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81.
Induction of collagenase mRNA in lapine articular chondrocytes by synovial factors and interleukin-1 总被引:1,自引:0,他引:1
C W Lin S L Phillips C E Brinckerhoff H I Georgescu G Bandara C H Evans 《Archives of biochemistry and biophysics》1988,264(1):351-354
The cDNA probe H-9, originally constructed to recognize a portion of the mRNA for lapine synovial collagenase, also hybridized with a RNA of the same size (approximately 2.0 kb) isolated from activated lapine articular chondrocytes. Primary, monolayer cultures of lapine articular chondrocytes did not contain detectable amounts of this RNA, nor did they secrete measurable amounts of collagenase into their culture media. Following exposure to synovial factors, the chondrocytes contained high levels of collagenase mRNA, while their conditioned media had considerable collagenolytic activity. Collagenase mRNA started to appear in chondrocytes 3-5 h after treatment with the synovial material. Maximum levels occurred after 12-24 h. Recombinant human interleukin-1 also induced the appearance of this mRNA. We conclude that chondrocyte collagenase is likely to be the same gene product as synovial collagenase, and that its regulation by lapine articular chondrocytes probably occurs at a pretranslational level. 相似文献
82.
G Bandara P D Robbins H I Georgescu G M Mueller J C Glorioso C H Evans 《DNA and cell biology》1992,11(3):227-231
Joints are difficult organs to target therapeutically. Intravenous, intramuscular, and oral routes of drug delivery provide poor access to the joint, and expose the body systemically to the therapeutic agent. Although intraarticular injection provides direct access to the joint, most injected materials have a short intraarticular half-life. We propose to circumvent these problems by introducing into the synovium gene(s) coding for proteins with antiarthritic properties. Two methods of gene delivery to synovium are under development. In the direct approach, in situ transduction of synoviocytes follows the injection of suitable vectors into the joint. In the indirect approach, synovium is removed from the joint, its synoviocytes are isolated, and the cells transduced in vitro. Genetically modified cells are subsequently transplanted back into the synovium. Using retroviral vectors, we have been able to express the lacZ and neo genes in lapine synovial fibroblasts in vitro. Following neoselection, all cells became LacZ+. Neo-selected cells carrying the lacZ marker gene were transplanted back into the knees of recipient rabbits to examine the persistence and expression of these genes in vivo. Islands of LacZ+, transplanted cells persisted in the recipient joints for at least 3 months. Furthermore, Neo+ cells could be grown from synovia recovered from these joints. Initial attempts to use retroviruses for the direct, in situ transduction of synovium have failed, probably because synoviocytes in the normal synovium are mitotically inactive. Present efforts are directed towards further development of our techniques for transferring genes to joints, and using these techniques to antagonize the intraarticular actions of interleukin-1.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
83.
Quantitative high-performance liquid chromatography analysis of DNA oxidized in vitro and in vivo 总被引:3,自引:0,他引:3
K Frenkel Z J Zhong H C Wei J Karkoszka U Patel K Rashid M Georgescu J J Solomon 《Analytical biochemistry》1991,196(1):126-136
Oxidative modification of genetic material has been implicated as a factor in carcinogenesis, particularly during promotion and progression, and therefore there is a need for sensitive detection of oxidized DNA bases. We developed a method that can be applied to DNA isolated from any source and used to simultaneously quantify oxidized nucleosides without a need to prelabel the DNA or use destructive hydrolytic procedures. This method is based on: (a) enzymatic DNA digestion; (b) HPLC separation of the resultant nucleosides; (c) acetylation of the oxidized nucleosides with [3H]Ac2O (acetic anhydride); (d) removal of the radioactive debris; and (e) quantitative analysis of tritiated nucleoside acetates by HPLC. Enzymatic DNA digestion was optimized using DNase I in the presence of Mg2+ (pH 7), followed by nuclease P1 in the presence of Zn2+ (pH 5.1) and alkaline phosphatase (pH 7.5). Analysis of DNA oxidized with H2O2 in the presence of Fe2+/EDTA for 30 min showed that the levels of 8-OHdG (8-hydroxy-2'-deoxyguanosine) were increased 2.7-fold, HMdU (5-hydroxymethyl-2'-deoxyuridine) 3.15-fold, and FdU (5-formyl-2'-deoxyuridine) 2.5-fold. Although the (-)-isomer of cis-dTG (cis-thymidine glycol) was enhanced 2.3 times, the (+)-isomer remained virtually unchanged. Analysis of DNA isolated from epidermal cells of mice treated in vivo with the tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) showed 4.8-, 2.7-, and 8.7-fold increases in the levels of total cis-dTG, 8-OHdG, and HMdU, respectively, and of some unknown DNA oxidation products. These results prove applicability of the 3H-postlabeling method to the analysis of DNA (and potentially RNA) isolated from many sources, including animals and humans. 相似文献
84.
85.
Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice 下载免费PDF全文
Sathyaseelan S. Deepa Gavin Pharaoh Michael Kinter Vivian Diaz Wilson C. Fok Kaitlyn Riddle Daniel Pulliam Shauna Hill Kathleen E. Fischer Vanessa Soto Constantin Georgescu Jonathan D. Wren Carlo Viscomi Arlan Richardson Holly Van Remmen 《Aging cell》2018,17(4)
Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1?/? mice. The lack of deleterious phenotypes in Surf1?/? mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1?/? vs. Surf1+/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1?/? mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1+/+ and Surf1?/? mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1?/? adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1?/? mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1?/? mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan. 相似文献
86.
Xiaoshan Zhang Xiaoyan Lu Shamima Akhter Maria-Magdalena Georgescu 《Cell cycle (Georgetown, Tex.)》2016,15(8):1134-1143
Akt is a critical mediator of the oncogenic PI3K pathway, and its activation is regulated by kinases and phosphatases acting in opposition. We report here the existence of a novel protein complex that is composed minimally of Akt, PHLPP1, PHLPP2, FANCI, FANCD2, USP1 and UAF1. Our studies show that depletion of FANCI, but not FANCD2 or USP1, results in increased phosphorylation and activation of Akt. This activation is due to a reduction in the interaction between PHLPP1 and Akt in the absence of FANCI. In response to DNA damage or growth factor treatment, the interactions between Akt, PHLPP1 and FANCI are reduced consistent with the known phosphorylation of Akt in response to these stimuli. Furthermore, depletion of FANCI results in reduced apoptosis after DNA damage in accord with its role as a negative regular of Akt. Our findings describe an unexpected function for FANCI in the regulation of Akt and define a previously unrecognized intersection between the PI3K-Akt and FA pathways. 相似文献
87.
Jan Naujoks Christoph Tabeling Brian D. Dill Christine Hoffmann Andrew S. Brown Mareike Kunze Stefan Kempa Andrea Peter Hans-Joachim Mollenkopf Anca Dorhoi Olivia Kershaw Achim D. Gruber Leif E. Sander Martin Witzenrath Susanne Herold Andreas Nerlich Andreas C. Hocke Ian van Driel Norbert Suttorp Sammy Bedoui Hubert Hilbi Matthias Trost Bastian Opitz 《PLoS pathogens》2016,12(2)
88.
Cristian Capitanescu Anca Monica Macovei Oprescu Dan Ionita Gabi Valeriu Dinca Claudiu Turculet Gheorghe Manole 《Journal of enzyme inhibition and medicinal chemistry》2016,31(6):1411-1414
The aim of this research is to evaluate the current streptokinase thrombolytic treatment and to identify or improve new techniques that will base new approaches with a higher efficiency in this area of expertise. In order to be as realistic as possible a new method was set up using magnetic vectorized nanoparticles streptokinase and human blood thrombus. The experimental data confirm the maximum 83% thrombus lyses whenever increase streptokinase concentration. It is very probable to happen because of the presence of high concentration of antiplasmin in the blood that neutralizes around half of the thrombolytic potential of the sanguine plasminogen. The experiment shows also that only free serum plasminogen are available for streptokinase action in order to generate plasmin. 相似文献
89.
90.
Valentin Flaudias Marie Christine Picot Jorge Lopez-Castroman Pierre-Michel Llorca Audrey Schmitt Jean Perriot Vera Georgescu Philippe Courtet Xavier Quantin Sébastien Guillaume 《PloS one》2016,11(3)