全文获取类型
收费全文 | 520篇 |
免费 | 48篇 |
专业分类
568篇 |
出版年
2021年 | 9篇 |
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 6篇 |
2016年 | 10篇 |
2015年 | 13篇 |
2014年 | 19篇 |
2013年 | 18篇 |
2012年 | 27篇 |
2011年 | 27篇 |
2010年 | 15篇 |
2009年 | 27篇 |
2008年 | 37篇 |
2007年 | 25篇 |
2006年 | 16篇 |
2005年 | 25篇 |
2004年 | 21篇 |
2003年 | 19篇 |
2002年 | 10篇 |
2001年 | 19篇 |
2000年 | 12篇 |
1999年 | 25篇 |
1998年 | 14篇 |
1997年 | 6篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 10篇 |
1988年 | 7篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 4篇 |
1983年 | 6篇 |
1981年 | 3篇 |
1979年 | 3篇 |
1977年 | 6篇 |
1976年 | 3篇 |
1975年 | 5篇 |
1974年 | 4篇 |
1971年 | 6篇 |
1970年 | 5篇 |
1968年 | 3篇 |
1967年 | 4篇 |
1966年 | 5篇 |
1965年 | 3篇 |
排序方式: 共有568条查询结果,搜索用时 15 毫秒
481.
Simon Ströbel Marko Loparic David Wendt Andreas D Schenk Christian Candrian Raija LP Lindberg Florina Moldovan Andrea Barbero Ivan Martin 《Arthritis research & therapy》2010,12(2):R34
Introduction
Oxygen is a critical parameter proposed to modulate the functions of chondrocytes ex-vivo as well as in damaged joints. This article investigates the effect of low (more physiological) oxygen percentage on the biosynthetic and catabolic activity of human articular chondrocytes (HAC) at different phases of in vitro culture. 相似文献482.
483.
Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts 总被引:23,自引:0,他引:23
T Saitoh M Sundsmo J M Roch N Kimura G Cole D Schubert T Oltersdorf D B Schenk 《Cell》1989,58(4):615-622
Fibroblasts that harbor an antisense construct of amyloid beta protein precursor (ABPP) cDNA, A-1, produced less ABPP mRNA and ABPP and grew poorly. Normal growth was restored when either parent cell conditioned medium (CM) or purified ABPP was provided. The capacity of the CM to restore cell growth was abolished by passage through an anti-ABPP immunoaffinity column; the activity was in the bound fraction. A Mr 90,000 protein recognized by the anti-ABPP antibody was diminished in the CM of A-1. CM from ABPP cDNA-transfected cells expressing high levels of ABPP was more potent than that from non-transfected parent cells in restoring A-1 growth. These results indicate that ABPP is released from cells into the medium and has an autocrine function in growth regulation. 相似文献
484.
Zhao B Yu M Neitzel M Marugg J Jagodzinski J Lee M Hu K Schenk D Yednock T Basi G 《The Journal of biological chemistry》2008,283(5):2927-2938
Production of amyloid beta peptides (Abeta), followed by their deposition in the brain as amyloid plaques, contributes to the hallmark pathology of Alzheimer disease. The enzymes responsible for production of Abeta, BACE1 and gamma-secretase, are therapeutic targets for treatment of Alzheimer disease. Two presenilin (PS) homologues, referred to as PS1 and PS2, comprise the catalytic core of gamma-secretase. In comparing presenilin selectivity of several classes of gamma-secretase inhibitors, we observed that sulfonamides in general tend to be more selective for inhibition of PS1-comprising gamma-secretase, as exemplified by ELN318463 and BMS299897. We employed a combination of chimeric constructs and point mutants to identify structural determinants for PS1-selective inhibition by ELN318463. Our studies identified amino acid residues Leu(172), Thr(281), and Leu(282) in PS1 as necessary for PS1-selective inhibition by ELN318463. These residues also contributed in part to the PS1-selective inhibition by BMS299897. Alanine scanning mutagenesis of areas flanking Leu(172), Thr(281), and Leu(282) identified additional amino acids that affect inhibitor potency of not only these sulfonamides but also nonsulfonamide inhibitors, without affecting Abeta production and presenilin endoproteolysis. Interestingly, many of these same residues have been identified previously to be important for gamma-secretase function. These findings implicate TM3 and a second region near the carboxyl terminus of PS1 aminoterminal fragment in mediating the activity of gamma-secretase inhibitors. Our observations demonstrate that PS-selective inhibitors of gamma-secretase are feasible, and such inhibitors may allow differential inhibition of Abeta peptide production and Notch signaling. 相似文献
485.
Kosodo Y Toida K Dubreuil V Alexandre P Schenk J Kiyokage E Attardo A Mora-Bermúdez F Arii T Clarke JD Huttner WB 《The EMBO journal》2008,27(23):3151-3163
Neuroepithelial (NE) cells, the primary stem and progenitor cells of the vertebrate central nervous system, are highly polarized and elongated. They retain a basal process extending to the basal lamina, while undergoing mitosis at the apical side of the ventricular zone. By studying NE cells in the embryonic mouse, chick and zebrafish central nervous system using confocal microscopy, electron microscopy and time-lapse imaging, we show here that the basal process of these cells can split during M phase. Splitting occurred in the basal-to-apical direction and was followed by inheritance of the processes by either one or both daughter cells. A cluster of anillin, an essential component of the cytokinesis machinery, appeared at the distal end of the basal process in prophase and was found to colocalize with F-actin at bifurcation sites, in both proliferative and neurogenic NE cells. GFP-anillin in the basal process moved apically to the cell body prior to anaphase onset, followed by basal-to-apical ingression of the cleavage furrow in telophase. The splitting of the basal process of M-phase NE cells has implications for cleavage plane orientation and the relationship between mitosis and cytokinesis. 相似文献
486.
Isolation of baculovirus-derived secreted and full-length beta-amyloid precursor protein 总被引:5,自引:0,他引:5
J Knops K Johnson-Wood D B Schenk S Sinha I Lieberburg L McConlogue 《The Journal of biological chemistry》1991,266(11):7285-7290
We have expressed two forms of the Alzheimer's beta-amyloid precursor protein (beta APP), the 695-amino acid form (695 beta APP), and the 751-amino acid form (751 beta APP) in a baculovirus system. Both forms were expressed as full-length precursor, and were subsequently processed in vivo to release extracellular secreted proteins. The secreted forms were cleaved from the full-length beta APP in a manner analogous to the cleavage of beta APP during constitutive secretion in mammalian cells (Weidemann, A., K?nig, G., Bunke, D., Fischer, P., Salbaum, J. M., Masters, C. L., Beyreuther, K. (1989) Cell 57, 115-126; Oltersdorf, T., Ward, P. J., Henriksson, T., Beattie, E. C., Neve, R., Lieberburg, I., and Fritz, L. J. (1990) J. Biol. Chem. 265, 4492-4497). High levels of expression of 20-50 mg/liter were achieved. Both full-length and secreted forms of the beta-amyloid precursor proteins were purified using a combination of ion-exchange and immunoaffinity chromatography using a monoclonal antibody directed against beta APP. The 751 beta APP-derived full-length and secreted forms, which contain the Kunitz protease inhibitor domain, were shown to be as active in the inhibition of trypsin as is mammalian-derived secreted beta APP. The availability of purified full-length beta APP from the baculovirus system will be valuable for biochemical and cell biological analyses that may elucidate the mechanism of the inappropriate processing that leads to beta-amyloid formation in Alzheimer's disease. 相似文献
487.
Molecular evolutionary dynamics of cytochrome b in strepsirrhine primates: the phylogenetic significance of third-position transversions 总被引:1,自引:2,他引:1
DNA sequences of the complete cytochrome b gene are shown to contain robust
phylogenetic signal for the strepsirrhine primates (i.e., lemurs and
lorises). The phylogeny derived from these data conforms to other molecular
studies of strepsirrhine relationships despite the fact that uncorrected
nucleotide distances are high for nearly all intrastrepsirrhine
comparisons, with most in the 15%-20% range. Cytochrome b sequences support
the hypothesis that Malagasy lemuriforms and Afro-Asian lorisiforms each
comprise clades that share a sister- group relationship. A study (Adkins
and Honeycutt 1994) of the cytochrome c oxidase subunit II (COII) gene
placed one Malagasy primate (Daubentonia) at the base of the strepsirrhine
clade, thereby suggesting a diphyletic Lemuriformes. The reanalysis of COII
third- position transversions, either alone or in combination with
cytochrome b third-position transversions, however, yields a tree that is
congruent with phylogenetic hypotheses derived from cytochrome b and other
genetic data sets.
相似文献
488.
M. M. Sohani P. M. Schenk C. J. Schultz & O. Schmidt 《Plant biology (Stuttgart, Germany)》2009,11(1):105-117
Protein domains with similarity to plant strictosidine synthase-like (SSL) sequences have been uncovered in the genomes of all multicellular organisms sequenced so far and are known to play a role in animal immune responses. Among several distinct groups of Arabidopsis thaliana SSL sequences, four genes ( AtSSL4–AtSSL7 ) arranged in tandem on chromosome 3 show more similarity to SSL genes from Drosophila melanogaster and Caenorhabditis elegans than to other Arabidopsis SSL genes. To examine whether any of the four AtSSL genes are immune-inducible, we analysed the expression of each of the four AtSSL genes after exposure to microbial pathogens, wounding and plant defence elicitors using real-time quantitative RT-PCR, Northern blot hybridisation and Western blot analysis with antibodies raised against recombinant At SSL proteins. While the AtSSL4 gene was constitutively expressed and not significantly induced by any treatment, the other three AtSSL genes were induced to various degrees by plant defence signalling compounds, such as salicylic acid, methyl jasmonate and ethylene, as well as by wounding and exposure to the plant pathogens Alternaria brassicicola and cucumber mosaic virus . Our data demonstrate that the four SSL-coding genes are regulated individually, suggesting specific roles in basal ( SSL4 ) and inducible ( SSL5-7 ) plant defence mechanisms. 相似文献
489.
Marko?Srdanovic Ulf?Schenk Michael?Schwieger Fabien?CampagneEmail author 《BMC bioinformatics》2005,6(1):5
Background
Complex biological database systems have become key computational tools used daily by scientists and researchers. Many of these systems must be capable of executing on multiple different hardware and software configurations and are also often made available to users via the Internet. We have used the Java Data Object (JDO) persistence technology to develop the database layer of such a system known as the SigPath information management system. SigPath is an example of a complex biological database that needs to store various types of information connected by many relationships. 相似文献490.
Mauricio Lanznaster Ademir Neves Adailton J. Bortoluzzi Veronika V. E. Aires Bruno Szpoganicz Hernán Terenzi Patricia Cardoso Severino Julie M. Fuller Simon C. Drew Lawrence R. Gahan Graeme R. Hanson Mark J. Riley Gerhard Schenk 《Journal of biological inorganic chemistry》2005,10(4):319-332
A novel heterobinuclear mixed valence complex [FeIIICuII(BPBPMP)(OAc)2]ClO4, 1, with the unsymmetrical N5O2 donor ligand 2-bis[{(2-pyridylmethyl)aminomethyl}-6-{(2-hydroxybenzyl)(2-pyridylmethyl)}aminomethyl]-4-methylphenol (H2BPBPMP) has been synthesized and characterized. A combination of data from mass spectrometry, potentiometric titrations, X-ray absorption and electron paramagnetic resonance spectroscopy, as well as kinetics measurements indicates that in ethanol/water solutions an [FeIII–()OH–CuIIOH2]+ species is generated which is the likely catalyst for 2,4-bis(dinitrophenyl)phosphate and DNA hydrolysis. Insofar as the data are consistent with the presence of an FeIII-bound hydroxide acting as a nucleophile during catalysis, 1 presents a suitable mimic for the hydrolytic enzyme purple acid phosphatase. Notably, 1 is significantly more reactive than its isostructural homologues with different metal composition (FeIIIMII, where MII is ZnII, MnII, NiII, or FeII). Of particular interest is the observation that cleavage of double-stranded plasmid DNA occurs even at very low concentrations of 1 (2.5 M), under physiological conditions (optimum pH of 7.0), with a rate enhancement of 2.7×107 over the uncatalyzed reaction. Thus, 1 is one of the most effective model complexes to date, mimicking the function of nucleases.Electronic Supplementary Material Supplementary material is available for this article at . 相似文献