全文获取类型
收费全文 | 5504篇 |
免费 | 435篇 |
国内免费 | 3篇 |
出版年
2023年 | 19篇 |
2022年 | 9篇 |
2021年 | 109篇 |
2020年 | 87篇 |
2019年 | 104篇 |
2018年 | 149篇 |
2017年 | 178篇 |
2016年 | 257篇 |
2015年 | 361篇 |
2014年 | 408篇 |
2013年 | 449篇 |
2012年 | 547篇 |
2011年 | 537篇 |
2010年 | 349篇 |
2009年 | 277篇 |
2008年 | 389篇 |
2007年 | 340篇 |
2006年 | 298篇 |
2005年 | 260篇 |
2004年 | 208篇 |
2003年 | 191篇 |
2002年 | 154篇 |
2001年 | 35篇 |
2000年 | 40篇 |
1999年 | 33篇 |
1998年 | 29篇 |
1997年 | 19篇 |
1996年 | 12篇 |
1995年 | 15篇 |
1994年 | 10篇 |
1993年 | 9篇 |
1992年 | 6篇 |
1991年 | 10篇 |
1990年 | 3篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 1篇 |
1986年 | 3篇 |
1985年 | 8篇 |
1984年 | 6篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有5942条查询结果,搜索用时 171 毫秒
1.
Jung Mi Lim Kyung S. Lee Hyun Ae Woo Dongmin Kang Sue Goo Rhee 《The Journal of cell biology》2015,210(1):935-945
Proteins associated with the centrosome play key roles in mitotic progression in mammalian cells. The activity of Cdk1-opposing phosphatases at the centrosome must be inhibited during early mitosis to prevent premature dephosphorylation of Cdh1—an activator of the ubiquitin ligase anaphase-promoting complex/cyclosome—and the consequent premature degradation of mitotic activators. In this paper, we show that reversible oxidative inactivation of centrosome-bound protein phosphatases such as Cdc14B by H2O2 is likely responsible for this inhibition. The intracellular concentration of H2O2 increases as the cell cycle progresses. Whereas the centrosome is shielded from H2O2 through its association with the H2O2-eliminating enzyme peroxiredoxin I (PrxI) during interphase, the centrosome-associated PrxI is selectively inactivated through phosphorylation by Cdk1 during early mitosis, thereby exposing the centrosome to H2O2 and facilitating inactivation of centrosome-bound phosphatases. Dephosphorylation of PrxI by okadaic acid–sensitive phosphatases during late mitosis again shields the centrosome from H2O2 and thereby allows the reactivation of Cdk1-opposing phosphatases at the organelle. 相似文献
2.
Molecular Biology Reports - We present here on an innovative assay for detecting miRNAs using a uniquely designed specific extension sequence that provides high efficiency and accuracy. This assay... 相似文献
3.
Pasupathi Sundaramoorthy Jae Jun Sim Yeong-Su Jang Siddhartha Kumar Mishra Keun-Yeong Jeong Poonam Mander Oh Byung Chul Won-Sik Shim Seung Hyun Oh Ky-Youb Nam Hwan Mook Kim 《PloS one》2015,10(1)
Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK) plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+) supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa), its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+) levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain) in a dose-dependent manner. Phosphorylated FAK (p-FAK) was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer. 相似文献
4.
Theoretical calculation of the sugar concentrations during enzymatic production of fructooligosaccharides 总被引:1,自引:0,他引:1
Summary In a batch production of fructooligosaccharides from sucrose, the concentrations of residual sucrose, glucose and fructooligosaccharides at a given reaction time(t) and initial sucrose concentration(S0) were theoretically calculated by the following correlation equations: Glucose(t) = 0.0653 S0 × ln(t); Fructooligosaccharides(t) = 0.1636 S0 × ln(t); Sucrose(t)=S0 - Glucose(t) + FOS(t). 相似文献
5.
6.
Hyun Soo Lee Romerson D. Dimla Peter G. Schultz 《Bioorganic & medicinal chemistry letters》2009,19(17):5222-5224
The photo-crosslinking amino acid, p-benzoyl-l-phenylalanine (pBpa), was genetically incorporated into Escherichia coli catabolite activator protein (CAP) in bacteria in response to an amber nonsense codon using an orthogonal tRNA/aminoacyl-tRNA synthetase pair. The mutant CAP (CAP-K26Bpa) containing pBpa formed a covalent complex with a DNA fragment containing the consensus operator sequence upon UV irradiation. Because this amino acid can be genetically incorporated into any DNA-binding protein in E. coli, yeast or mammalian cells with minimal perturbation of protein structure, this method should be generally useful for investigating DNA–protein interactions. 相似文献
7.
Dong Hyun Jo Chang Sik Cho Jin Hyoung Kim Hyoung Oh Jun Jeong Hun Kim 《Journal of biomedical science》2013,20(1):38
Effective and validated animal models are valuable to investigate the pathogenesis and potential therapeutics for human diseases. There is much concern for diabetic retinopathy (DR) in that it affects substantial number of working population all around the world, resulting in visual deterioration and social deprivation. In this review, we discuss animal models of DR based on different species of animals from zebrafish to monkeys and prerequisites for animal models. Despite criticisms on imprudent use of laboratory animals, we hope that animal models of DR will be appropriately utilized to deepen our understanding on the pathogenesis of DR and to support our struggle to find novel therapeutics against catastrophic visual loss from DR. 相似文献
8.
Nayoung Kang Ah Hyun Jun Yangzom Doma Bhutia Natarajan Kannan Jashvant D. Unadkat Rajgopal Govindarajan 《The Journal of biological chemistry》2010,285(36):28343-28352
Accumulating evidence reveals that sole mutations in hENT3 cause a spectrum of human genetic disorders. Among these include H syndrome, characterized by scleroderma, hyperpigmentation, hypertrichosis, hepatomegaly, cardiac abnormalities and musculoskeletal deformities, pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndrome, characterized by autoantibody-negative diabetes mellitus and skin deformities, familial Rosai-Dorfman disease, characterized by short stature, familial histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), characterized by severe tissue infiltration of immune cells and swollen lymph nodes. hENT3 spectrum disorders share a common mutation and share overlapping clinical manifestations that display many intriguing resemblances to mitochondrial and lysosomal disorders. Although earlier studies identify hENT3 as a mitochondrial and a lysosomal nucleoside transporter, the precise connections between hENT3 and the pathophysiology of these disorders remain unresolved. In this study, we performed functional and biochemical characterization of these mutations in hENT3. We report severe reductions/losses of hENT3 nucleoside transport functions of hENT3 syndrome mutants. In addition to transport alterations, we provide evidence for possible loss of hENT3 functions in all H and pigmented hypertrichotic dermatosis with insulin-dependent diabetes syndromes due to either mistrafficking or altered stability of mutant hENT3 proteins. 相似文献
9.
Hyun I. Park 《Analytical biochemistry》2010,396(2):262-60
Matrix metalloproteinases (MMPs) are a family of hydrolytic enzymes that play significant roles in development, morphogenesis, inflammation, and cancer invasion. Endometase (matrilysin 2 or MMP-26) is a putative early biomarker for human carcinomas. The effects of the ionic and nonionic detergents on catalytic activity of endometase were investigated. The hydrolytic activity of endometase was detergent concentration dependent, exhibiting a bell-shaped curve with its maximum activity near the critical micelle concentration (CMC) of nonionic detergents tested. The effect of Brij-35 on human gelatinase B (MMP-9), matrilysin (MMP-7), and membrane-type 1 MMP (MT1-MMP) was further explored. Their maximum catalysis was observed near the CMC of Brij-35 (∼ 90 μM). Their IC50 values were above the CMC. The inhibition mechanism of MMP-7, MMP-9, and MT1-MMP by Brij-35 was a mixed type as determined by Dixon’s plot; however, the inhibition mechanism of endometase was noncompetitive with a Ki value of 240 μM. The catalytic activities of MMPs are influenced by detergents. Monomer of detergents may activate and stabilize MMPs to enhance catalysis, but micelle of detergents may sequester enzyme and block the substrate binding site to impede catalysis. Under physiological conditions, a lipid or membrane microenvironment may regulate enzymatic activity. 相似文献
10.
Seunghun Lee Won Yeong Park Hoonchul Chang Bumju Kim Won Hyuk Jang Seonghan Kim Younghoon Shin Myoung Joon Kim Kyung Hwa Lee Eui Hyun Kim Euiheon Chung Ki Hean Kim 《Journal of biophotonics》2020,13(1)
Delineation of brain tumor margins during surgery is critical to maximize tumor removal while preserving normal brain tissue to obtain optimal clinical outcomes. Although various imaging methods have been developed, they have limitations to be used in clinical practice. We developed a high‐speed cellular imaging method by using clinically compatible moxifloxacin and confocal microscopy for sensitive brain tumor detection and delineation. Moxifloxacin is a Food and Drug Administration (FDA) approved antibiotic and was used as a cell labeling agent through topical administration. Its strong fluorescence at short visible excitation wavelengths allowed video‐rate cellular imaging. Moxifloxacin‐based confocal microscopy (MBCM) was characterized in normal mouse brain specimens and visualized their cytoarchitecture clearly. Then, MBCM was applied to both brain tumor murine models and two malignant human brain tumors of glioblastoma and metastatic cancer. MBCM detected tumors in all the specimens by visualizing dense and irregular cell distributions, and tumor margins were easily delineated based on the cytoarchitecture. An image analysis method was developed for automated detection and delineation. MBCM demonstrated sensitive delineation of brain tumors through cytoarchitecture visualization and would have potentials for human applications, such as a surgery‐guiding method for tumor removal. 相似文献