全文获取类型
收费全文 | 883篇 |
免费 | 63篇 |
出版年
2023年 | 4篇 |
2022年 | 15篇 |
2021年 | 28篇 |
2020年 | 13篇 |
2019年 | 16篇 |
2018年 | 25篇 |
2017年 | 16篇 |
2016年 | 31篇 |
2015年 | 45篇 |
2014年 | 52篇 |
2013年 | 51篇 |
2012年 | 83篇 |
2011年 | 87篇 |
2010年 | 53篇 |
2009年 | 44篇 |
2008年 | 52篇 |
2007年 | 67篇 |
2006年 | 57篇 |
2005年 | 42篇 |
2004年 | 32篇 |
2003年 | 30篇 |
2002年 | 28篇 |
2001年 | 2篇 |
2000年 | 5篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 8篇 |
1995年 | 2篇 |
1993年 | 3篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1964年 | 2篇 |
1961年 | 1篇 |
1957年 | 1篇 |
1936年 | 2篇 |
1932年 | 1篇 |
1931年 | 1篇 |
排序方式: 共有946条查询结果,搜索用时 15 毫秒
811.
Accelerated prion disease pathogenesis in Toll-like receptor 4 signaling-mutant mice 总被引:1,自引:0,他引:1
Spinner DS Cho IS Park SY Kim JI Meeker HC Ye X Lafauci G Kerr DJ Flory MJ Kim BS Kascsak RB Wisniewski T Levis WR Schuller-Levis GB Carp RI Park E Kascsak RJ 《Journal of virology》2008,82(21):10701-10708
Prion diseases such as scrapie involve the accumulation of disease-specific prion protein, PrP(Sc), in the brain. Toll-like receptors (TLRs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. The TLR9 agonist unmethylated CpG DNA was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. Thus, it was predicted that ablation of TLR signaling would result in accelerated pathogenesis. C3H/HeJ (Tlr4(Lps-d)) mice, which possess a mutation in the TLR4 intracellular domain preventing TLR4 signaling, and strain-matched wild-type control (C3H/HeOuJ) mice were infected intracerebrally or intraperitoneally with various doses of scrapie inoculum. Incubation periods were significantly shortened in C3H/HeJ compared with C3H/HeOuJ mice, regardless of the route of infection or dose administered. At the clinical phase of disease, brain PrP(Sc) levels in the two strains of mice showed no significant differences by Western blotting. In addition, compared with macrophages from C3H/HeOuJ mice, those from C3H/HeJ mice were unresponsive to fibrillogenic PrP peptides (PrP residues 106 to 126 [PrP(106-126)] and PrP(118-135)) and the TLR4 agonist lipopolysaccharide but not to the TLR2 agonist zymosan, as measured by cytokine production. These data confirm that innate immune activation via TLR signaling interferes with scrapie infection. Furthermore, the results also suggest that the scrapie pathogen, or a component(s) thereof, is capable of stimulating an innate immune response that is active in the central nervous system, since C3H/HeJ mice, which lack the response, exhibit shortened incubation periods following both intraperitoneal and intracerebral infections. 相似文献
812.
Parthymou A Lampropoulou E Mikelis C Drosou G Papadimitriou E 《European journal of cell biology》2008,87(1):17-29
Heparin affin regulatory peptide (HARP) or pleiotrophin seems to be involved in the progression of several tumors of diverse origin. In this study, we tried to determine the role of HARP in rat C6 glioma cells by using an antisense strategy for inhibition of HARP expression. Decrease of the expression of endogenous HARP in C6 cells (AS-C6 cells) significantly increased proliferation, migration, and anchorage-independent growth of cells. Implantation of AS-C6 cells onto chicken embryo chorioallantoic membranes resulted in a significant increase of tumor-induced angiogenesis compared with that induced by non-transfected or C6 cells transfected with the plasmid alone (PC-C6 cells). In the same line, conditioned medium from AS-C6 cells significantly increased endothelial cell proliferation, migration, and tube formation in vitro compared with the effect of conditioned medium from C6 or PC-C6 cells. Interestingly, vascular endothelial growth factor (VEGF) induced C6 cell proliferation and migration, and SU1496, a selective inhibitor of VEGF receptor 2 (VEGFR2), blocked increased glioma cell growth, migration, and angiogenicity observed in AS-C6 cell cultures. The above results seem to be due to a direct interaction between HARP and VEGF in the culture medium of C6 and PC-C6 cells, while AS-C6 cells secreted comparable amounts of VEGF that do not interact with HARP. Collectively, these data suggest that HARP negatively affects diverse biological activities in C6 glioma cells, mainly due to binding of HARP to VEGF, which may sequester secreted VEGF from signalling through VEGFR2. 相似文献
813.
814.
815.
Melagraki G Afantitis A Sarimveis H Igglessi-Markopoulou O Supuran CT 《Bioorganic & medicinal chemistry》2006,14(4):1108-1114
A linear quantitative structure-activity relationship has been developed for a series of para-substituted aromatic sulfonamides by using topological index methodologies. The compounds were studied for their carbonic anhydrase II (CAII) inhibitory activity. A large series of topological indices were calculated and the stepwise regression method was used to derive the most significant model. Very good results were obtained using multi-parametric regressions and showed that the information approach used in the present work is quite useful for modeling carbonic anhydrase inhibition. 相似文献
816.
Plakoutsi G Bemporad F Monti M Pagnozzi D Pucci P Chiti F 《Structure (London, England : 1993)》2006,14(6):993-1001
Over 40 human diseases are associated with the formation of well-defined proteinaceous fibrillar aggregates. Since the oligomers precursors to the fibrils are increasingly recognized to be the causative agents of such diseases, it is important to elucidate the mechanism of formation of these early species. The acylphosphatase from Sulfolobus solfataricus is an ideal system as it was found to form, under conditions in which it is initially native, two types of prefibrillar aggregates: (1) initial enzymatically active aggregates and (2) oligomers with characteristics reminiscent of amyloid protofibrils, with the latter originating from the structural reorganization of the initial assemblies. By studying a number of protein variants with a variety of biophysical techniques, we have identified the regions of the sequence and the driving forces that promote the first aggregation phase and show that the second phase consists in a cooperative conversion involving the entire globular fold. 相似文献
817.
In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags 总被引:2,自引:0,他引:2
Qian X Peng XH Ansari DO Yin-Goen Q Chen GZ Shin DM Yang L Young AN Wang MD Nie S 《Nature biotechnology》2008,26(1):83-90
We describe biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on pegylated gold nanoparticles and surface-enhanced Raman scattering (SERS). Colloidal gold has been safely used to treat rheumatoid arthritis for 50 years, and has recently been found to amplify the efficiency of Raman scattering by 14-15 orders of magnitude. Here we show that large optical enhancements can be achieved under in vivo conditions for tumor detection in live animals. An important finding is that small-molecule Raman reporters such as organic dyes were not displaced but were stabilized by thiol-modified polyethylene glycols. These pegylated SERS nanoparticles were considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor-targeting ligands such as single-chain variable fragment (ScFv) antibodies, the conjugated nanoparticles were able to target tumor biomarkers such as epidermal growth factor receptors on human cancer cells and in xenograft tumor models. 相似文献
818.
819.
Tucker TJ Saggar S Sisko JT Tynebor RM Williams TM Felock PJ Flynn JA Lai MT Liang Y McGaughey G Liu M Miller M Moyer G Munshi V Perlow-Poehnelt R Prasad S Sanchez R Torrent M Vacca JP Wan BL Yan Y 《Bioorganic & medicinal chemistry letters》2008,18(9):2959-2966
Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations. 相似文献
820.
Antonopoulou G Barbayianni E Magrioti V Cotton N Stephens D Constantinou-Kokotou V Dennis EA Kokotos G 《Bioorganic & medicinal chemistry》2008,16(24):10257-10269
A variety of 2-oxoamides and related amides based on natural and non-natural amino acids were synthesized. Their activity on two human intracellular phospholipases (GIVA cPLA(2) and GVIA iPLA(2)) and one human secretory phospholipase (GV sPLA(2)) was evaluated. We show that an amide based on (R)-gamma-norleucine is a highly selective inhibitor of GV sPLA(2). 相似文献