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81.
The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells 总被引:2,自引:0,他引:2
Rao N Lupher ML Ota S Reedquist KA Druker BJ Band H 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(9):4616-4626
The protooncogene product Cbl has emerged as a negative regulator of tyrosine kinases. We have shown previously that Cbl binds to ZAP-70 through its N-terminal tyrosine kinase binding (TKB) domain. In this study, we demonstrate that overexpression of Cbl in Jurkat T cells decreases the TCR-induced phosphorylation of ZAP-70 and other cellular phosphoproteins. Coexpression of Cbl with ZAP-70 in COS cells reproduced the Cbl-induced reduction in the level of phosphorylated ZAP-70. The effect of Cbl was eliminated by the TKB-inactivating G306E mutation in Cbl as well as by a phenylalanine mutation of Tyr292 within the TKB domain binding site on ZAP-70. Notably, the oncogenic Cbl-70Z/3 mutant associated with ZAP-70, but did not reduce the levels of phosphorylated ZAP-70. Overexpression of Cbl, but not Cbl-G306E, in Jurkat T cells led to a decrease in the TCR-induced NF-AT luciferase reporter activity. Overexpression of the TKB domain itself, but not its G306E mutant, functioned in a dominant-negative manner and led to an increase in NF-AT reporter activity. Cbl-70Z/3-overexpressing cells exhibited an increase in both basal and TCR-induced NF-AT luciferase reporter activity, and this trend was reversed by the G306E mutation. Finally, by reconstituting a ZAP-70-deficient Jurkat T cell line, p116, we demonstrate that wild-type ZAP-70 is susceptible to the negative regulatory effect of Cbl, whereas the ZAP-70-Y292F mutant is resistant. Together, our results establish that the linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells. 相似文献
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Aebersold R Anderson L Caprioli R Druker B Hartwell L Smith R 《Journal of proteome research》2005,4(4):1104-1109
Biomarkers for cancer risk, early detection, prognosis, and therapeutic response promise to revolutionize cancer management. Protein biomarkers offer tremendous potential in this regard due to their great diversity and intimate involvement in physiology. An effective program to discover protein biomarkers using existing technology will require team science, an integrated informatics platform, identification and quantitation of candidate biomarkers in disease tissue, mouse models of disease, standardized reagents for analyzing candidate biomarkers in bodily fluids, and implementation of automation. Technology improvements for better fractionation of the proteome, selection of specific biomarkers from complex mixtures, and multiplexed assay of biomarkers would greatly enhance progress. 相似文献
84.
Kara J. Johnson Ian J. Griswold Thomas O'Hare Amie S. Corbin Marc Loriaux Michael W. Deininger Brian J. Druker 《PloS one》2009,4(10)
The BCR-ABL tyrosine kinase is the defining feature of chronic myeloid leukemia (CML) and its kinase activity is required for induction of this disease. Current thinking holds that BCR-ABL forms a multi-protein complex that incorporates several substrates and adaptor proteins and is stabilized by multiple direct and indirect interactions. Signaling output from this highly redundant network leads to cellular transformation. Proteins known to be associated with BCR-ABL in this complex include: GRB2, c-CBL, p62DOK, and CRKL. These proteins in turn, link BCR-ABL to various signaling pathways indicated in cellular transformation. In this study we show that a triple mutant of BCR-ABL with mutations of the direct binding sites for GRB2, CBL, p62DOK and CRKL, is defective for transformation of primary hematopoietic cells in vitro and in a murine CML model, while it retains the capacity to induce IL-3 independence in 32D cells. Compared to BCR-ABL, the triple mutant''s ability to activate the MAP kinase and PI3-kinase pathways is severely compromised, while STAT5 phosphorylation is maintained, suggesting that the former are crucial for the transformation of primary cells, but dispensable for transformation of factor dependent cell lines. Our data suggest that inhibition of BCR-ABL-induced leukemia by disrupting protein interactions could be possible, but would require blocking of multiple sites. 相似文献
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Alejandro Cantarero Toni Laaksonen Pauliina E. Järvistö Diego Gil Jimena López‐Arrabé Alberto J. Redondo Juan Moreno 《Ethology : formerly Zeitschrift fur Tierpsychologie》2015,121(10):946-957
Nesting holes are a scarce resource for obligated cavity‐nesting birds and an important selective force for the evolution of aggressive female behaviours, which may be mediated by testosterone (T) levels. It is known that during periods of intense intrasexual competition such as initial breeding stages, females are highly aggressive towards intruding females. Here, we studied the implications of T levels for female–female competition by comparing levels of aggressiveness towards simulated female intruders (decoys) in two populations of the pied flycatcher (Ficedula hypoleuca) with a marked difference in breeding density. To this end, we exposed free‐living females to simulated territorial intrusions during 30 min when nest construction was almost complete. T levels of females were measured at the beginning of incubation under the assumption that they are positively associated with T levels during nest building. We also related aggressiveness to T levels in both populations. Furthermore, we aimed at detecting whether variation of T levels may explain female incubation attendance. Females showed higher T levels in the populations where pied flycatchers were exposed to a higher likelihood of conspecific interactions (high breeding density) than in the population with low breeding density. Female territorial presence, vigilance at the nest box and proximity to decoys were negatively related to circulating T levels in the high‐density population, but not in the low‐density population. Differences in T levels between populations did not result in differences in female incubation attendance, but T levels were negatively related to the incubation attendance in females from the population showing high T levels. In our populations, T levels in females prior to laying reflect the need to defend nesting cavities which is higher at high breeding density and in subdominant females. High T levels are costly in terms of incubation attendance. 相似文献
87.
Kim-Hien T. Dao Michael D. Rotelli Brieanna R. Brown Jane E. Yates Juha Rantala Cristina Tognon Jeffrey W. Tyner Brian J. Druker Grover C. Bagby 《Molecular biology of the cell》2013,24(16):2582-2592
Fanconi anemia hematopoietic stem cells display poor self-renewal capacity when subjected to a variety of cellular stress. This phenotype raises the question of whether the Fanconi anemia proteins are stabilized or recruited as part of a stress response and protect against stem cell loss. Here we provide evidence that FANCL, the E3 ubiquitin ligase of the Fanconi anemia pathway, is constitutively targeted for degradation by the proteasome. We confirm biochemically that FANCL is polyubiquitinated with Lys-48–linked chains. Evaluation of a series of N-terminal–deletion mutants showed that FANCL''s E2-like fold may direct ubiquitination. In addition, our studies showed that FANCL is stabilized in a complex with axin1 when glycogen synthase kinase-3β is overexpressed. This result leads us to investigate the potential regulation of FANCL by upstream signaling pathways known to regulate glycogen synthase kinase-3β. We report that constitutively active, myristoylated-Akt increases FANCL protein level by reducing polyubiquitination of FANCL. Two-dimensional PAGE analysis shows that acidic forms of FANCL, some of which are phospho-FANCL, are not subject to polyubiquitination. These results indicate that a signal transduction pathway involved in self-renewal and survival of hematopoietic stem cells also functions to stabilize FANCL and suggests that FANCL participates directly in support of stem cell function. 相似文献
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Ferraris J Radl DB Zárate S Jaita G Eijo G Zaldivar V Clapp C Seilicovich A Pisera D 《PloS one》2011,6(7):e21806
The anterior pituitary is under a constant cell turnover modulated by gonadal steroids. In the rat, an increase in the rate of apoptosis occurs at proestrus whereas a peak of proliferation takes place at estrus. At proestrus, concomitant with the maximum rate of apoptosis, a peak in circulating levels of prolactin is observed. Prolactin can be cleaved to different N-terminal fragments, vasoinhibins, which are proapoptotic and antiproliferative factors for endothelial cells. It was reported that a 16 kDa vasoinhibin is produced in the rat anterior pituitary by cathepsin D. In the present study we investigated the anterior pituitary production of N-terminal prolactin-derived fragments along the estrous cycle and the involvement of estrogens in this process. In addition, we studied the effects of a recombinant vasoinhibin, 16 kDa prolactin, on anterior pituitary apoptosis and proliferation. We observed by Western Blot that N-terminal prolactin-derived fragments production in the anterior pituitary was higher at proestrus with respect to diestrus and that the content and release of these prolactin forms from anterior pituitary cells in culture were increased by estradiol. A recombinant preparation of 16 kDa prolactin induced apoptosis (determined by TUNEL assay and flow cytometry) of cultured anterior pituitary cells and lactotropes from ovariectomized rats only in the presence of estradiol, as previously reported for other proapoptotic factors in the anterior pituitary. In addition, 16 kDa prolactin decreased forskolin-induced proliferation (evaluated by BrdU incorporation) of rat total anterior pituitary cells and lactotropes in culture and decreased the proportion of cells in S-phase of the cell cycle (determined by flow cytometry). In conclusion, our study indicates that the anterior pituitary production of 16 kDa prolactin is variable along the estrous cycle and increased by estrogens. The antiproliferative and estradiol-dependent proapoptotic actions of this vasoinhibin may be involved in the control of anterior pituitary cell renewal. 相似文献
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