全文获取类型
收费全文 | 2285篇 |
免费 | 17篇 |
国内免费 | 11篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 19篇 |
2020年 | 26篇 |
2019年 | 28篇 |
2018年 | 42篇 |
2017年 | 30篇 |
2016年 | 18篇 |
2015年 | 111篇 |
2014年 | 316篇 |
2013年 | 277篇 |
2012年 | 312篇 |
2011年 | 432篇 |
2010年 | 283篇 |
2009年 | 47篇 |
2008年 | 63篇 |
2007年 | 38篇 |
2006年 | 43篇 |
2005年 | 27篇 |
2004年 | 35篇 |
2003年 | 30篇 |
2002年 | 21篇 |
2001年 | 5篇 |
2000年 | 13篇 |
1999年 | 9篇 |
1998年 | 10篇 |
1997年 | 8篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 8篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1975年 | 1篇 |
1974年 | 2篇 |
排序方式: 共有2313条查询结果,搜索用时 234 毫秒
991.
《Bioorganic & medicinal chemistry》2014,22(17):4968-4997
TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50 = 3.6 nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described. 相似文献
992.
《Bioorganic & medicinal chemistry》2014,22(5):1773-1781
The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway. 相似文献
993.
Dhananjayan Karthik Pulak Majumder Sivanandy Palanisamy Kalathil Khairunnisa Varsha Venugopal 《Bioinformation》2014,10(9):580-585
Kinase Suppressor of Ras (KSR) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Raf,
MEK, ERK to provide spatial and temporal regulation of Ras-dependent ERK cascade signaling. Interruption of this mechanism
can have a high influence in inhibiting the downstream signaling of the mutated tyrosine kinase receptor kinase upon ligand
binding. Still none of the studies targeted to prevent the binding of Raf, MEK binding on kinase suppressor of RAS. In that
perspective the cysteine rich C1 domain of scaffold proteins kinase suppressor of Ras-1 was targeted rather than its ATP binding
site with small ligand molecules like flavones and anthocyanidins and analyzed through insilico docking studies. The binding
energy evaluation shows the importance of hydroxyl groups at various positions on the flavone and anthocyanidin nucleus. Over
all binding interaction shows these ligands occupied the potential sites of cysteine rich C1 domain of scaffold protein KSR. 相似文献
994.
We describe here a simple, miniaturized radiation-based phosphorylation assay that can be used to monitor phosphorylation of a diverse range of small molecule substrates in the presence of purified and crude enzyme preparations. Ba(OH)2 and ZnSO4 are used to terminate phosphoryl transfer and to precipitate selectively the phosphorylated reaction product in a single step; non-phosphorylated substrate is removed by filtration prior to quantification. The key advantages over alternative radiation-based assays are that: (i) high-energy/short-lived radioactive emitters are not required; (ii) high-quality data can be obtained without the need for high radioactivity concentrations; and (iii) the assay is compatible with high-throughput applications. 相似文献
995.
Mina Sasaki Hiroshi Kajiya Satoru Ozeki Koji Okabe Tetsuro Ikebe 《Biochemical and biophysical research communications》2014
Reactive oxygen species (ROS) can cause severe damage to DNA, proteins and lipids in normal cells, contributing to carcinogenesis and various pathological conditions. While cellular senescence arrests the early phase of cell cycle without any detectable telomere loss or dysfunction. ROS is reported to contribute to induction of cellular senescence, as evidence by its premature onset upon treatment with antioxidants or inhibitors of cellular oxidant scavengers. Although cellular senescence is known to be implicated in tumor suppression, it remains unknown whether ROS initially contributed to be cellular senescence in normal human epidermal keratinocytes (NHEK) and their malignant counterparts. To clarify whether ROS induce cellular senescence in NHEKs, we examined the effect of hydrogen peroxide (H2O2) on the expression of cellular senescence-associated molecules in NHEKs, compared to in squamous carcinoma cells (SCCs). Hydrogen peroxide increased the number of cells positive in senescence associated-β-galactosidase (SA-β-Gal) activity in NHEKs, but not SCCs. The expression of cyclin-dependent kinase (CDK) inhibitors, especially p16INK4a was upregulated in NHEKs treated with H2O2. Interestingly, H2O2 suppressed the methylation of p16INK4a, promoter region in NHEKs, but not in SCCs. Hydrogen peroxide also suppressed the expression of phosphorylated Rb and CDK4, resulting in arrest in G0/G1 phase in NHEKs, but not SCCs. 相似文献
996.
Tristan Thwaites Ana T. Nogueira Ivan Campeotto Ana P. Silva Scott S. Grieshaber Rey A. Carabeo 《The Journal of biological chemistry》2014,289(44):30426-30442
Host cell signal transduction pathways are often targets of bacterial pathogens, especially during the process of invasion when robust actin remodeling is required. We demonstrate that the host cell focal adhesion kinase (FAK) was necessary for the invasion by the obligate intracellular pathogen Chlamydia caviae. Bacterial adhesion triggered the transient recruitment of FAK to the plasma membrane to mediate a Cdc42- and Arp2/3-dependent actin assembly. FAK recruitment was via binding to a domain within the virulence factor TarP that mimicked the LD2 motif of the FAK binding partner paxillin. Importantly, bacterial two-hybrid and quantitative imaging assays revealed a similar level of interaction between paxillin-LD2 and TarP-LD. The conserved leucine residues within the L(D/E)XLLXXL motif were essential to the recruitment of FAK, Cdc42, p34Arc, and actin to the plasma membrane. In the absence of FAK, TarP-LD-mediated F-actin assembly was reduced, highlighting the functional relevance of this interaction. Together, the data indicate that a prokaryotic version of the paxillin LD2 domain targets the FAK signaling pathway, with TarP representing the first example of an LD-containing Type III virulence effector. 相似文献
997.
In bacterial pathogenesis, monitoring and adapting to the dynamically changing environment in the host and an ability to disrupt host immune responses are critical. The virulence determinants of pathogenic bacteria include the sensor/signaling proteins of the serine/threonine protein kinase (STPK) family that have a dual role of sensing the environment and subverting specific host defense processes. STPKs can sense a wide range of signals and coordinate multiple cellular processes to mount an appropriate response. Here, we review some of the well studied bacterial STPKs that are essential virulence factors and that modify global host responses during infection. 相似文献
998.
Nicole A. LaRonde 《The Journal of biological chemistry》2014,289(14):9488-9492
The RIO kinases existed before the split between Archaea and Eubacteria and are essential in eukaryotes. Although much has been elucidated in the past few years regarding the function of these proteins in eukaryotes, questions remain about their role in prokaryotes. Comparison of structure and sequence suggests that the ancient RIO kinases may have similar functional properties in prokaryotes as they do in eukaryotes. The conservation of charge distribution, functional residues, and overall structure supports a role for these proteins in ribosome interactions, as is their purpose in eukaryotes. However, a lack of study in this area has left little direct evidence in support of this function. 相似文献
999.
Imoh S. Okon Kathleen A. Coughlan Ming-Hui Zou 《The Journal of biological chemistry》2014,289(3):1639-1648
Aberrant receptor tyrosine kinase phosphorylation (pRTK) has been associated with diverse pathological conditions, including human neoplasms. In lung cancer, frequent liver kinase B1 (LKB1) mutations correlate with tumor progression, but potential links with pRTK remain unknown. Heightened and sustained receptor activation was demonstrated by LKB1-deficient A549 (lung) and HeLaS3 (cervical) cancer cell lines. Depletion (siRNA) of endogenous LKB1 expression in H1792 lung cancer cells also correlated with increased pRTK. However, ectopic LKB1 expression in A549 and HeLaS3 cell lines, as well as H1975 activating-EGF receptor mutant lung cancer cell resulted in dephosphorylation of several tumor-enhancing RTKs, including EGF receptor, ErbB2, hepatocyte growth factor receptor (c-Met), EphA2, rearranged during transfection (RET), and insulin-like growth factor I receptor. Receptor abrogation correlated with attenuation of phospho-Akt and increased apoptosis. Global phosphatase inhibition by orthovanadate or depletion of protein tyrosine phosphatases (PTPs) resulted in the recovery of receptor phosphorylation. Specifically, the activity of SHP-2, PTP-1β, and PTP-PEST was enhanced by LKB1-expressing cells. Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells. 相似文献