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51.
Gene synthesis, expression, structures, and functional activities of site-specific mutants of ubiquitin 总被引:9,自引:0,他引:9
D J Ecker T R Butt J Marsh E J Sternberg N Margolis B P Monia S Jonnalagadda M I Khan P L Weber L Mueller 《The Journal of biological chemistry》1987,262(29):14213-14221
To study the structure and function of ubiquitin we have chemically synthesized a ubiquitin gene that encodes the amino acid sequence of animal ubiquitin, inserting a series of restriction enzyme sites that divide the gene into eight "mutagenesis modules." A series of site-specific mutations were constructed to selectively perturb various regions of the molecule. The mutant genes were expressed in a large quantity of Escherichia coli, and the modified proteins were purified. To determine the structural effects of the amino acid substitutions, the solution structure of ubiquitin was investigated by two-dimensional NMR and each of the mutant proteins were screened for structural perturbations. With one exception, virtually no changes were seen other than at the point of mutation. Functional studies of the mutant proteins with the ubiquitin-activating enzyme E1 and in the reticulocyte protein degradation assay were used to identify regions of the molecule important to ubiquitin's activity in intracellular proteolysis. 相似文献
52.
B P Monia T R Butt D J Ecker C K Mirabelli S T Crooke 《The Journal of biological chemistry》1986,261(24):10957-10959
Metallothioneins are low molecular weight, cysteine-rich proteins believed to participate in metal detoxification. Turnover of Cd-, Zn-, and Au-induced metallothionein was studied in a Chinese hamster ovary cell line which was resistant to Cd and the Au-containing drug auranofin. Cd, Zn, and Au were potent inducers of metallothionein mRNA and resulted in accumulation of approximately equal amounts of mRNA. Pulse-chase studies with [35S]cysteine revealed that the half-life of Au-, Zn-, and Cd-induced metallothionein was 0.75, 10, and 24 h, respectively. The differences in the half-life of metallothionein may be related to the tertiary structure of metal-metallothionein complexes. These results have implications in the mechanism of resistance to gold compounds. 相似文献
53.
Gene synthesis, expression, and processing of human ubiquitin carboxyl extension proteins 总被引:5,自引:0,他引:5
B P Monia D J Ecker S Jonnalagadda J Marsh L Gotlib T R Butt S T Crooke 《The Journal of biological chemistry》1989,264(7):4093-4103
In order to study 1) the mechanisms responsible for generating free ubiquitin monomer and 2) the function of ubiquitin carboxyl extension proteins in eukaryotes, we have developed a system for expression of human ubiquitin carboxyl extension proteins in prokaryotic and eukaryotic hosts. When expressed in Saccharomyces cerevisiae, the intact ubiquitin carboxyl extension proteins were rapidly processed to free ubiquitin monomer and extension protein. Furthermore, expression in this host conferred a slow growth phenotype mediated by the extension protein. Expression in Escherichia coli did not result in processing of the fusion proteins. However, when the expressed fusion proteins were purified from E. coli and incubated with a rabbit reticulocyte extract, the proteins were rapidly processed to free ubiquitin monomer and extension protein. These results show that human ubiquitin carboxyl extension proteins are processed to ubiquitin and extension protein when expressed in eukaryotic but not prokaryotic cells and that pre- and co-translational events are not necessary for their processing. Establishment of this system will allow for large scale purification of these proteins which will aid future studies on the function and structure of ubiquitin carboxyl extension proteins, as well as the mechanisms responsible for their processing. 相似文献
54.
Alzheimer amyloid precursor protein (APP) is the precursor for the Abeta peptide involved in pathogenesis of Alzheimer's disease. The soluble ectodomain fragment of APP (sAPP) functions as a growth factor for epithelial cells, suggesting an important function for APP outside neuronal tissue. Previous studies have shown that in polarized epithelial cells, APP is targeted to the basolateral domain. Tyr653 within the cytoplasmic tail of APP mediates the basolateral targeting of APP, but the sorting machinery that binds to this residue has largely remained unknown. In this study, we analyzed the role of adaptor complexes in the polarized sorting of APP. We show that the medium subunit mu1B of the epithelia-specific adaptor protein (AP)-1B binds onto the cytoplasmic tail of APP in a Tyr653-dependent way. Moreover, ectopic expression of mu1B in cells lacking AP-1B resulted in correction of apical missorting of wild-type but not Tyr653Ala APP. Basolateral secretion of sAPP was found to be independent of Tyr653. We propose a model for polarized targeting of APP according to which sorting of APP to basolateral domain is dependent on binding of AP-1B on Tyr653 in basolateral endosomes. This model is in accordance with the current understanding of sorting mechanisms mediating polarized targeting of membrane proteins. 相似文献
55.
Qi J Lang W Geisler JG Wang P Petrounia I Mai S Smith C Askari H Struble GT Williams R Bhanot S Monia BP Bayoumy S Grant E Caldwell GW Todd MJ Liang Y Gaul MD Demarest KT Connelly MA 《Journal of lipid research》2012,53(6):1106-1116
Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5)-glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol. 相似文献
56.
Amaddii M Meister M Banning A Tomasovic A Mooz J Rajalingam K Tikkanen R 《The Journal of biological chemistry》2012,287(10):7265-7278
Our previous work has shown that the membrane microdomain-associated flotillin proteins are potentially involved in epidermal growth factor (EGF) receptor signaling. Here we show that knockdown of flotillin-1/reggie-2 results in reduced EGF-induced phosphorylation of specific tyrosines in the EGF receptor (EGFR) and in inefficient activation of the downstream mitogen-activated protein (MAP) kinase and Akt signaling. Although flotillin-1 has been implicated in endocytosis, its depletion affects neither the endocytosis nor the ubiquitination of the EGFR. However, EGF-induced clustering of EGFR at the cell surface is altered in cells lacking flotillin-1. Furthermore, we show that flotillins form molecular complexes with EGFR in an EGF/EGFR kinase-independent manner. However, knockdown of flotillin-1 appears to affect the activation of the downstream MAP kinase signaling more directly. We here show that flotillin-1 forms a complex with CRAF, MEK1, ERK, and KSR1 (kinase suppressor of RAS) and that flotillin-1 knockdown leads to a direct inactivation of ERK1/2. Thus, flotillin-1 plays a direct role during both the early phase (activation of the receptor) and late (activation of MAP kinases) phase of growth factor signaling. Our results here unveil a novel role for flotillin-1 as a scaffolding factor in the regulation of classical MAP kinase signaling. Furthermore, our results imply that other receptor-tyrosine kinases may also rely on flotillin-1 upon activation, thus suggesting a general role for flotillin-1 as a novel factor in receptor-tyrosine kinase/MAP kinase signaling. 相似文献
57.
58.
Giammarino A Manera M Robbe D Perugini M Amorena M 《Animal reproduction science》2009,112(3-4):325-333
The aim of this study was to evaluate, in vitro, the effects of increasing concentrations of GnRH on spontaneous mechanical activity patterns of uterine smooth muscle preparations of cows during the follicular and the luteal phases of the oestrus cycle. Uterine smooth muscle strips from 14 cows in follicular and 9 in luteal phase were collected immediately after slaughter and processed within 60 min from collection. Two strips of the same uterus were mounted in an isolated organ bath with two chambers to evaluate the role of decapeptide GnRH on spontaneous myometrial contractility. After equilibration period at 20 mN resting tension, the mechanical activity of the uterus was recorded for 10 min and the mean contractile force (MCF) was calculated. Then GnRH antagonist (antide) was added to one chamber at fixed concentration (10(-4)mol) and allowed to diffuse in solution and make contact with the strips. Subsequently, GnRH was added to the two baths at the same time at increasing concentration and MCF was recorded for 10 min. The effect of GnRH on spontaneous myometrial activity was evident only in the strips from subjects in follicular phase. Our results are suggestive of the presence of GnRH receptors in bovine myometrial tissue. The involvement of GnRH on uterine contractions at mating can be postulated. 相似文献
59.
60.