全文获取类型
收费全文 | 758篇 |
免费 | 47篇 |
出版年
2021年 | 13篇 |
2020年 | 7篇 |
2019年 | 5篇 |
2018年 | 11篇 |
2017年 | 11篇 |
2016年 | 21篇 |
2015年 | 21篇 |
2014年 | 28篇 |
2013年 | 33篇 |
2012年 | 29篇 |
2011年 | 46篇 |
2010年 | 21篇 |
2009年 | 24篇 |
2008年 | 36篇 |
2007年 | 32篇 |
2006年 | 39篇 |
2005年 | 36篇 |
2004年 | 28篇 |
2003年 | 24篇 |
2002年 | 29篇 |
2001年 | 18篇 |
2000年 | 20篇 |
1999年 | 19篇 |
1998年 | 13篇 |
1997年 | 9篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1993年 | 10篇 |
1992年 | 11篇 |
1991年 | 12篇 |
1990年 | 20篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 8篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 6篇 |
1981年 | 7篇 |
1979年 | 12篇 |
1978年 | 5篇 |
1977年 | 11篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 7篇 |
1973年 | 7篇 |
1972年 | 5篇 |
1971年 | 6篇 |
1968年 | 8篇 |
排序方式: 共有805条查询结果,搜索用时 15 毫秒
91.
We assessed the catalase bioactivity and hydrogen peroxide (H(2)O(2)) production rate in human breast cancer (HBC) cell lines and compared these with normal human breast epithelial (HBE) cells. We observed that the bioactivity of catalase was decreased in HBC cells when compared with HBE cells. This was also accompanied by an increase in H(2)O(2) steady-state levels in HBC cells. Silencing the catalase gene led to a further increase in the steady-state level of H(2)O(2) which was also accompanied by an increase in growth rate of HBC cells. Catalase activity was up regulated on treatment with superoxide (O(2)(-)) scavengers such as pegylated SOD (PEG-SOD, indicating inhibition of catalase by the increased O(2)(-) produced by HBC cells. Transfection of either catalase or glutathione peroxidase to HBC cells decreased intracellular H(2)O(2) levels and led to apoptosis of these cells. The H(2)O(2) produced by HBC cells inhibited PP2A activity accompanied by increased phosphorylation of Akt and ERK1/2. The importance of catalase bioactivity in breast cancer was further confirmed as its bioactivity was also decreased in human breast cancer tissues when compared to normal breast tissues. We conclude that inhibition of catalase bioactivity by O(2)(-) leads to an increase in steady-state levels of H(2)O(2) in HBC cells, which in turn inhibits PP2A activity, leading to phosphorylation of ERK 1/2 and Akt and resulting in HBC cell proliferation. 相似文献
92.
Pahari B Chakraborty S Chaudhuri S Sengupta B Sengupta PK 《Chemistry and physics of lipids》2012,165(4):488-496
Plant flavonoids are emerging as novel therapeutic drugs for free radical mediated diseases, for which cell membranes mainly serve as targets for lipid peroxidation and related deleterious effects. Screening and characterization of these ubiquitous, therapeutically potent polyphenolic compounds require a clear understanding regarding their binding and possible locations in membranes, as well as quantitative estimates of relevant parameters such as partition coefficients, antioxidant and radical scavenging capacities. In this article we present perspectives emphasizing novel uses of the exquisitely sensitive 'two color' intrinsic fluorescence of plant flavonoids (which arise due to highly efficient photoinduced excited state intramolecular proton transfer (ESIPT) reactions) to explore their binding to model biomembranes consisting of phosphatidylcholine liposomes. Extension of such studies to natural biomembranes of relevant interest is also exemplified. Spectrophotometric assays reveal that typical mono- as well as poly-hydroxy substituted flavonoids have remarkable inhibitory actions on lipid peroxidation, and are significantly more potent antioxidants (2.5-4 times higher) compared to the reference compound Trolox (an water soluble derivative of vitamin E). The structure-activity relationships emerging from such studies are consistent with theoretical predictions based on quantum chemical computations. 相似文献
93.
94.
Sitaram A Dennis MK Chaudhuri R De Jesus-Rojas W Tenza D Setty SR Wood CS Sviderskaya EV Bennett DC Raposo G Bonifacino JS Marks MS 《Molecular biology of the cell》2012,23(16):3178-3192
Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine-based sorting signal in the pigment cell-specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1- and AP-3-favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs. 相似文献
95.
96.
Subhankar Paul Madhuchhanda Kundu Kali P. Das Saroj Mishra Tapan K. Chaudhuri 《Journal of biological physics》2008,34(6):539-550
Equilibrium unfolding of a 69-kDa monomeric Escherichia coli maltodextrin glucosidase (MalZ) was studied using intrinsic and extrinsic fluorescence spectroscopy. The unfolding transition
of MalZ followed a three-state process, involving the formation of a stable intermediate state having more exposed hydrophobic
surface. It was found that the protein structure can be easily perturbed by low concentration of guanidium hydrochloride (GdnHCl)
and, at a GdnHCl concentration of 2 M, MalZ was denatured completely. The active site of the protein also has been proved
to be sensitive to a low concentration of GdnHCl since MalZ deactivated at 0.5 M GdnHCl completely. The surface hydrophobicity
and ANS-binding site of the protein have been determined to be 150.7 and 0.24, respectively. Perhaps the formation of the
stable unfolding intermediate, having higher surface hydrophobicity, may be one of the reasons for aggregation of MalZ and
its recognition by chaperonin GroEL during the assisted folding pathway. 相似文献
97.
GLUT1 and GLUT9 as major contributors to glucose influx in HepG2 cells identified by a high sensitivity intramolecular FRET glucose sensor 总被引:2,自引:0,他引:2
Genetically encoded FRET glucose nanosensors have proven to be useful for imaging glucose flux in HepG2 cells. However, the dynamic range of the original sensor was limited and thus it did not appear optimal for high throughput screening of siRNA populations for identifying proteins involved in regulation of sugar flux. Here we describe a hybrid approach that combines linker-shortening with fluorophore-insertion to decrease the degrees of freedom for fluorophore positioning leading to improved nanosensor dynamics. We were able to develop a novel highly sensitive FRET nanosensor that shows a 10-fold higher ratio change and dynamic range (0.05-11 mM) in vivo, permitting analyses in the physiologically relevant range. As a proof of concept that this sensor can be used to screen for proteins playing a role in sugar flux and its control, we used siRNA inhibition of GLUT family members and show that GLUT1 is the major glucose transporter in HepG2 cells and that GLUT9 contributes as well, however to a lower extent. GFP fusions suggest that GLUT1 and 9 are preferentially localized to the plasma membrane and thus can account for the transport activity. The improved sensitivity of the novel glucose nanosensor increases the reliability of in vivo glucose flux analyses, and provides a new means for the screening of siRNA collections as well as drugs using high-content screens. 相似文献
98.
Chaudhuri B Hörmann F Lalonde S Brady SM Orlando DA Benfey P Frommer WB 《The Plant journal : for cell and molecular biology》2008,56(6):948-962
Although soil contains only traces of soluble carbohydrates, plant roots take up glucose and sucrose efficiently when supplied in artificial media. Soluble carbohydrates and other small metabolites found in soil are in part products from exudation from plant roots. The molecular nature of the transporters for uptake and exudation is unknown. Here, fluorescence resonance energy transfer (FRET) glucose and sucrose sensors were used to characterize accumulation and elimination of glucose and sucrose in Arabidopsis roots tips. Using an improved image acquisition set-up, FRET responses to perfusion with carbohydrates were detectable in roots within less than 10 sec and over a wide concentration range. Accumulation was fully reversible within 10-180 sec after glucose or sucrose had been withdrawn; elimination may be caused by metabolism and/or efflux. The rate of elimination was unaffected by pre-incubation with high concentrations of glucose, suggesting that elimination is not due to accumulation in a short-term buffer such as the vacuole. Glucose and sucrose accumulation was insensitive to protonophores, was comparable in media differing in potassium levels, and was similar at pH 5.8, 6.8 and 7.8, suggesting that both influx and efflux may be mediated by proton-independent transport systems. High-resolution expression mapping in root tips showed that only a few proton-dependent transport of the STP (Sugar Transport Protein) and SUT/SUC (Sucrose Transporter/Carrier) families are expressed in the external cell layers of root tips. The root expression maps may help to pinpoint candidate genes for uptake and release of carbohydrates from roots. 相似文献
99.
Wilfred U Ajayi Minu Chaudhuri George C Hill 《The Journal of biological chemistry》2002,277(10):8187-8193
Trypanosoma brucei possesses a non-cytochrome, salicylhydroxamic acid (SHAM)-sensitive ubiquinol:oxygen oxidoreductase known as trypanosome alternative oxidase (TAO). TAO and similar SHAM-sensitive alternative oxidases (AOXs) contain 2-3 conserved diiron-binding motifs (EXXH). Site-directed mutagenesis of residues H165A, E214A, E266A, and H269L within the conserved EXXH motif abolished the ability of TAO to complement the heme-deficient Escherichia coli strain GE1387. These mutations also reduced the growth of this E. coli auxotroph to about 85% of the control cells containing wild type TAO. In contrast, mutation of residues outside the EXXH motifs, e.g. V205A, L243A, C261A, and V271A, had little effect on complementation, and the reduction in the cell growth was about 5-10%. Mutations of the putative iron-binding residues within the EXXH motifs of TAO abolished the ability to confer SHAM-sensitive respiration to E. coli heme mutant, whereas mutations of the non-conserved/non-iron binding residues resulted in 20-30% reduction of SHAM-sensitive respiration of the E. coli auxotroph. Immunoblot analysis of the total cellular protein of transformed E. coli revealed that the expression level of mutated and wild type TAO (35 kDa) remained unaltered. Mutation at C261A produced a truncated but functional protein of 28 kDa. The addition of ortho-phenanthroline to the growth medium produces a non-functional TAO. The effect of ortho-phenanthroline on the activity of TAO was completely alleviated by the addition of iron in the medium, which suggests that iron is needed for the activity of TAO. This work demonstrates that His-165, Glu-214, Glu-266, and His-269 and the presence of iron are essential for the activity of TAO. 相似文献
100.
U Chaudhuri J Das K Haberer J Maniloff 《Biochemical and biophysical research communications》1979,89(2):643-649
Acriflavine inhibits the growth of a double stranded DNA mycoplasmavirus, but stimulates the growth of a single stranded DNA mycoplasmavirus. Maximal stimulation occurs when acriflavine is added late during infection and reflects an increased synthesis of viral relative to cellular DNA. 相似文献