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101.
beta-Cyclodextrin tetradecasulfate was found to have a very strong affinity for fibroblast growth factor (FGF) and could substitute for heparin in FGF purification. Basic FGF was purified about 200,000-fold from a rat chondrosarcoma using a method of biaffinity chromatography in which the beta-cyclodextrin tetradecasulfate polymer was mixed with copper-Sepharose. This method takes advantage of the strong affinity of FGF for both beta-cyclodextrin tetradecasulfate and copper. 相似文献
102.
E Persico M Scalona L Cicatiello V Sica F Bresciani A Weisz 《Biochemical and biophysical research communications》1990,171(1):287-292
17 beta-estradiol, a long acting estrogen that is mitogenic for rat uterus in vivo, or the short acting estrogens estriol and 16 alpha-estradiol, not mitogenic on their own, were injected into adult, castrated rats and their effect on uterine gene expression and rate of DNA synthesis were compared. All three compounds increased steady-state mRNA concentration of c-fos, c-jun and c-myc proto-oncogenes to comparable levels (2 hrs after treatment), whereas only 17 beta-estradiol was found to stimulate significantly DNA synthesis (20-22 hrs later). Based on the different retention time of the tested estrogens in rat tissues, it is concluded that a short exposure to the hormone is sufficient to render uterine cells competent to progress through the cell cycle, via activation of 'immediate-early' genes expression, but that stimulation of DNA synthesis requires further changes, achieved via a prolonged exposure of the cells to the estrogenic stimulus. 相似文献
103.
Lanza R Shieh JH Wettstein PJ Sweeney RW Wu K Weisz A Borson N Henderson B West MD Moore MA 《Cloning and stem cells》2005,7(2):95-106
Therapeutic cloning by somatic cell nuclear transfer offers potential for treatment of a wide range of degenerative disease. Nuclear transplantation with neo (r)-marked somatic nuclei from 10-13-year-old cows was used to generate cloned bovine fetuses. Clone fetal liver (FL) hematopoietic stem cells (HSC) were transplanted into two busulfan-treated and one untreated nuclear donor cows. Hematopoiesis was monitored over 13-16 months by in vitro progenitor and HSC assays. Chimerism was demonstrated by PCR in blood, marrow, lymph nodes, and endothelium, peaking at levels of 9-17% in blood granulocytes but at lower levels in lymphocyte subsets (0.1-0.01%). Circulating progenitors showed high levels of chimerism (up to 60% neo (r+)) with persisting fetal features. At sacrifice, the animal that had no pre-transplant myelosupression showed persisting donor cells in blood and lymph nodes, and in marrow 0.25% of progenitor cells and a detectable fraction of stem cells were neo (r+). The fetal HSC showed a 10-fold competition advantage over adult HSC. Cloning generated histocompatible HSC capable of long-term multilineage engraftment in a large animal model. 相似文献
104.
105.
Specific N-glycans direct apical delivery of transmembrane, but not soluble or glycosylphosphatidylinositol-anchored forms of endolyn in Madin-Darby canine kidney cells
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The sialomucin endolyn is a transmembrane protein with a unique trafficking pattern in polarized Madin-Darby canine kidney cells. Despite the presence of a cytoplasmic tyrosine motif that, in isolation, is sufficient to mediate basolateral sorting of a reporter protein, endolyn predominantly traverses the apical surface en route to lysosomes. Apical delivery of endolyn is disrupted in tunicamycin-treated cells, implicating a role for N-glycosylation in apical sorting. Site-directed mutagenesis of endolyn's eight N-glycosylation sites was used to identify two N-glycans that seem to be the major determinants for efficient apical sorting of the protein. In addition, apical delivery of endolyn was disrupted when terminal processing of N-glycans was blocked using glycosidase inhibitors. Missorting of endolyn occurred independently of the presence or absence of the basolateral sorting signal, because apical delivery was also inhibited by tunicamycin when the cytoplasmic tyrosine motif was mutated. However, we found that apical secretion of a soluble mutant of endolyn was N-glycan independent, as was delivery of glycosylphosphatidylinositol-anchored endolyn. Thus, specific N-glycans are only essential for the apical sorting of transmembrane endolyn, suggesting fundamental differences in the mechanisms by which soluble, glycosylphosphatidylinositol-anchored, and transmembrane proteins are sorted. 相似文献
106.
107.
Chen C Vincent O Jin J Weisz OA Montelaro RC 《The Journal of biological chemistry》2005,280(49):40474-40480
The proline-rich L domains of human immunodeficiency virus 1 (HIV-1) and other retroviruses interact with late endocytic proteins during virion assembly and budding. In contrast, the YPDL L domain of equine infectious anemia virus (EIAV) is apparently unique in its reported ability to interact both with the mu2 subunit of the AP-2 adaptor protein complex and with ALG-2-interacting protein 1 (AIP1/Alix) protein factors involved in early and late endosome formation, respectively. To define further the mechanisms by which EIAV adapts vesicle trafficking machinery to facilitate virion production, we have examined the specificity of EIAV p9 binding to endocytic factors and the effects on virion production of alterations in early and late endocytic protein expression. The results of these studies demonstrated that (i) an approximately 300-residue region of AIP1/Alix-(409-715) was sufficient for binding to the EIAV YPDL motif; (ii) overexpression of AIP1/Alix or AP-2 mu2 subunit specifically inhibited YPDL-mediated EIAV budding; (iii) virion budding from a replication-competent EIAV variant with its L domain replaced by the HIV PTAP sequence was inhibited by wild type or mutant mu2 to a level similar to that observed when a dominant-negative mutant of Tsg101 was expressed; and (iv) overexpression or siRNA silencing of AIP1/Alix and AP-2 revealed additive suppression of YPDL-mediated EIAV budding. Taken together, these results indicated that both early and late endocytic proteins facilitate EIAV production mediated by either YPDL or PTAP L domains, suggesting a comprehensive involvement of endocytic factors in retroviral assembly and budding that can be accessed by distinct L domain specificities. 相似文献
108.
Forskolin-induced apical membrane insertion of virally expressed, epitope-tagged CFTR in polarized MDCK cells 总被引:2,自引:0,他引:2
Howard M Jiang X Stolz DB Hill WG Johnson JA Watkins SC Frizzell RA Bruton CM Robbins PD Weisz OA 《American journal of physiology. Cell physiology》2000,279(2):C375-C382
Channel gating ofthe cystic fibrosis transmembrane conductance regulator (CFTR) isactivated in response to cAMP stimulation. In addition, CFTR activationmay also involve rapid insertion of a subapical pool of CFTR into theplasma membrane (PM). However, this issue has been controversial, inpart because of the difficulty in distinguishing cell surface vs.intracellular CFTR. Recently, a fully functional, epitope-tagged formof CFTR (M2-901/CFTR) that can be detected immunologically innonpermeabilized cells was characterized (Howard M, Duvall MD,Devor DC, Dong J-Y, Henze K, and Frizzell RA. Am J PhysiolCell Physiol 269: C1565-C1576, 1995; and Schultz BD,Takahashi A, Liu C, Frizzell RA, and Howard M. Am J PhysiolCell Physiol 273: C2080-C2089, 1997). We have developedreplication-defective recombinant adenoviruses that expressM2-901/CFTR and used them to probe cell surface CFTR in forskolin(FSK)-stimulated polarized Madin-Darby canine kidney (MDCK) cells.Virally expressed M2-901/CFTR was functional and was readilydetected on the apical surface of FSK-stimulated polarized MDCK cells.Interestingly, at low multiplicity of infection, we observedFSK-stimulated insertion of M2901/CFTR into the apical PM, whereas athigher M2-901/CFTR expression levels, no increase in surfaceexpression was detected using indirect immunofluorescence. Immunoelectron microscopy of unstimulated and FSK-stimulated cells confirmed the M2-901/CFTR redistribution to the PM upon FSKstimulation and demonstrates that the apically insertedM2-901/CFTR originates from a population of subapical vesicles.Our observations may reconcile previous conflicting reports regardingthe effect of cAMP stimulation on CFTR trafficking. 相似文献
109.
Altschuler Y Kinlough CL Poland PA Bruns JB Apodaca G Weisz OA Hughey RP 《Molecular biology of the cell》2000,11(3):819-831
MUC1 is a mucin-like type 1 transmembrane protein associated with the apical surface of epithelial cells. In human tumors of epithelial origin MUC1 is overexpressed in an underglycosylated form with truncated O-glycans and accumulates in intracellular compartments. To understand the basis for this altered subcellular localization, we compared the synthesis and trafficking of various glycosylated forms of MUC1 in normal (Chinese hamster ovary) cells and glycosylation-defective (ldlD) cells that lack the epimerase to make UDP-Gal/GalNAc from UDP-Glc/GlcNAc. Although the MUC1 synthesized in ldlD cells was rapidly degraded, addition of GalNAc alone to the culture media resulted in stabilization and near normal surface expression of MUC1 with truncated but sialylated O-glycans. Interestingly, the initial rate of endocytosis of this underglycosylated MUC1 was stimulated by twofold compared with fully glycosylated MUC1. However, the half-lives of the two forms were not different, indicating that trafficking to lysosomes was not affected. Both the normal and stimulated internalization of MUC1 could be blocked by hypertonic media, a hallmark of clathrin-mediated endocytosis. MUC1 endocytosis was also blocked by expression of a dominant-negative mutant of dynamin-1 (K44A), and MUC1 was observed in both clathrin-coated pits and vesicles by immunoelectron microscopy of ultrathin cryosections. Our data suggest that the subcellular redistribution of MUC1 in tumor cells could be a direct result of altered endocytic trafficking induced by its aberrant glycosylation; potential models are discussed. These results also implicate a new role for O-glycans on mucin-like membrane proteins entering the endocytic pathway through clathrin-coated pits. 相似文献
110.
Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells 总被引:11,自引:0,他引:11
Nebbioso A Clarke N Voltz E Germain E Ambrosino C Bontempo P Alvarez R Schiavone EM Ferrara F Bresciani F Weisz A de Lera AR Gronemeyer H Altucci L 《Nature medicine》2005,11(1):77-84
Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34(+) progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs. 相似文献