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91.
Janelle-Montcalm A Boileau C Poirier F Pelletier JP Guévremont M Duval N Martel-Pelletier J Reboul P 《Arthritis research & therapy》2007,9(1):R20
In this study we examine the extracellular role of galectin-3 (gal-3) in joint tissues. Following intra-articular injection
of gal-3 or vehicle in knee joints of mice, histological evaluation of articular cartilage and subchondral bone was performed.
Further studies were then performed using human osteoarthritic (OA) chondrocytes and subchondral bone osteoblasts, in which
the effect of gal-3 (0 to 10 μg/ml) was analyzed. Osteoblasts were incubated in the presence of vitamin D3 (50 nM), which is an inducer of osteocalcin, encoded by an osteoblast terminal differentiation gene. Genes of interest mainly
expressed in either chondrocytes or osteoblasts were analyzed with real-time RT-PCR and enzyme immunoassays. Signalling pathways
regulating osteocalcin were analyzed in the presence of gal-3. Intra-articular injection of gal-3 induced knee swelling and
lesions in both cartilage and subchondral bone. On human OA chondrocytes, gal-3 at 1 μg/ml stimulated ADAMTS-5 expression
in chondrocytes and, at higher concentrations (5 and 10 μg/ml), matrix metalloproteinase-3 expression. Experiments performed
with osteoblasts showed a weak but bipolar effect on alkaline phosphatase expression: stimulation at 1 μg/ml or inhibition
at 10 μg/ml. In the absence of vitamin D3, type I collagen alpha 1 chain expression was inhibited by 10 μg/ml of gal-3. The vitamin D3induced osteocalcin was strongly inhibited in a dose-dependent manner in the presence of gal-3, at both the mRNA and protein
levels. This inhibition was mainly mediated by phosphatidylinositol-3-kinase. These findings indicate that high levels of
extracellular gal-3, which could be encountered locally during the inflammatory process, have deleterious effects in both
cartilage and subchondral bone tissues. 相似文献
92.
Frank Schwede Daniela Bertinetti Carianne N. Langerijs Michael A. Hadders Hans Wienk Johanne H. Ellenbroek Eelco J. P. de Koning Johannes L. Bos Friedrich W. Herberg Hans-Gottfried Genieser Richard A. J. Janssen Holger Rehmann 《PLoS biology》2015,13(1)
The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp-8-BnT-cAMPS (S-220), enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment. 相似文献
93.
94.
Tang Z Luca M Taggart-Murphy L Portillio J Chang C Guven A Lin RJ Murray J Carr A 《Experimental cell research》2012,318(16):2071-2084
Schizosaccharomyces pombe Dsk1 is an SR protein-specific kinase (SRPK), whose homologs have been identified in every eukaryotic organism examined. Although discovered as a mitotic regulator with protein kinase activity toward SR splicing factors, it remains largely unknown about what and how Dsk1 contributes to cell cycle and pre-mRNA splicing. In this study, we investigated the Dsk1 function by determining interacting factors and cellular localization of the kinase. Consistent with its reported functions, we found that pre-mRNA processing and cell cycle factors are prominent among the proteins co-purified with Dsk1. The identification of these factors led us to find Rsd1 as a novel Dsk1 substrate, as well as the involvement of Dsk1 in cellular distribution of poly(A)(+) RNA. In agreement with its role in nuclear events, we also found that Dsk1 is mainly localized in the nucleus during G(2) phase and at mitosis. Furthermore, we revealed the oscillation of Dsk1 protein in a cell cycle-dependent manner. This paper marks the first comprehensive analysis of in vivo Dsk1-associated proteins in fission yeast. Our results reflect the conserved role of SRPK family in eukaryotic organisms, and provide information about how Dsk1 functions in pre-mRNA processing and cell-division cycle. 相似文献
95.
Julia Ekeruche-Makinde Mathew Clement David K. Cole Emily S. J. Edwards Kristin Ladell John J. Miles Katherine K. Matthews Anna Fuller Katy A. Lloyd Florian Madura Garry M. Dolton Johanne Pentier Anna Lissina Emma Gostick Tiffany K. Baxter Brian M. Baker Pierre J. Rizkallah David A. Price Linda Wooldridge Andrew K. Sewell 《The Journal of biological chemistry》2012,287(44):37269-37281
Altered peptide antigens that enhance T-cell immunogenicity have been used to improve peptide-based vaccination for a range of diseases. Although this strategy can prime T-cell responses of greater magnitude, the efficacy of constituent T-cell clonotypes within the primed population can be poor. To overcome this limitation, we isolated a CD8+ T-cell clone (MEL5) with an enhanced ability to recognize the HLA A*0201-Melan A27–35 (HLA A*0201-AAGIGILTV) antigen expressed on the surface of malignant melanoma cells. We used combinatorial peptide library screening to design an optimal peptide sequence that enhanced functional activation of the MEL5 clone, but not other CD8+ T-cell clones that recognized HLA A*0201-AAGIGILTV poorly. Structural analysis revealed the potential for new contacts between the MEL5 T-cell receptor and the optimized peptide. Furthermore, the optimized peptide was able to prime CD8+ T-cell populations in peripheral blood mononuclear cell isolates from multiple HLA A*0201+ individuals that were capable of efficient HLA A*0201+ melanoma cell destruction. This proof-of-concept study demonstrates that it is possible to design altered peptide antigens for the selection of superior T-cell clonotypes with enhanced antigen recognition properties. 相似文献
96.
Goetz R Ohnishi M Kir S Kurosu H Wang L Pastor J Ma J Gai W Kuro-O M Razzaque MS Mohammadi M 《The Journal of biological chemistry》2012,287(34):29134-29146
FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity. 相似文献
97.
Renslo AR Gao H Jaishankar P Venkatachalam R Gómez M Blais J Huband M Vara Prasad JV Gordeev MF 《Bioorganic & medicinal chemistry letters》2006,16(5):1126-1129
A new class of oxazolidinone antibacterials incorporating oxygen-, nitrogen-, or sulfur-containing heterobicyclic C-rings is described. The in vitro potency and in vivo efficacy of these conformationally constrained oxazolidinone analogs are discussed. 相似文献
98.
99.
W. Scott Armbruster Thomas F. Hansen Christophe P��labon Roc��o P��rez-Barrales Johanne Maad 《Annals of botany》2009,103(9):1529-1545