全文获取类型
收费全文 | 1059篇 |
免费 | 73篇 |
国内免费 | 2篇 |
出版年
2022年 | 8篇 |
2021年 | 16篇 |
2019年 | 8篇 |
2018年 | 14篇 |
2017年 | 8篇 |
2016年 | 18篇 |
2015年 | 24篇 |
2014年 | 34篇 |
2013年 | 42篇 |
2012年 | 54篇 |
2011年 | 60篇 |
2010年 | 41篇 |
2009年 | 39篇 |
2008年 | 78篇 |
2007年 | 52篇 |
2006年 | 55篇 |
2005年 | 47篇 |
2004年 | 42篇 |
2003年 | 53篇 |
2002年 | 62篇 |
2001年 | 17篇 |
2000年 | 10篇 |
1999年 | 18篇 |
1998年 | 17篇 |
1997年 | 15篇 |
1996年 | 10篇 |
1995年 | 15篇 |
1994年 | 8篇 |
1993年 | 14篇 |
1992年 | 15篇 |
1991年 | 10篇 |
1990年 | 13篇 |
1989年 | 14篇 |
1988年 | 14篇 |
1987年 | 13篇 |
1986年 | 10篇 |
1985年 | 6篇 |
1984年 | 13篇 |
1983年 | 9篇 |
1982年 | 6篇 |
1981年 | 14篇 |
1980年 | 7篇 |
1979年 | 8篇 |
1976年 | 8篇 |
1975年 | 10篇 |
1974年 | 14篇 |
1973年 | 9篇 |
1971年 | 10篇 |
1969年 | 9篇 |
1967年 | 7篇 |
排序方式: 共有1134条查询结果,搜索用时 31 毫秒
21.
Ramesh N. Patel Robert S. Robison Laszlo J. Szarka 《Applied microbiology and biotechnology》1990,34(1):10-14
Summary A key intermediate (S(–) 2-cyclohexyl-1,3-propanediol monoacetate) was made with high optical purity for the total synthesis of a new angiotensin converting enzyme inhibitor, Fosinopril. The stereoselective hydrolysis of 2-cyclohexyl-1,3-propanediol diacetate (I) and 2-phenyl-1,3-propanediol diacetate (II) was carried out with lipases. Among various lipases evaluated, only porcine pancreatic lipase (PPL) and Chromobacterium viscosum lipase demonstrated efficient conversion and gave the desired enantiomer of monoacetate. In aqueous solution, the desired S(–) monoacetate exhibited an optical purity of 65%–80% (30%–60% enantiomeric excess [e.e.]). However, when the same reactions were conducted in a biphasic system, the product S(–) monoacetate exhibited an optical purity of 99%–100% (98%–100% e.e.). The high purity product was achieved with 65 mol% yield at 1% substrate concentration. Among various solvents evaluated in biphasic systems, efficient hydrolysis was achieved in toluene, cyclohexane, and trichloro-trifluoroethane. The crude PPL was partially purified and two lipase fractions (A and B) were identified. Lipases A and B had a molecular mass of 38 000 and 40 000 daltons, respectively, and both were found to catalyze the hydrolysis of I and II to the appropriate monoacetate in a biphasic system.
Offprint requests to: R. N. Patel 相似文献
22.
The selectivity of statine-based inhibitors against various human aspartic proteinases. 总被引:7,自引:0,他引:7
下载免费PDF全文
![点击此处可从《The Biochemical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
R A Jupp B M Dunn J W Jacobs G Vlasuk K E Arcuri D F Veber D S Perlow L S Payne J Boger S de Laszlo et al. 《The Biochemical journal》1990,265(3):871-878
The interactions of five human enzymes (renin, pepsin, gastricsin, cathepsin D and cathepsin E) and the aspartic proteinase from Endothia parasitica with several series of synthetic inhibitors were examined. All of the inhibitors contained the dipeptide analogue statine or its phenylalanine or cyclohexylalanine homologues in the P1-P1' positions. The residues occupying the peripheral sub-sites (P4 to P3') were varied systematically and inhibitory constants were determined for the interactions with each of the proteinases. Inhibitors were elucidated that specifically inhibited human renin and did not affect any of the other human enzymes or the fungal proteinase. With suitable selection of residues to occupy individual sub-sites, effective inhibitors of specific human aspartic proteinases may now be designed. 相似文献
23.
Gudrun Borchert Sabine Bartel Inge Beyerdörfer Irmgard Küttner Laszlo Szekeres Ernst-Georg Krause 《Molecular and cellular biochemistry》1994,132(1):57-67
Evidence is accumulating that 7-oxo-prostacyclin (7-oxo-PGI2) induces a delayed indirect anti-adrenergic and cytoprotective effect on the myocardium, the mechanism of which is still unclear. To demonstrate that a single application of 7-oxo-PGI2 (50 g/kg i.m.) 48 h prior to starting experiments attenuates the isoprenaline inducible inotropic response and accumulation of cAMP, isolated hearts of pretreated animals were perfused in the Langendorff mode with and without isoprenaline (1 to 100 nM). The late anti-adrenergic effect of the drug was manifested by a significant attenuation in the elevation of cAMP levels as well as in contractile force development. This effect was not due to changes in cAMP generation as there were identical 1-adrenoceptor densities and affinities (as calculated from [3H]-CGP binding studies), Gi and Gs protein patterns (as taken from Western blots) as well as adenylyl cyclase activity measurements in the hearts studied. The anti-adrenergic potency of 7-oxo-PGI2, however, was found to be related to a significant rise in cyclic nucleotide hydrolysis by phosphodiesterase (PDE). Using the fast-performance liquid chromatographic separation for PDE isoforms, a significant increase in the activity of PDE isoforms I and IV (260±28 vs 110±12 pmol cGMP/min x enzyme fraction and 77±11 vs 34±3 pmol cAMP/min x enzyme fraction, respectively) was found in the solubilized fraction of cardiac membranes in comparison to untreated controls; PDE IV activity was also increased in the cytosolic fraction (106±14 vs 65±6 pmol cAMP/min x enzyme fraction). The hypothesis that the delayed anti-adrenergic effect of 7-oxo-PGI2 is initiated by an induction and accelerated synthesis of PDE I and IV in the heart is underlined by the fact that cycloheximide suppresses completely both the rise in PDE activities and the anti-adrenergic effects studied. It is suggested that an inducible predominance of cAMP degradation over its generation may be of relevance in processes related to heart protection. 相似文献
24.
Aniko Pay Claudia Jonak Laszlo Bögre Irute Meskiene Theresia Mairinger Aladar Szalay Erwin Heberle-Bors Heribert Hirt 《The Plant journal : for cell and molecular biology》1993,3(6):847-856
This paper reports on the isolation of a novel class of plant serine/threonine protein kinase genes, MsK-1 , MsK-2 and MsK-3 . They belong to the superfamily of cdc2 -like genes, but show highest identity to the Drosophila shaggy and rat GSK-3 proteins (66–70%). All of these kinases share a highly conserved catalytic protein kinase domain. Different amino-terminal extensions distinguish the different proteins. The different plant kinases do not originate from differential processing of the same gene as is found for shaggy , but are encoded by different members of a gene family. Similarly to the shaggy kinases, the plant kinases show different organ-specific and stage-specific developmental expression patterns. Since the shaggy kinases play an important role in intercellular communication in Drosophila development, the MsK kinases are expected to perform a similar function in plants. 相似文献
25.
26.
Yuan-Pu Di Elizabeth Repasky Andrei Laszlo Stuart Calderwood John Subjeck 《Journal of cellular physiology》1995,165(2):228-238
The percentage of T and B lymphocytes expressing a distinct cytoplasmic aggregate enriched in spectrin, ankyrin, and in several other proteins including protein kinase C greatly increases following various activation protocols. Members of the 70 kDa family of heat shock proteins (hsp70) temporarily bind to and stabilize unfolded segments of other proteins, a function apparently required for proper protein folding and assembly. Considering the multiprotein and dynamic nature of the lymphocyte aggregate, the possibility that hsp70 also might be associated with componets of this structure is considered here. Double immunofluorescence analysis indicates that hsp70 is a component of the lymphocyte aggregate and is coincident with spectrin in a subpopulation of freshly isolated, untreated lymphocytes from various murine tissues and in a T-lymphocyte hybridoma. When cell lysates of lymph node T cells are immunoprecipitated using an antibody against hsp70 or spectrin and then analyzed by Western blot utilizing the alternate antibody, it was found that hsp70 and spectrin coprecipitated with one another. Moreover, this coprecipitation could be abolished by addition of ATP. This latter observation was extended to lymphoid cells using a transient permeabilization procedure, and it was shown that addition of exogenous ATP results in the dissipation of the aggregate structure itself. Finally, conditions that result in T-cell activation and aggregate formation, i.e., treatment with the phorbol ester PMA or T-cell receptor cross-linking, also lead to the repositioning of hsp70 into the aggregate from a membrane/cytosolic locale in congruence with spectrin. These data suggest that hsp70 is an active component of the aggregate and that it may function in the interactions believed to occur in this unique activation-associated organelle. © 1995 Wiley-Liss, Inc. 相似文献
27.
Summary To study the influence of phosphorylation and oxidation on the repeat domains of human Tau protein, we faced the challenge to selectively dimerize two cysteine-containing peptides in the presence of a nearby phosphate group. To this end, we were able to demonstrate the utility of a selective dimerization approach by forming disulfide bonds in unprotected phosphopeptides and extended the methodology to unprotected glycopeptides. Activation of one cysteine of a peptide chain with 2,2-dithiodipyridine and coupling this thiopyridyl-peptide to another peptide chain, containing an unprotected cysteine residue, yielded the mixed dimers in high purities and reasonable yields. Phosphate or sugar side chains on either peptide component remained unaffected during the activation and dimerization processes. While for mixed dimers the activated peptides were isolated by chromatography, homodimers were obtained by a simple one-pot reaction after 1 h. We demonstrate that cysteines can be dimerized in unprotected phosphopeptides and glycopeptides, without any side reactions affecting these posttranslational modifications.Abbreviations DCM
dichloromethane
- DMF
N,N-dimethylformamide
- DTP
2,2-dithiodipyridine
- Fmoc
9-fluorenylmethyloxycarbonyl
- HPLC
high-performance liquid chromatography
- MALDI
matrix-assisted laser desorption/ionization
- MS
mass spectrometry
- NFT
neurofibrillary tangles
- PHF
paired helical filaments
- PKC
protein kinase C
- RP
reversed phase
-
human Tau protein
- TFA
trifluoroacetic acid
Parts of this paper were presented at the 24th European Peptide Symposium in Edinburgh, Scotland, U.K., September 8–13, 1996. 相似文献
28.
Transformation of Arabidopsis thaliana with the codA gene for choline oxidase; accumulation of glycinebetaine and enhanced tolerance to salt and cold stress 总被引:12,自引:0,他引:12
Hidenori Hayashi Alia Laszlo Mustardy Patchraporn Deshnium Miki Ida Norio Murata 《The Plant journal : for cell and molecular biology》1997,12(1):133-142
Glycinebetaine is one of the compatible solutes that accumulate in the chloroplasts of certain halotolerant plants when these plants are exposed to salt or cold stress. The codA gene for choline oxidase, the enzyme that converts choline into glycinebetaine, has previously been cloned from a soil bacterium, Arthrobacter globiformis. Transformation of Arabidopsis thaliana with the cloned codA gene under the control of the 35S promoter of cauliflower mosaic virus enabled the plant to accumulate glycinebetaine and enhanced its tolerance to salt and cold stress. At 300 mM NaCl, considerable proportions of seeds of transformed plants germinated well, whereas seeds of wild-type plants failed to germinate. At 100 mM NaCl, transformed plants grew well whereas wild-type plants did not do so. The transformed plants tolerated 200 mM NaCl, which was lethal to wild-type plants. After plants had been incubated with 400 mM NaCl for two days, the photosystem II activity of wild-type plants had almost completely disappeared, whereas that of transformed plants remained at more than 50% of the original level. When exposed to a low temperature in the light, leaves of wild-type plants exhibited symptoms of chlorosis, whereas those of transformed plants did not. These observations demonstrate that the genetic modification of Arabidopsis thaliana that allowed it to accumulate glycinebetaine enhanced its ability to tolerate salt and cold stress. 相似文献
29.
30.
Summary Unique fusiform or spindle-shaped particles (Phi bodies) and rods with hydroperoxidase (catalase and/or peroxidase) activity are present in human granulocyte precursors only in acute myelogenous leukemia (AML). These newly recognized particles are much more numerous and prominent than Auer rods. They may be rapidly and readily identified using the microscope in marrow or peripheral blood films when the procedures recommended in this paper for fixation, incubation for hydroperoxidase demonstration in 3,3-diaminobenzidine (DAB)/H2O2 medium, copper salt treatment and counterstaining (optional) with the Papanicolaou method are employed. Films prepared in the same manner but treated with benzidine/H2O2 medium for myeloperoxidase did not reveal these particles.We believe that Phi bodies are pathognomonic of AML since they are almost invariably present in AML patients with active disease. Their presence serves to distinguish AML from acute lymphocytic leukemia and from chronic granulocytic leukemia in blast crisis. Since the particles disappear in disease remission and reappear upon relapse, the recommended procedure is not only useful in diagnosis but in guiding therapy.When a very rapid diagnosis is needed, it is not necessary to counterstain the preparations, but the nuclei, cytoplasm and plasmalemma can readily be observed in the granulocyte precursors when they are counterstained by the Papanicolaou method. This treatment does not diminish the clarity of the Phi bodies and rods which stain by virtue of their peroxidatic activity.This cytochemical diagnostic procedure should be considered for adoption by hematology laboratories.This investigation was supported by NIH research grants DE02668, CA11265, DE04730, and RR05333 相似文献