全文获取类型
收费全文 | 645篇 |
免费 | 45篇 |
专业分类
690篇 |
出版年
2024年 | 1篇 |
2023年 | 3篇 |
2022年 | 7篇 |
2021年 | 16篇 |
2020年 | 15篇 |
2019年 | 9篇 |
2018年 | 19篇 |
2017年 | 12篇 |
2016年 | 28篇 |
2015年 | 26篇 |
2014年 | 35篇 |
2013年 | 57篇 |
2012年 | 49篇 |
2011年 | 64篇 |
2010年 | 25篇 |
2009年 | 26篇 |
2008年 | 46篇 |
2007年 | 40篇 |
2006年 | 23篇 |
2005年 | 31篇 |
2004年 | 35篇 |
2003年 | 33篇 |
2002年 | 30篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 8篇 |
1998年 | 3篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1987年 | 3篇 |
1985年 | 1篇 |
1984年 | 6篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1979年 | 3篇 |
排序方式: 共有690条查询结果,搜索用时 15 毫秒
21.
A mixture of 4-chloro-1-butanol and 2,2,2-Trifluoroethanol (TFE) has been used to generate Molten globule (MG) state of structurally
homologous but functionally different proteins bovine α-lactalbumin and hen egg-white lysozyme. The thermal denaturation was
done using UV–Visible spectroscopy. From UV–Visible profile, thermal transition was not observed beyond a particular concentration.
There was an indication of molten globule state in case of α-lactalbumin from circular dichroism experiments. By intrinsic
tryptophan fluorescence, acrylamide and potassium iodide quenching, 8-anilino-naphthalene sulfonic acid (ANS) binding and
energy transfer studies the presence of molten globule state was confirmed. Quantitative characterization of MG state and
determining the binding thermodynamics of ANS to the MG state was done using Isothermal Titration Calorimetry (ITC). Results
show that α-lactalbumin exists in MG state at a particular concentration but lysozyme does not show features of MG state. 相似文献
22.
Anu Manhas Dhaval Patel Mohsin Y. Lone Prakash C. Jha 《Journal of cellular biochemistry》2019,120(9):14531-14543
In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D -xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors. 相似文献
23.
Heat Shock Response and Protein Degradation: Regulation of HSF2 by the Ubiquitin-Proteasome Pathway 总被引:8,自引:3,他引:8 下载免费PDF全文
Anu Mathew Sameer K. Mathur Richard I. Morimoto 《Molecular and cellular biology》1998,18(9):5091-5098
Mammalian cells coexpress a family of heat shock factors (HSFs) whose activities are regulated by diverse stress conditions to coordinate the inducible expression of heat shock genes. Distinct from HSF1, which is expressed ubiquitously and activated by heat shock and other stresses that result in the appearance of nonnative proteins, the stress signal for HSF2 has not been identified. HSF2 activity has been associated with development and differentiation, and the activation properties of HSF2 have been characterized in hemin-treated human K562 erythroleukemia cells. Here, we demonstrate that a stress signal for HSF2 activation occurs when the ubiquitin-proteasome pathway is inhibited. HSF2 DNA-binding activity is induced upon exposure of mammalian cells to the proteasome inhibitors hemin, MG132, and lactacystin, and in the mouse ts85 cell line, which carries a temperature sensitivity mutation in the ubiquitin-activating enzyme (E1) upon shift to the nonpermissive temperature. HSF2 is labile, and its activation requires both continued protein synthesis and reduced degradation. The downstream effect of HSF2 activation by proteasome inhibitors is the induction of the same set of heat shock genes that are induced during heat shock by HSF1, thus revealing that HSF2 affords the cell with a novel heat shock gene-regulatory mechanism to respond to changes in the protein-degradative machinery. 相似文献
24.
A complete synthesis of 1-O-hexadecyl-2-O-N-(heptadec-8-cis-enyl)carbamyl-sn-glycero-3-Phosphocholine, a novel analog of phosphatidylcholine, has been described. Each step is simple to perform and gives the desired products in high yield. Also, some of the intermediates formed during the synthesis have been efficiently utilized to prepare 1-O-hexadecyl-2-O-oleyl-sn-glycero-3-phosphocholine, 1-O-hexadecyl-2-oleoyl-sn-glycero-3-phosphochloine and 3-O-hexadecyl-2-oeloyl-sn-glycero-1-phosphocholine. These phosphatidylcholine (PC) analogs are useful for studying the possible role of phospholipases in the capture and lyses of liposomes in vivo. 相似文献
25.
Effects of SO2, aqueous fluoride (NaF) and a solution of nitrogen compounds (NH4NO3) on the visible symptoms, pollutant accumulation and ultrastructure of Scots pine (Pinus sylvestris L.) and Norway spruce [Picea abies (L.) Karst.] seedlings were studied in an open-air experiment lasting for 3 consecutive years. Visible injury symptoms were
most pronounced in combination exposures and whenever F was applied. Visible symptoms correlated well with needle pollutant
concentrations. Exposure to NaF increased needle F contents particularly when F was applied with SO2 or NH4NO3. This suggests that a reduction in N or SO2 emissions, in F polluted areas, could improve the condition of conifers via decreased accumulation of phytotoxic F in the
needles. Norway spruce needles accumulated 2 – 10 times as much S and F as those of Scots pine. Microscopic observations showed
various changes in the needle mesophyll cell ultrastructure. In both species, exposure to SO2 increased significantly the amount of cytoplasmic vacuoles, suggesting detoxification of excess sulphate or low pH. F treatments
resulted in a significant enlargement of plastoglobuli in Scots pine and a darkening of plastoglobuli in Norway spruce. All
exposures enhanced the accumulation of lipid bodies. An increased portion of translucent plastoglobuli was most pronounced
in N treatments. Many of the ultrastructural changes and visible symptoms appeared only as number of years exposed increased,
indicating that long-term experiments are needed. Both visible symptoms and ultrastructural changes pointed to the more pronounced
sensitivity of Norway spruce compared to Scots pine. Ultrastructural results mostly supported earlier qualitative observations
of F, N and SO2 effects on needle mesophyll cell ultrastructure. However, no reduction of thylakoids in SO2 containing exposure or curling of thylakoids in F exposure could be detected in the present study.
Received: 5 December 1994 / Accepted: 28 April 1995 相似文献
26.
Juha Heijari Minna Kivimäenpää Helinä Hartikainen Riitta Julkunen-Tiitto Anu Wulff 《Plant and Soil》2006,282(1-2):27-39
In greenhouse experiments, selenium (Se) has been shown to defend plants against detrimental effects of heavy UV-B radiation
stress. The aim of this study was to investigate whether this positive effect can be found in open-field conditions with enhancement
of UV-B radiation. In the experiment, conducted with strawberry (Fragaria×ananassa, cultivars “Jonsok” and “Polka”) over two growing seasons, plants were exposed to UV-B radiation (including UV-A) and cultivated
without Se or supplied with Se added at two levels (0.1 and 1.0 mg kg−1). The plants were monitored for growth, flavonoids, chlorophyll fluorescence, net photosynthesis as well as tissue and cell
structure. Photosystem II was observed to be sensitive to UV-B stress under field conditions. In the leaves, a decrease in
Fv/Fm was seen at the end of the growing season, implying a cumulative effect of UV-B stress. Several parameters, especially cell
and tissue structures, were affected by UV-B and UV-A treatments, which proves the need for UV-A control in outdoor UV-B supplementation
studies. Addition of Se did not ameliorate the harmful effects of UV-B but the lower Se-increment level increased leaf growth.
The effects of UV-B and Se differed during the two experimental years, indicating the need to repeat experiments during several
growing seasons. 相似文献
27.
The NF-kappaB p50 is the N-terminal processed product of the precursor, p105. It has been suggested that p50 is generated not from full-length p105 but cotranslationally from incompletely synthesized molecules by the proteasome. We show that the 20S proteasome endoproteolytically cleaves the fully synthesized p105 and selectively degrades the C-terminus of p105, leading to p50 generation in a ubiquitin-independent manner. As small as 25 residues C-terminus to the site of processing are sufficient to promote processing in vivo. However, any p105 mutant that lacks complete ankyrin repeat domain (ARD) is processed aberrantly, suggesting that native processing must occur from a precursor, which extends beyond the ARD. Remarkably, the mutant p105 that lacks the internal region including the glycine-rich region (GRR) is completely degraded by 20S proteasome in vitro. This suggests that the GRR impedes the complete degradation of the p105 precursor, thus contributing to p50 generation. 相似文献
28.
Vivek Kumar Mukesh M. Mudgal Nidhi Rani Amrita Jha Manu Jaggi Anu T. Singh 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):763-770
A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC50 = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC50 = 6.1 μm) and oral (IC50 = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents. 相似文献
29.
30.
Premkumar L Sawkar AR Boldin-Adamsky S Toker L Silman I Kelly JW Futerman AH Sussman JL 《The Journal of biological chemistry》2005,280(25):23815-23819
Gaucher disease is an inherited metabolic disorder caused by mutations in the lysosomal enzyme acid-beta-glucosidase (GlcCerase). We recently determined the x-ray structure of GlcCerase to 2.0 A resolution (Dvir, H., Harel, M., McCarthy, A. A., Toker, L., Silman, I., Futerman, A. H., and Sussman, J. L. (2003) EMBO Rep.4, 704-709) and have now solved the structure of Glc-Cerase conjugated with an irreversible inhibitor, conduritol-B-epoxide (CBE). The crystal structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the catalytic nucleophile. However, only one of two alternative conformations of a pair of flexible loops (residues 345-349 and 394-399) located at the entrance to the active site in native GlcCerase is observed in the GlcCerase-CBE structure, a conformation in which the active site is accessible to CBE. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. This possibility is supported by a cluster of mutations in loop 394-399 that cause Gaucher disease by reducing catalytic activity. Moreover, in silico mutational analysis demonstrates that all these mutations stabilize the conformation that limits access to the active site, thus providing a mechanistic explanation of how mutations in this loop result in Gaucher disease. 相似文献