全文获取类型
收费全文 | 785篇 |
免费 | 92篇 |
国内免费 | 16篇 |
出版年
2024年 | 8篇 |
2023年 | 16篇 |
2022年 | 14篇 |
2021年 | 19篇 |
2020年 | 14篇 |
2019年 | 24篇 |
2018年 | 26篇 |
2017年 | 22篇 |
2016年 | 20篇 |
2015年 | 15篇 |
2014年 | 40篇 |
2013年 | 43篇 |
2012年 | 32篇 |
2011年 | 48篇 |
2010年 | 50篇 |
2009年 | 66篇 |
2008年 | 68篇 |
2007年 | 64篇 |
2006年 | 48篇 |
2005年 | 28篇 |
2004年 | 28篇 |
2003年 | 20篇 |
2002年 | 17篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 10篇 |
1998年 | 5篇 |
1997年 | 8篇 |
1996年 | 5篇 |
1995年 | 8篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1992年 | 3篇 |
1991年 | 4篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1985年 | 6篇 |
1984年 | 10篇 |
1983年 | 7篇 |
1982年 | 15篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1979年 | 9篇 |
1978年 | 4篇 |
1976年 | 4篇 |
1975年 | 7篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1971年 | 2篇 |
排序方式: 共有893条查询结果,搜索用时 15 毫秒
71.
The purpose of this research was to develop and optimize a controlled-release multiunit floating system of a highly water
soluble drug, ranitidine HCl, using Compritol, Gelucire 50/13, and Gelucire 43/01 as lipid carriers. Ranitidine HCl-lipid
granules were prepared by the melt granulation technique and evaluated for in vitro floating and drug release. ethyl cellulose,
methylcellulose, and hydroxypropyl methylcellulose were evaluated as release rate modifiers. A 32 full factorial design was used for optimization by taking the amounts of Gelucire 43/01 (X
1) and ethyl cellulose (X
2) as independent variables, and the percentage drug released in 1(Q1), 5(Q5), and 10 (Q10) hours as dependent variables. The results revealed that the moderate amount of Gelucire 43/01 and ethyl cellulose provides
desired release of ranitidine hydrochloride from a floating system. Batch F4 was considered optimum since it contained less
Gelucire and was more similar to the theoretically predicted dissolution profile (f2=62.43). The temperature sensitivity studies for the prepared formulations at 40°C/75% relative humidity for 3 months showed
no significant change in in vitro drug release pattern. These studies indicate that the hydrophobic lipid Gelucire 43/01 can
be considered an effective carrier for design of a multiunit floating drug delivery system for highly water soluble drugs
such as ranitidine HCl.
Published: April 13, 2007 相似文献
72.
A novel method was developed using capillary electrophoresis (CE) coupled with tris(2,2′‐bipyridyl)ruthenium(II) electrogenerated chemiluminescence (ECL) for highly sensitive detection of metformin hydrochloride (MH) derivatizatized with acetaldehyde. The precolumn derivatization of MH with acetaldehyde was performed in phosphate buffer solution (0.3 mol/L, pH 7.5) at room temperature for 120 min. The effects of acetaldehyde concentration, buffer pH, electrokinetic voltage and injection time were investigated. Under optimized detection conditions, the MH ECL detection sensitivity was more than 120 times that without derivatization. The linear concentration range for MH was 0.001–15.00 μg/mL (with a correlation coefficient of 0.9992). The detection limit was 0.31 ng/mL with a signal:noise ratio of 3. The recoveries of MH in human urine were in the range 98.50–99.72%. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
73.
The objective of this study was to synthesize and characterize the hydrochloride salt of carbendazim with the aim of improving
the intrinsic solubility of the parent compound. Carbendazim hydrochloride dihydrate was synthesized for the purpose of increasing
the aqueous solubility of the parent drug, carbendazim. This was done with the commonly used saturation and cooling method.
The structure was determined by single crystal radiograph crystallography, and the hydrochloride salt was found to be a dihydrate.
The salt crystallized in a P 21 21 21 (#19) space group, which is typical for nonplanar, achiral, and noncentrosymmetric molecules. The asymmetric unit is comprised
of 1 molecule each of carbendazim and chloride and 2 water molecules. The carbendazim molecules arrange themselves in a helical
structure, with the waters and the chloride molecules in the channel linking the helix. The crystal lattice is held together
by numerous hydrogen bonds, as well as van der Waals interactions. The melting point of the salt is 125.6°C. The solubility
of the salt is 6.08 mg/mL, which is a thousand-fold increase from the intrinsic solubility (6.11 μg/mL) of the free base.
Published: September 20, 2005 相似文献
74.
Zhang F Ji LN Tang L Hu J Hu HY Xu HJ He JH 《Acta biochimica et biophysica Sinica》2005,37(2):113-118
Human α-synuclein is a presynaptic terminal protein and can form insoluble fibrils that are believed to play an important role in the pathogenesis of several neurodegenerative diseases such as Parkinson‘s disease, dementia with Lewy bodies and Lewy body variant of Alzheimer‘s disease. In this paper, in situ atomic force microscopy has been used to study the structural properties of α-synuclein fibrils in solution using two different atomic force microscopy imaging modes: tapping mode and contact mode. In the in situ contact mode atomic force microscopy experiments α-synuclein fibrils quickly broke into fragments, and a similar phenomenon was found using tapping mode atomic force microscopy in which α-synuclein fibrils were incubated with guanidine hydrochloride (0.6 M). The α-synuclein fibrils kept their original filamentous topography for over 1h in the in situ tapping mode atomic force microscopy experiments. The present results provide indirect evidence on how 13-sheets assemble into α-synuclein fibrils on a nanometer scale. 相似文献
75.
Native insulin denatures and unfolds in the presence of thiol catalyst via disulfide scrambling (isomerization). It undergoes two transient non-native conformational isomers, followed by an irreversible breakdown of the protein to form oxidized A- and B-chain. Denaturation and breakdown of native insulin may occur under physiological conditions. At 37 degrees C, pH 7.4, and in the presence of cysteine (0.2 mM), native insulin decomposes with a pseudo first order kinetic of 0.075 h(-1). At 50 degrees C, the rate increases by 5-fold. GdnCl and urea induced denaturation of insulin follows the same mechanism. These results demonstrate that stability and unfolding pathway of insulin in the presence of endogenous thiol differ fundamentally from its reversible denaturation observed in the absence of thiol, in which native disulfide bonds of insulin were kept intact during the process of denaturation. 相似文献
76.
Angiotensin II (Ang II) induces a prominent and sustained nitration and activation of ERK1/2 in rat vascular smooth muscle cells, both mediated via AT1 receptor. Nitration and activation was also shown for recombinant non-activated extracellular signal-regulated kinase (ERK) and MEK. Nitration and phosphorylation of ERK1/2 by Ang II was significantly inhibited by NAD(P)H inhibitors and scavengers of oxygen and nitrogen reactive species and completely blocked by a selective inducible nitric-oxide synthase inhibitor. MEK inhibitor U0126 did not affect ERK nitration but completely blocked activation. These data indicate that Ang II nitrates and activates ERK1/2 via a reactive species-sensitive pathway. 相似文献
77.
Narimoto T Sakurai K Okamoto A Chatani E Hoshino M Hasegawa K Naiki H Goto Y 《FEBS letters》2004,576(3):313-319
Although the stability of globular proteins has been studied extensively, that of amyloid fibrils is scarcely characterized. Beta2-microglobulin (beta2-m) is a major component of the amyloid fibrils observed in patients with dialysis-related amyloidosis. We studied the effects of guanidine hydrochloride on the amyloid fibrils of beta2-m, revealing a cooperative unfolding transition similar to that of the native state. The stability of amyloid fibrils increased on the addition of ammonium sulfate, consistent with a role of hydrophobic interactions. The results indicate that the analysis of unfolding transition is useful to obtain insight into the structural stability of amyloid fibrils. 相似文献
78.
目的观察盐酸氨溴索联合吸入布地奈德对致敏大鼠气道炎症及肺组织氧化应激水平的影响。方法32只雄性Wistar大鼠随机分为对照组、致敏组、布地奈德干预组(BUD)和氨溴索+布地奈德干预组(AMB+BUD)。测定各组大鼠支气管肺泡灌洗液(ABLF)细胞计数及分类;取部分肺组织行HE染色病理学观察;测定肺组织中活性氧(ROS)、谷胱甘肽(GSH)含量。结果BUD+AMB组BALF中细胞总数、嗜酸粒细胞数、淋巴细胞数以及肺组织ROS含量均明显低于BUD组(P〈0.05,P〈0.01),而肺组织GSH含量明显高于BUD组(P〈0.01);同时BUD+AMB组大鼠支气管壁炎症反应及病理损伤程度也较BUD组明显减轻。相关性分析显示:各组大鼠BALF中细胞总数、嗜酸性粒细胞数、淋巴细胞数与肺组织ROS含量之间均呈正相关(P〈0.05)。结论氧化应激在哮喘发病过程中发挥着重要作用。盐酸氨溴索通过其抗炎、抗氧化作用,与吸入糖皮质激素合用对哮喘急性发作有协同治疗效果。 相似文献
79.
The folding rates of two-state single-domain proteins are generally resistant to small-scale changes in amino acid sequence. For example, having surveyed here over 700 single-residue substitutions in 24 well-characterized two-state proteins, we find that the majority (55%) of these substitutions affect folding rates by less than a factor of 2, and that only 9% affect folding rates by more than a factor of 8. Among those substitutions that significantly affect folding rates, we find that accelerating substitutions are an order of magnitude less common than those that decelerate the process. One of the most extreme outliers in this data set, an arginine-to-phenylalanine substitution at position 48 (R48F) of chymotrypsin inhibitor 2 (CI2), accelerates the protein's folding rate by a factor of 36 relative to that of the wild-type protein and is the most accelerating substitution reported to date in a two-state protein. In order to better understand the origins of this anomalous behavior, we have characterized the kinetics of multiple additional substitutions at this position. We find that substitutions at position 48 in CI2 fall into two distinct classes. The first, comprising residues that ablate the charge of the wild-type arginine but retain the hydrophobicity of its alkane chain, accelerate folding by at least 10-fold. The second class, comprising all other residues, produces folding rates within a factor of two of the wild-type rate. A significant positive correlation between hydrophobicity and folding rate across all of the residues we have characterized at this position suggests that the hydrophobic methylene units of the wild-type arginine play a significant role in stabilizing the folding transition state. Likewise, studies of the pH dependence of the histidine substitution indicate a strong correlation between folding rate and charge state. Thus, mutations that ablate the arginine's positive charge while retaining the hydrophobic contacts of its methylene units tend to dramatically accelerate folding. Previous studies have suggested that arginine 48 plays an important functional role in CI2, which may explain why it is highly conserved despite the anomalously large deceleration it produces in the folding of this protein. 相似文献
80.
Designed ankyrin repeat proteins (DARPins) that specifically bind to almost any target can be obtained by ribosome display or phage display from combinatorial libraries. Although DARPins are already very stable molecules, molecular dynamics simulations, equilibrium denaturation experiments, structural studies, and recent NMR experiments suggested that the unfolding of the original C-terminal capping repeat (C-cap), taken from a natural ankyrin repeat protein, limits the stability of the initial DARPin design. Several point mutations had been introduced to optimize the C-cap and were shown to indeed further increase the stability of DARPins. We now determined crystal structures of DARPins with one or three full-consensus internal repeats (NI1C or NI3C) between an N-terminal capping repeat and mutants of the C-cap. An NI1C mutant, in which the C-cap was only extended by three additional helix-forming residues, showed no structural change but reduced B-factors in the C-cap. An NI3C C-cap mutant carrying five additional mutations in the interface to the preceding repeat, previously designed by using the consensus sequence as a guide, showed a rigid-body movement of the C-cap towards the internal repeat. This movement results in an increased buried surface area and a superior surface complementarity and explains the improved stability in equilibrium unfolding, compared to the original C-cap. A C-cap mutant with three additional mutations introducing suitably spaced charged residues did not show formation of salt bridges, explaining why its stability was not increased further. These structural studies underline the importance of repeat coupling for stability and help in the further design of this protein family. 相似文献