全文获取类型
收费全文 | 631篇 |
免费 | 47篇 |
出版年
2023年 | 3篇 |
2022年 | 4篇 |
2021年 | 15篇 |
2020年 | 5篇 |
2019年 | 13篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 13篇 |
2015年 | 22篇 |
2014年 | 24篇 |
2013年 | 23篇 |
2012年 | 37篇 |
2011年 | 36篇 |
2010年 | 28篇 |
2009年 | 17篇 |
2008年 | 25篇 |
2007年 | 26篇 |
2006年 | 23篇 |
2005年 | 38篇 |
2004年 | 28篇 |
2003年 | 27篇 |
2002年 | 21篇 |
2001年 | 15篇 |
2000年 | 11篇 |
1999年 | 20篇 |
1998年 | 5篇 |
1997年 | 15篇 |
1996年 | 6篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 4篇 |
1992年 | 10篇 |
1991年 | 8篇 |
1990年 | 9篇 |
1989年 | 14篇 |
1988年 | 13篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1985年 | 16篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 8篇 |
1978年 | 5篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1972年 | 3篇 |
1970年 | 4篇 |
1949年 | 2篇 |
排序方式: 共有678条查询结果,搜索用时 15 毫秒
41.
The quantification of -acetolactate (AAL) extracellular oxidative decarboxylation during an AAL overproducing strain culture shows that this reaction is at the origin of about 90% of the diacetyl production and that only a small proportion of extracellular AAL is readily transformed to diacetyl. These results, compared with previous ones obtained with a non AAL accumulating strain, allow research options to be put forward for the improvement of microbiological diacetyl production. 相似文献
42.
43.
The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan 总被引:11,自引:0,他引:11
Maeda N Nigou J Herrmann JL Jackson M Amara A Lagrange PH Puzo G Gicquel B Neyrolles O 《The Journal of biological chemistry》2003,278(8):5513-5516
Interactions between dendritic cells (DCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, most likely play a key role in anti-mycobacterial immunity. We have recently shown that M. tuberculosis binds to and infects DCs through ligation of the DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and that M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) inhibits binding of the bacilli to the lectin, suggesting that ManLAM might be a key DC-SIGN ligand. In the present study, we investigated the molecular basis of DC-SIGN ligation by LAM. Contrary to what was found for slow growing mycobacteria, such as M. tuberculosis and the vaccine strain Mycobacterium bovis bacillus Calmette-Guérin, our data demonstrate that the fast growing saprophytic species Mycobacterium smegmatis hardly binds to DC-SIGN. Consistent with the former finding, we show that M. smegmatis-derived lipoarabinomannan, which is capped by phosphoinositide residues (PILAM), exhibits a limited ability to inhibit M. tuberculosis binding to DC-SIGN. Moreover, using enzymatically demannosylated and chemically deacylated ManLAM molecules, we demonstrate that both the acyl chains on the ManLAM mannosylphosphatidylinositol anchor and the mannooligosaccharide caps play a critical role in DC-SIGN-ManLAM interaction. Finally, we report that DC-SIGN binds poorly to the PILAM and uncapped AraLAM-containing species Mycobacterium fortuitum and Mycobacterium chelonae, respectively. Interestingly, smooth colony-forming Mycobacterium avium, in which ManLAM is capped with single mannose residues, was also poorly recognized by the lectin. Altogether, our results provide molecular insight into the mechanisms of mycobacteria-DC-SIGN interaction, and suggest that DC-SIGN may act as a pattern recognition receptor and discriminate between Mycobacterium species through selective recognition of the mannose caps on LAM molecules. 相似文献
44.
Transforming growth factor-beta (TGF-beta) is a key modulator of epidermal development and homeostasis, and has been shown to potently regulate keratinocyte migration and function during wound repair. There are three cloned TGF-beta receptors termed type I, type II, and type III that are found on most cell types. The types I and II are the signaling receptors, while the type III is believed to facilitate TGF-beta binding to the types I and II receptors. Recently, we reported that in addition to these receptors, human keratinocytes express a 150 kDa TGF-beta 1 binding protein (r150) which forms a heteromeric complex with the TGF-beta signaling receptors. This accessory receptor was described as glycosyl phosphatidylinositol-specific anchored based on its sensitivity to phosphatidylinositol phospholipase C (PIPLC). In the present study, we demonstrate that the GPI-anchor is contained in r150 itself and not on a tightly associated protein and that it binds TGF-beta 1 with an affinity similar to those of the types I and II TGF-beta signaling receptors. Furthermore, the PIPLC released (soluble) form of this protein is capable of binding TGF-beta 1 independently from the signaling receptors. In addition, we provide evidence that r150 is released from the cell surface by an endogenous phospholipase C. Our observation that r150 interacts with the TGF-beta signaling receptors, together with the finding that the soluble r150 binds TGF-beta 1 suggest that r150 in either its membrane anchored or soluble form may potentiate or antagonize TGF-beta signaling. Elucidating the mechanism by which r150 functions as an accessory molecule in TGF-beta signaling may be critical to understanding the molecular mechanisms underlying the regulation of TGF-beta action in keratinocytes. 相似文献
45.
46.
Germain DP 《Journal de la Société de Biologie》2002,196(2):127-134
Lysosomal storage disorders (LSDs) are monogenic inborn errors of metabolism. Various groups have been delineated according to the affected pathway and the accumulated substrate, and new entities are still being identified. They are severe disorders with a heterogeneous clinical spectrum encompassing visceral, skeletal and neurologic involvement, and high morbidity and mortality. Most of the genes encoding the lysosomal enzymes have been cloned, and animal models have been obtained for almost each disease. In the last decades, LSDs have been models for the development of molecular and cellular therapies for inherited metabolic diseases. Studies in preclinical in vitro systems and animal models have allowed the successful development of bone marrow transplantation, substrate deprivation, enzyme replacement therapy and gene transfer methods as therapeutic options for several LSDs. The aim of this paper is to review the biology of acid hydrolases and lysosomal membrane proteins, to describe the systematic classification of LSDs and the most recently identified entities, and to briefly review novel therapeutic approaches for two lipidoses: Gaucher disease and Fabry disease. 相似文献
47.
Using primers for the MCT118, YNZ22, and COL2A1 loci in polymerase chain reaction analysis we could distinguish among the approximately 20 cell lines routinely maintained in our laboratory. We also demonstrated that the cell line NB-1691 (a neuroblastoma) and its xenograft had an identical number of repeats at two loci. Rh30 (a rhabdomyosarcoma) made resistant to rapamycin was identical to its parent line and to a subline that had reverted to sensitivity after it was cultured without rapamycin in the medium. 相似文献
48.
Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo 总被引:11,自引:0,他引:11
Kawabata H Germain RS Vuong PT Nakamaki T Said JW Koeffler HP 《The Journal of biological chemistry》2000,275(22):16618-16625
In most cells, transferrin receptor (TfR1)-mediated endocytosis is a major pathway for cellular iron uptake. We recently cloned the human transferrin receptor 2 (TfR2) gene, which encodes a second receptor for transferrin (Kawabata, H., Yang, R., Hirama, T., Vuong, P. T., Kawano, S., Gombart, A. F., and Koeffler, H. P. (1999) J. Biol. Chem. 274, 20826-20832). In the present study, the regulation of TfR2 expression and function was investigated. A select Chinese hamster ovary (CHO)-TRVb cell line that does not express either TfR1 or TfR2 was stably transfected with either TfR1 or TfR2-alpha cDNA. TfR2-alpha-expressing cells had considerably lower affinity for holotransferrin when compared with TfR1-expressing CHO cells. Interestingly, in contrast to TfR1, expression of TfR2 mRNA in K562 cells was not up-regulated by desferrioxamine (DFO), a cell membrane-permeable iron chelator. In MG63 cells, expression of TfR2 mRNA was regulated in the cell cycle with the highest expression in late G(1) phase and no expression in G(0)/G(1). DFO reduced cell proliferation and DNA synthesis of CHO-TRVb control cells, whereas it had little effect on TfR2-alpha-expressing CHO cells when measured by clonogenic and cell cycle analysis. In addition, CHO cells that express TfR2-alpha developed into tumors in nude mice whereas CHO control cells did not. In conclusion, TfR2 expression may be regulated by the cell cycle rather than cellular iron status and may support cell growth both in vitro and in vivo. 相似文献
49.
Molecular mechanism of cGMP-mediated smooth muscle relaxation 总被引:24,自引:0,他引:24
Carvajal JA Germain AM Huidobro-Toro JP Weiner CP 《Journal of cellular physiology》2000,184(3):409-420
Contraction and relaxation of smooth muscle is a tightly regulated process involving numerous endogenous substances and their intracellular second messengers. We examine the key role of cyclic guanosine monophosphate (cGMP) in mediating smooth muscle relaxation. We briefly review the current art regarding cGMP generation and degradation, while focusing on the recent identification of the molecular mechanisms underlying cGMP-mediated smooth muscle relaxation. cGMP-induced SM relaxation is mediated mainly by cGMP-dependent protein kinase activation. It involves several molecular events culminating in a reduction in intracellular Ca(2+) concentration and a decrease in the sensitivity of the contractile system to Ca(2+). We propose that the cGMP-induced decrease in Ca(2+) sensitivity is a strategic way to achieve "active relaxation" of the smooth muscle. In summary, we present compelling evidence supporting a key role for cGMP as a mediator of smooth muscle relaxation in physiological and pharmacological settings. 相似文献
50.
Sherson SM Hemmann G Wallace G Forbes S Germain V Stadler R Bechtold N Sauer N Smith SM 《The Plant journal : for cell and molecular biology》2000,24(6):849-857
The aim of this study was to investigate the in vivo properties and function of the high-affinity monosaccharide/proton symporter AtSTP1 of Arabidopsis. We isolated an Atstp1 knock-out mutant and found that this plant grows and develops normally. The AtSTP1 gene is expressed in germinating seeds and seedlings, with AtSTP1 activity found mainly in the seedling root. The rate of uptake of [(14)C]-3-O-methylglucose and [(14)C]-D-glucose is 60% less in Atstp1 seedlings than in the wild type, showing that AtSTP1 is the major monosaccharide transporter in Arabidopsis seedlings. Transport of D-galactose and D-mannose is also up to 60% less in Atstp1 seedlings compared to wild type, but transport of D-fructose, L-arabinose and sucrose is not reduced. Germination of Atstp1 seed shows reduced sensitivity to D-mannose, demonstrating that AtSTP1 is active before germination. Atstp1 seedlings grow effectively on concentrations of D-galactose that inhibit wild-type growth, even at up to 100 mM D-galactose, indicating that active transport by AtSTP1 plays a major role at very high concentrations of exogenous sugar. These findings provide insight into the physiological function of AtSTP1 and clearly establish its importance in the uptake of extracellular sugars by the embryo and in seedlings. 相似文献