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排序方式: 共有134条查询结果,搜索用时 31 毫秒
81.
Hepatocyte-specific c-Met deletion disrupts redox homeostasis and sensitizes to Fas-mediated apoptosis 总被引:1,自引:0,他引:1
Gómez-Quiroz LE Factor VM Kaposi-Novak P Coulouarn C Conner EA Thorgeirsson SS 《The Journal of biological chemistry》2008,283(21):14581-14589
The hepatocyte growth factor and its receptor c-Met direct a pleiotropic signal transduction pathway that controls cell survival. We previously demonstrated that mice lacking c-Met (Met-KO) in hepatocytes were hypersensitive to Fas-induced liver injury. In this study, we used primary hepatocytes isolated from Met-KO and control (Cre-Ctrl) mice to address more directly the protective effects of c-Met signaling. Loss of c-Met function increased sensitivity to Fas-mediated apoptosis. Hepatocyte growth factor suppressed apoptosis in Cre-Ctrl but not Met-KO hepatocytes concurrently with up-regulation of NF-kappaB and major antiapoptotic proteins Bcl-2 and Bcl-xL. Intriguingly, Met-KO hepatocytes exhibited intrinsic activation of NF-kappaBas well as Bcl-2 and Bcl-xL. Furthermore, unchallenged Met-KO cells displayed oxidative stress as evidenced by overproduction of reactive oxygen species, which was associated with greater NADPH and Rac1 activities, was blocked by the known NADPH oxidase inhibitors, and was paralleled by increased lipid peroxidation and reduced glutathione (GSH) content. N-Acetylcysteine, an antioxidant and GSH precursor, significantly reduced Jo2-induced cell death. Conversely, the GSH-depleting agent buthionine sulfoximine completely abolished the protective effects of N-acetylcysteine in Met-KO hepatocytes. In conclusion, genetic inactivation of c-Met in mouse hepatocytes caused defects in redox regulation, which may account for the increased sensitivity to Fas-induced apoptosis and adaptive up-regulation of NF-kappaB survival signaling. These data provide evidence that intact c-Met signaling is a critical factor in the protection against excessive generation of endogenous reactive oxygen species. 相似文献
82.
Zimonjic DB Zhang H Shan Z Factor V Trent J Thorgeirsson SS Popescu NC 《Cytogenetics and cell genetics》2001,93(1-2):114-116
DNA amplification is associated with genomic instability, the main characteristic of cancer cells, and it frequently involves protooncogenes. Double minute chromosomes (DM) and homogeneously stained regions (HSR) are cytological manifestations of DNA amplification. Gain of chromosome 19 is a recurrent alteration in mouse hepatocellular carcinoma (HCC). In one tumor cell line established from HCC developed in myc transgenic mice, DM derived from chromosome 19 were identified by spectral karyotyping and confirmed by fluorescence in situ hybridization (FISH). A probe generated by PCR from microdissected DM was localized by FISH on normal and HCC-derived cell lines on DM and chromosome 19 at two sites separated by several medium size G-bands. This organization of DM containing amplified sequences from separate loci of the same chromosome, indicates a complex mechanism of DNA amplification, possibly involving more than one gene. DM or HSR were not previously identified in mouse HCC and adult human HCC. The recognition of these loci could lead to the cloning of new genes or identification of known genes important in development or progression of HCC. 相似文献
83.
Role of the IkappaB kinase complex in oncogenic Ras- and Raf-mediated transformation of rat liver epithelial cells 下载免费PDF全文
Arsura M Mercurio F Oliver AL Thorgeirsson SS Sonenshein GE 《Molecular and cellular biology》2000,20(15):5381-5391
NF-kappaB/Rel factors have been implicated in the regulation of liver cell death during development, after partial hepatectomy, and in hepatocytes in culture. Rat liver epithelial cells (RLEs) display many biochemical and ultrastructural characteristics of oval cells, which are multipotent cells that can differentiate into mature hepatocytes. While untransformed RLEs undergo growth arrest and apoptosis in response to transforming growth factor beta1 (TGF-beta1) treatment, oncogenic Ras- or Raf-transformed RLEs are insensitive to TGF-beta1-mediated growth arrest. Here we have tested the hypothesis that Ras- or Raf-transformed RLEs have altered NF-kappaB regulation, leading to this resistance to TGF-beta1. We show that classical NF-kappaB is aberrantly activated in Ras- or Raf-transformed RLEs, due to increased phosphorylation and degradation of IkappaB-alpha protein. Inhibition of NF-kappaB activity with a dominant negative form of IkappaB-alpha restored TGF-beta1-mediated cell killing of transformed RLEs. IKK activity mediates this hyperphosphorylation of IkappaB-alpha protein. As judged by kinase assays and transfection of dominant negative IKK-1 and IKK-2 expression vectors, NF-kappaB activation by Ras appeared to be mediated by both IKK-1 and IKK-2, while Raf-induced NF-kappaB activation was mediated by IKK-2. NF-kappaB activation in the Ras-transformed cells was mediated by both the Raf and phosphatidylinositol 3-kinase pathways, while in the Raf-transformed cells, NF-kappaB induction was mediated by the mitogen-activated protein kinase cascade. Last, inhibition of either IKK-1 or IKK-2 reduced focus-forming activity in Ras-transformed RLEs. Overall, these studies elucidate a mechanism that contributes to the process of transformation of liver cells by oncogene Ras and Raf through the IkappaB kinase complex leading to constitutive activation of NF-kappaB. 相似文献
84.
85.
Localization of a susceptibility gene for common forms of stroke to 5q12 总被引:21,自引:0,他引:21 下载免费PDF全文
Gretarsdottir S Sveinbjörnsdottir S Jonsson HH Jakobsson F Einarsdottir E Agnarsson U Shkolny D Einarsson G Gudjonsdottir HM Valdimarsson EM Einarsson OB Thorgeirsson G Hadzic R Jonsdottir S Reynisdottir ST Bjarnadottir SM Gudmundsdottir T Gudlaugsdottir GJ Gill R Lindpaintner K Sainz J Hannesson HH Sigurdsson GT Frigge ML Kong A Gudnason V Stefansson K Gulcher JR 《American journal of human genetics》2002,70(3):593-603
Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9×10-6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke. 相似文献
86.
Ritter LM Garfield SH Thorgeirsson UP 《Biochemical and biophysical research communications》1999,257(2):494-499
To study cellular and subcellular localization of TIMP-1, we constructed a cDNA which would express a chimeric protein, TIMP-1-EGFP, having the enhanced green fluorescent protein of the jelly fish Aequorea victoria fused to the carboxyl-terminus of TIMP-1. Chinese Hamster Ovary (CHO) cells were stably transfected with the TIMP-1-EGFP expressing plasmid. The secreted chimera was processed through the endoplasmic reticulum and Golgi, as was shown by fluorescent confocal microscopy after incubations at temperatures which block processing at the intermediate compartment and the trans-Golgi network. In a co-culture system, secreted TIMP-1-EGFP could be visualized binding to the surface of MCF-7 breast carcinoma cells but not non-neoplastic HBL-100 breast epithelial cells. TIMP-1-EGFP localized to the nucleus of MCF-7 cells after 72 hrs in co-culture. These findings suggest that TIMP-1 may preferentially bind to and be taken up by malignant breast epithelial cells and that TIMP-1 may play a yet unidentified role in nuclear functions. 相似文献
87.
88.
T Turpeenniemi-Hujanen U P Thorgeirsson C N Rao L A Liotta 《The Journal of biological chemistry》1986,261(4):1883-1889
We have studied the effect of laminin on type IV collagenolytic activity elaborated by malignant cells in culture. Laminin (at concentrations of 4-8 micrograms/ml) added to serum-free culture supernatants of subconfluent A2058 human melanoma cells significantly increased the release of the type IV collagenolytic activity (200-300%). The induction of type IV collagenase was more pronounced (580%) using a fragment of laminin which binds to the cell surface laminin receptor. A monoclonal antibody against the human laminin receptor blocked the effect of laminin on type IV collagenase, suggesting that occupation of the laminin receptor may be necessary for the effect. Increase in the type IV collagenolytic activity mediated by laminin was also demonstrated in two other malignant cell lines, HT fibrosarcoma (168%) and mouse melanoma (B16-F10) (271%). The increase in type IV collagenase was found to be specific for laminin because another cell-binding matrix protein, fibronectin, did not have any effect, and epidermal growth factor and transferrin actually decreased the type IV collagenase in human melanoma culture medium (epidermal growth factor, 50% at 20 ng/ml; and transferrin, 20% at 10 micrograms/ml). These studies suggest that tumor cell binding to laminin, which comprises the first step of basement membrane invasion, will induce the second step, namely the collagenolytic dissolution of the basement membrane. 相似文献
89.
90.
Herman A. J. Schut Everard H. Hughes Snorri S. Thorgeirsson 《In vitro cellular & developmental biology. Plant》1981,17(4):275-283
Summary Radioimmunoassay was used to determine α-fetoprotein (AFP), albumin, and transferrin production (ng/105 cells/24 h) by two cell lines (7777 and 8994) derived from chemically induced rat hepatomas. α-Fetoprotein production was
high (2000 to 4400) in 7777, but was very low (0.2 to 0.4) in 8994. Albumin production varied from 0.4–0.8 (7777) to 14–26
(8994). Both lines produced substantial amounts of transferrin (180 to 240 by 7777 and 29 to 42 by 8994). Addition of dimethyl
sulfoxide (DMSO, 1 to 4%) or sodium butyrate (BA, 0.5 to 2.0 mM) to the medium inhibited growth in both lines, but 8994 was more sensitive to these agents than 7777. Dimethyl sulfoxide
treatment (2 to 4%) resulted in a dose-related decrease (<10% of control at 4% DMSO) in AFP, albumin, and transferrin production
by 7777, but in 8994, DMSO (1 to 2%) resulted in an increase, (up to sixfold) in albumin and transferrin production, without
affecting AFP production. By contrast, BA (2 to 4 mM) stimulated the production of all three proteins in both lines, most notably that of albumin (up to sixfold) by 7777 and
that of AFP (up to 20-fold) by 8994. It is concluded that both DMSO and BA can enhance the expression of differentiated functions
of the hepatoma cell, and that DMSO at the same time can suppress the expression of an oncofetal function. However, neither
DMSO nor BA is selective in its effects on specific genes (i.e., normal, adult vs. oncofetal genes), and it appears that their
effects may be the result of a more general phenomenon, the expression of which may be related to the stage of differentiation
of the cell. 相似文献