全文获取类型
收费全文 | 587篇 |
免费 | 12篇 |
国内免费 | 1篇 |
出版年
2023年 | 3篇 |
2022年 | 6篇 |
2021年 | 5篇 |
2020年 | 4篇 |
2019年 | 11篇 |
2018年 | 19篇 |
2017年 | 10篇 |
2016年 | 6篇 |
2015年 | 6篇 |
2014年 | 43篇 |
2013年 | 37篇 |
2012年 | 33篇 |
2011年 | 60篇 |
2010年 | 31篇 |
2009年 | 40篇 |
2008年 | 28篇 |
2007年 | 28篇 |
2006年 | 34篇 |
2005年 | 27篇 |
2004年 | 18篇 |
2003年 | 14篇 |
2002年 | 7篇 |
2001年 | 7篇 |
2000年 | 9篇 |
1999年 | 5篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 6篇 |
1993年 | 6篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1983年 | 9篇 |
1982年 | 9篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有600条查询结果,搜索用时 46 毫秒
11.
12.
M D Leuther B G Barisas J S Peacock H Krakauer 《Biochemical and biophysical research communications》1979,89(1):85-90
Fluorescence photobleaching recovery methods reveal marked changes in lateral mobilities of rabbit lymphocyte membrane components during the course of stimulation with succinyl concanavalin A (S Con A). The diffusion constant of S Con A receptors on T lymphocytes falls from 1.6×10?10 cm2/sec to 6.5×10?11 cm2/sec within 4 hr after stimulation, remains constant for 14 hr, and returns to its former value. The mobility of B cell receptors similarly falls from 1.4×10?10 cm2/sec to 5.5×10?11 cm2/sec but regains its unstimulated value much more slowly. In contrast, a fluorescent phospholipid analog shows constant mobilities of 1.9×10?8 cm2/sec and 1.5×10?8 cm2/sec in T and B cells, respectively, throughout the experiment. 相似文献
13.
14.
Peter F. T. Vaughan David F. Kaye Helen L. Reeve Stephen G. Ball Chris Peers 《Journal of neurochemistry》1993,60(6):2159-2166
Abstract: Dimethylphenylpiperazinium iodide (a nicotinic agonist) evokes noradrenaline release from human neuroblastoma SH-SY5Y cells that have been pretreated with 12- O -tetradecanoylphorbol 13-acetate for 8 min. This effect of dimethylphenylpiperazinium iodide was inhibited by 1 μ M mecamylamine but not by 1 μ M atropine, which suggests that SH-SY5Y cells express nicotinic receptors coupled to the release of noradrenaline. Dimethylphenylpiperazinium iodide-evoked release was enhanced by 5 μ M Bay K 8644 (an L-type calcium agonist) and inhibited by 1 μ M nifedipine. Dimethylphenylpiperazinium iodide depolarised SH-SY5Y cells and enhanced the level of intracellular calcium in cells loaded with fura 2. The effects of dimethylphenylpiperazinium iodide on noradrenaline release, depolarisation, and intracellular calcium levels were all inhibited by 1 μ M desmethylimipramine. The results of this study show that nicotinic receptors in SH-SY5Y cells stimulate noradrenaline release by activation of L-type calcium channels. 相似文献
15.
Jie Ni Paul Cozzi Jingli Hao Julia Beretov Lei Chang Wei Duan Sarah Shigdar Warick Delprado Peter Graham Joseph Bucci John Kearsley Yong Li 《The international journal of biochemistry & cell biology》2013,45(12):2736-2748
Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p-Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy. 相似文献
16.
Sulindac modulates secreted protein expression from LIM1215 colon carcinoma cells prior to apoptosis
David W. Greening Hong Ji Eugene A. Kapp Richard J. Simpson 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(11):2293-2307
Colorectal cancer (CRC) is a major cause of mortality in Western populations. Growing evidence from human and rodent studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) cause regression of existing colon tumors and act as effective chemopreventive agents in sporadic colon tumor formation. Although much is known about the action of the NSAID sulindac, especially its role in inducing apoptosis, mechanisms underlying these effects is poorly understood. In previous secretome-based proteomic studies using 2D-DIGE/MS and cytokine arrays we identified over 150 proteins released from the CRC cell line LIM1215 whose expression levels were dysregulated by treatment with 1 mM sulindac over 16 h; many of these proteins are implicated in molecular and cellular functions such as cell proliferation, differentiation, adhesion, angiogenesis and apoptosis (Ji et al., Proteomics Clin. Appl. 2009, 3, 433–451). We have extended these studies and describe here an improved protein/peptide separation strategy that facilitated the identification of 987 proteins and peptides released from LIM1215 cells following 1 mM sulindac treatment for 8 h preceding the onset of apoptosis. This peptidome separation strategy involved fractional centrifugal ultrafiltration of concentrated cell culture media (CM) using nominal molecular weight membrane filters (NMWL 30 K, 3 K and 1 K). Proteins isolated in the > 30 K and 3–30 K fractions were electrophoretically separated by SDS-PAGE and endogenous peptides in the 1–3 K membrane filter were fractioned by RP-HPLC; isolated proteins and peptides were identified by nanoLC-MS–MS. Collectively, our data show that LIM1215 cells treated with 1 mM sulindac for 8 h secrete decreased levels of proteins associated with extracellular matrix remodeling (e.g., collagens, perlecan, syndecans, filamins, dyneins, metalloproteinases and endopeptidases), cell adhesion (e.g., cadherins, integrins, laminins) and mucosal maintenance (e.g., glycoprotein 340 and mucins 5 AC, 6, and 13). A salient finding of this study was the increased proteolysis of cell surface proteins following treatment with sulindac for 8 h (40% higher than from untreated LIM1215 cells); several of these endogenous peptides contained C-terminal amino acids from transmembrane domains indicative of regulated intramembrane proteolysis (RIP). Taken together these results indicate that during the early-stage onset of sulindac-induced apoptosis (evidenced by increased annexin V binding, dephosphorylation of focal adhesion kinase (FAK), and cleavage of caspase-3), 1 mM sulindac treatment of LIM1215 cells results in decreased expression of secreted proteins implicated in ECM remodeling, mucosal maintenance and cell–cell-adhesion. This article is part of a Special Issue entitled: An Updated Secretome. 相似文献
17.
Jorge Soriano María García-Díaz Margarita Mora Maria Lluïsa Sagristá Santi Nonell Angeles Villanueva Juan Carlos Stockert Magdalena Cañete 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The cell death pathway activated after photodynamic therapy (PDT) is controlled by a variety of parameters including the chemical structure of the photosensitizer, its subcellular localization, and the photodynamic damage induced. The present study aims to characterize a suitable m-THPPo liposomal formulation, to determine its subcellular localization in HeLa cells and to establish the cell death mechanisms that are activated after photodynamic treatments.Methods
Liposomes containing m-THPPo were prepared from a mixture of DPPC and DMPG at a 9:1 molar ratio. In order to procure the best encapsulation efficiency, the m-THPPo/lipid molar ratio was considered. HeLa cells were incubated with liposomal m-THPPo and the subcellular localization of m-THPPo was studied. Several assays such as TUNEL, annexin V/propidium iodide and Hoechst-33258 staining were performed after photodynamic treatments. The apoptotic initiation was assessed by cytochrome c and caspase-2 immunofluorescence.Results
m-THPPo encapsulated in liposomes showed a decrease of the fluorescence and singlet oxygen quantum yields, compared to those of m-THPPo dissolved in tetrahydrofuran. Liposomal m-THPPo showed colocalization with LysoTracker® and it induced photoinactivation of HeLa cells by an apoptotic mechanism. In apoptotic cells no relocalization of cytochrome c could be detected, but caspase-2 was positive immediately after photosensitizing treatments.Conclusions
Photodynamic treatment with liposomal m-THPPo leads to a significant percentage of apoptotic morphology of HeLa cells. The activation of caspase-2, without the relocalization of cytochrome c, indicates a mitochondrial-independent apoptotic mechanism.General significance
These results provide a better understanding of the cell death mechanism induced after liposomal m-THPPo photodynamic treatment. 相似文献18.
We have previously shown that the natural diterpenoid derivative S3 induced Bim upregulation and apoptosis in a Bax/Bak-independent manner. However, the exact molecular target(s) of S3 and the mechanism controlling Bim upregulation are still not clear. Here, we identify that S3 targets the selenoproteins TrxR1 and TrxR2 at the selenocysteine residue of the reactive center of the enzymes and inhibits their antioxidant activities. Consequently, cellular ROS is elevated, leading to the activation of FOXO3a, which contributes to Bim upregulation in Bax/Bak-deficient cells. Moreover, S3 retards tumor growth in subcutaneous xenograft tumors by inhibiting TrxR activity in vivo. Our studies delineate the signaling pathway controlling Bim upregulation, which results in Bax/Bak-independent apoptosis and provide evidence that the compounds can act as anticancer agents based on mammalian TrxRs inhibition. 相似文献
19.
Alleviation of chromium toxicity in rice seedlings by applying exogenous glutathione 总被引:1,自引:0,他引:1
Boyin Qiu Fanrong Zeng Shengguan Cai Xiaojian Wu Shamsi Imran Haider Feibo Wu Guoping Zhang 《Journal of plant physiology》2013
The effect of exogenous reduced glutathione (GSH) on alleviation of hexavalent chromium (Cr6+) toxicity to rice seedlings and its physiological mechanisms were comprehensively investigated in a series of experiments. Our results showed that growth and nutrient uptake of rice seedlings were dramatically reduced under 100 μM Cr6+ stress, and the reduction was significantly alleviated by exogenous GSH. Cr6+ stress also reduced cell viability in root tips and damaged ultrastructure of both chloroplasts and root cells, while the addition of GSH alleviates those negative effects. Cr-induced toxicity and GSH-caused Cr alleviation differed significantly between Cr-tolerant Line 117 (L117) and Cr-sensitive Line 41 (L41). Under Cr6+ stress, cystine content was increased and GSH content was decreased in rice plants, exogenous GSH, however, mitigated the Cr-toxicity by reversing the Cr-induced changes of the two compounds. The types of Cr-induced secretion of organic acids varied between the genotypes, where reduction in the contents of acetic and lactic acids and tartaric and malic acids were observed in L117 and L41, respectively. The addition of GSH alleviated the reduction of secretion of these organic acids. Exogenous GSH also altered the forms of Cr ions in the rhizosphere and the fraction of distribution at subcellular level in both shoots and roots. It may be concluded that the alleviation of Cr6+ toxicity by exogenous GSH is directly attributed to its regulation on forms of Cr ions in rhizosphere and their distribution at subcellular levels. 相似文献
20.
The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA. 相似文献