,但在不同生长期内变化规律大致相似。N、P含量从幼苗期到结实期逐渐减少,而C含量则长期趋于稳定。整个生长期内,P、C∶P的变异幅度较大,相反,C、N∶P的变异幅度较小。4种植物在不同生长期的化学计量特征差异与生长期、植物种类存在显著相关性。②0~5 cm土层有机碳(SOC)、总氮(TN)、总磷(TP)含量最高,且随土层的加深逐渐减少。随着植物的生长,0~5 cm土层中SOC和TN含量呈明显增加的趋势,而TP含量却呈现抛物线状变化趋势。在植物不同生长期内,土壤TP含量稳定性最强,SOC、TN的变异性较强,较低的N含量及TN∶TP比显示出该区域土壤属于N素缺乏类型。3个土层土壤在不同生长期的化学计量特征差异受土层、生长期的影响显著。③4种植物与各层次土壤化学计量特征的相关性无一致规律。植物化学计量指标仅与0~10 cm土层SOC、SOC∶TP相关性较强,而大部分化学计量特征间未显示出相关性。上述结果说明植物化学计量特征并非全部由土壤养分特征直接决定,其明显的种间差异显示了植物自身遗传特性在土壤—植物计量特征耦合关系的重要性。 相似文献
95.
高质量的生物多样性数据能够为生物多样性的研究与保护提供数据支撑。目前研究人员开发了大量的生物多样性数据处理软件或工具, 包括工作流系统、R语言包、Python语言包和Excel工具等, 但是使用这些软件或工具需要用户安装相应的软件客户端, 并掌握一定的编程语言、软件开发和复杂的Excel公式等知识和技能。为降低用户的学习成本和使用门槛, 本文采用了Browser/Server模式设计技术、Web技术、可视化技术、响应式开发技术、网络爬虫技术、数据处理技术和Solr智能检索技术等, 针对不同维度的生物多样性数据设计和开发了相应的数据处理模块, 构建了中国生物多样性在线数据处理平台(http://dp.iflora.cn/ )。该平台能够有效地帮助科研人员对物种名称、地理位置、时间日期和经纬度等数据进行处理, 并提供数据格式转换、数据质量评测和资源统计分析等辅助功能, 帮助科研人员实现零代码和低门槛地处理生物多样性数据, 提供便捷、高效和简单的数据清洗、校正、转换和整合等数据处理渠道, 为生物多样性研究和保护提供信息化技术支持与服务。 相似文献
96.
国土空间规划背景下, 生态保护红线是在生态空间的现有基础上提出管控要求, 但其与各类生态空间的管控要求之间是否兼容以及如何协调, 仍需要梳理。本研究首先将生态空间划分为自然和管理两大属性和宏观、中观和微观三个层次进行类型体系梳理; 然后, 基于管控视角, 从管理目标、管控内容与管控强度三方面着重探讨13类生态空间与生态保护红线的差异。在管控目标方面, 两者的支持与调节目标兼容度较高, 供给与文化目标定位差异较大; 在管控内容方面, 差异主要表现在培育修复类和人工利用类; 在管控强度方面, 生态保护红线两级管控强度和生态空间三级管控强度不完全匹配。建议以“两大属性三个层次”系统完善生态空间类型体系, 从管理目标、管控内容与管控强度三方面进行生态空间管控要求体系化构建; 进一步完善生态保护红线管控内容和管控强度, 使其与对应的各类生态空间管控要求更好地协调。 相似文献
97.
In our previous studies, programmed cell death (PCD) was induced in human periodontal ligament (PDL) cells, through activation of caspase-3 and upregulation of CASP5 gene (encoding caspase-5 protein), in response to mechanical stretch loading. The aim of this study is to explore the relationship between the inflammatory caspase, caspase-5, and the apoptotic executioner protein, caspase-3, in human PDL cells. Here, we found that cyclic stretching upregulated the activity and the protein expression level of caspase-3 and -5 and the addition of the caspase-3 inhibitor or caspase-5 inhibitor significantly inhibited the stretch-induced PCD. Meanwhile, the inhibition of caspase-5 inhibited the activation of caspase-3 and vice versa. The result of coimmunoprecipitation also demonstrated that the expression of caspase-3 was immunoprecipitated with caspase-5. Thus, our study revealed that the in vitro application of cyclic stretching induced PCD by activation of caspase-3 and -5 in human PDL cells, and these two caspases could interact with each other after mechanical stretch loading. The study may facilitate further studies on the mechanism of stretch-induced PCD and help us understand the force-related periodontal homeostasis and remodeling better. 相似文献
98.
Guangwei Sun Yalun Li Yangjie Peng Dapeng Lu Fuqiang Zhang Xueyang Cui Qingyue Zhang Zhuang Li 《Journal of cellular physiology》2019,234(4):3829-3836
Colorectal cancer (CRC) ranks as one of the most commonly diagnosed malignancies worldwide. Although mortality rates have been decreasing, the prognosis of CRC patients is still highly dependent on the individual. Therefore, identifying and understanding novel biomarkers for CRC prognosis remains crucial. The gene expression profiles of five-gene expression omnibus (GEO) data sets of CRC were first downloaded. A total of 352 consistent differentially expressed genes (DEGs) were identified for CRC and paired with normal tissues. Functional analysis including gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment revealed that these DEGs were related to metabolic pathways, tight junctions, and the cell cycle. Ten hub DEGs were identified based on the search tool for the retrieval of interacting genes database and protein–protein interaction networks. By using univariate Cox proportional hazard regression analysis, we found 11 survival-related genes among these DEGs. We finally established a five-gene signature (kinesin family member 15, N-acetyltransferase 2, glutathione peroxidase 3, secretogranin II, and chloride channel accessory 1) with prognostic value in CRC by step multivariate Cox regression analysis. Based on this risk scoring system, patients in the high-risk group had significantly poorer survival results compared with those in the low-risk group (log-rank test, p < 0.0001). Finally, we validated our gene signature scoring system in two independent GEO cohorts (GSE17536 and GSE33113). We found all five of the signature genes to be DEGs in The Cancer Genome Atlas database. In conclusion, our findings suggest that our five DEG-based signature can provide a novel biomarker with useful applications in CRC prognosis. 相似文献
99.
100.
Zhoukang Zhuang Chengzhou Jiang Fan Zhang Rong Huang Liwei Yi Yong Huang Xiaohui Yan Yanwen Duan Xiangcheng Zhu 《Biotechnology and bioengineering》2019,116(6):1304-1314
Tiancimycins (TNMs) are a group of 10-membered anthraquinone-fused enediynes, newly discovered from Streptomyces sp. CB03234. Among them, TNM-A and TNM-D have exhibited excellent antitumor performances and could be exploited as very promising warheads for the development of anticancer antibody-drug conjugates (ADCs). However, their low titers, especially TNM-D, have severely limited following progress. Therefore, the streptomycin-induced ribosome engineering was adopted in this work for strain improvement of CB03234, and a TNMs high producer S. sp. CB03234-S with the K43N mutation at 30S ribosomal protein S12 was successfully screened out. Subsequent media optimization revealed the essential effects of iodide and copper ion on the production of TNMs, while the substitution of nitrogen source could evidently promote the accumulation of TNM-D, and the ratio of produced TNM-A and TNM-D was responsive to the change of carbon and nitrogen ratio in the medium. Further amelioration of the pH control in scaled up 25 L fermentation increased the average titers of TNM-A and TNM-D up to 13.7 ± 0.3 and 19.2 ± 0.4 mg/L, respectively. The achieved over 45-fold titer improvement of TNM-A, and 109-fold total titer improvement of TNM-A and TNM-D enabled the efficient purification of over 200 mg of each target molecule from 25 L fermentation. Our efforts have demonstrated a practical strategy for titer improvement of anthraquinone-fused enediynes and set up a solid base for the pilot scale production and preclinical studies of TNMs to expedite the future development of anticancer ADC drugs. 相似文献