全文获取类型
收费全文 | 13052篇 |
免费 | 943篇 |
国内免费 | 361篇 |
出版年
2024年 | 19篇 |
2023年 | 92篇 |
2022年 | 290篇 |
2021年 | 407篇 |
2020年 | 299篇 |
2019年 | 362篇 |
2018年 | 414篇 |
2017年 | 329篇 |
2016年 | 436篇 |
2015年 | 724篇 |
2014年 | 840篇 |
2013年 | 906篇 |
2012年 | 1146篇 |
2011年 | 1077篇 |
2010年 | 679篇 |
2009年 | 575篇 |
2008年 | 781篇 |
2007年 | 689篇 |
2006年 | 588篇 |
2005年 | 541篇 |
2004年 | 567篇 |
2003年 | 442篇 |
2002年 | 357篇 |
2001年 | 276篇 |
2000年 | 241篇 |
1999年 | 236篇 |
1998年 | 104篇 |
1997年 | 73篇 |
1996年 | 63篇 |
1995年 | 69篇 |
1994年 | 60篇 |
1993年 | 46篇 |
1992年 | 85篇 |
1991年 | 81篇 |
1990年 | 61篇 |
1989年 | 50篇 |
1988年 | 38篇 |
1987年 | 26篇 |
1986年 | 28篇 |
1985年 | 26篇 |
1984年 | 13篇 |
1983年 | 17篇 |
1982年 | 16篇 |
1980年 | 21篇 |
1979年 | 19篇 |
1978年 | 12篇 |
1977年 | 18篇 |
1975年 | 15篇 |
1974年 | 17篇 |
1970年 | 14篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
991.
Oral administration of high molecular mass poly-gamma-glutamate induces NK cell-mediated antitumor immunity 总被引:1,自引:0,他引:1
Kim TW Lee TY Bae HC Hahm JH Kim YH Park C Kang TH Kim CJ Sung MH Poo H 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(2):775-780
We analyzed the in vivo tumor regression activity of high molecular mass poly-gamma-glutamate (gamma-PGA) from Bacillus subtilis sups. chungkookjang. C57BL/6 mice were orally administered 10-, 100-, or 2000-kDa gamma-PGA or beta-glucan (positive control), and antitumor immunity was examined. Our results revealed higher levels of NK cell-mediated cytotoxicity and IFN-gamma secretion in mice treated with higher molecular mass gamma-PGA (2000 kDa) vs those treated with lower molecular mass gamma-PGA (10 or 100 kDa) or beta-glucan. We then examined the effect of oral administration of 10- or 2000-kDa gamma-PGA on protection against B16 tumor challenge in C57BL/6 mice. Mice receiving high molecular mass gamma-PGA (2000 kDa) showed significantly smaller tumor sizes following challenge with the MHC class I-down-regulated tumor cell lines, B16 and TC-1 P3 (A15), but not with TC-1 cells, which have normal MHC class I expression. Lastly, we found that gamma-PGA-induced antitumor effect was decreased by in vivo depletion of NK cells using mAb PK136 or anti-asialo GM1 Ab, and that was completely blocked in NK cell-deficient B6 beige mice or IFN-gamma knockout mice. Taken together, we demonstrated that oral administration of high molecular mass gamma-PGA (2000 kDa) generated significant NK cell-mediated antitumor activity in mice bearing MHC class I-deficient tumors. 相似文献
992.
The activating immunoreceptor NKG2D and its ligands are involved in allograft transplant rejection 总被引:2,自引:0,他引:2
Kim J Chang CK Hayden T Liu FC Benjamin J Hamerman JA Lanier LL Kang SM 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(10):6416-6420
Although the linkage between innate and adaptive immunity in transplantation has been recognized, the mechanisms underlying this cooperation remain to be fully elucidated. In this study, we show that early "danger" signals associated with transplantation lead to rapid up-regulation of NKG2D ligands. A second wave of NKG2D ligand up-regulation is mediated by the adaptive immune response to allografts. Treatment with an Ab to NKG2D was highly effective in preventing CD28-independent rejection of cardiac allografts. Notably, NKG2D blockade did not deplete CD8(+) T cells or NK1.1(+) cells nor affect their migration to the allografts. These results establish a functional role of NKG2D and its ligands in the rejection of solid organ transplants. 相似文献
993.
Absence seizure has been of interest because the symptom is related to sensory processing. However, the mechanism that causes the disease is not understood yet. To better understand the molecular mechanism related to the disease progress at protein level, we performed proteomic studies using the thalamus of mice for which absence seizure was induced by gamma-butyrolactone (GBL). Differential proteome expression between GBL-treated mice and control mice was examined by fluorescence 2D difference gel electrophoresis (DIGE) at three different time points (5, 10, and 30 min) after GBL-administration. We identified 16 proteins differentially expressed by >1.4-fold at any of the three time points. All proteins besides the serine protease inhibitor EIA were down-regulated in absence seizure-induced mice. The down-regulated proteins can be classified into five groups by their biological functions: cytoskeleton rearrangement, neuroprotection, neurotransmitter secretion, calcium binding, and metabolism. The maximum level of change was reached by 10 min after GBL-treatment, with the expression level returning back to the original at 30 min when mice were awakened from absence seizure thereby demonstrating the proteomic response is reversible. Our results suggest that absence seizures are associated with restricted functional sets of proteins, whose down-regulation may interfere with general function of neuronal cells. 相似文献
994.
Kang SH Kim GR Seong M Baek SH Seol JH Bang OS Ovaa H Tatsumi K Komatsu M Tanaka K Chung CH 《The Journal of biological chemistry》2007,282(8):5256-5262
Ubiquitin-fold modifier 1 (Ufm1) is a recently identified new ubiquitin-like protein, whose tertiary structure displays a striking resemblance to ubiquitin. Similar to ubiquitin, it has a Gly residue conserved across species at the C-terminal region with extensions of various amino acid sequences that need to be processed in vivo prior to conjugation to target proteins. Here we report the isolation, cloning, and characterization of two novel mouse Ufm1-specific proteases, named UfSP1 and UfSP2. UfSP1 and UfSP2 are composed of 217 and 461 amino acids, respectively, and they have no sequence homology with previously known proteases. UfSP2 is present in most, if not all, of multicellular organisms including plant, nematode, fly, and mammal, whereas UfSP1 could not be found in plant and nematode upon data base search. UfSP1 and UfSP2 cleaved the C-terminal extension of Ufm1 but not that of ubiquitin or other ubiquitin-like proteins, such as SUMO-1 and ISG15. Both were also capable of releasing Ufm1 from Ufm1-conjugated cellular proteins. They were sensitive to inhibition by sulfhydryl-blocking agents, such as N-ethylmaleimide, and their active site Cys could be labeled with Ufm1-vinylmethylester. Moreover, replacement of the conserved Cys residue by Ser resulted in a complete loss of the UfSP1 and UfSP2 activities. These results indicate that UfSP1 and UfSP2 are novel thiol proteases that specifically process the C terminus of Ufm1. 相似文献
995.
v-SNARE cellubrevin is required for basolateral sorting of AP-1B-dependent cargo in polarized epithelial cells 下载免费PDF全文
Fields IC Shteyn E Pypaert M Proux-Gillardeaux V Kang RS Galli T Fölsch H 《The Journal of cell biology》2007,178(3):477-488
The epithelial cell-specific adaptor complex AP-1B is crucial for correct delivery of many transmembrane proteins from recycling endosomes to the basolateral plasma membrane. Subsequently, membrane fusion is dependent on the formation of complexes between SNARE proteins located at the target membrane and on transport vesicles. Although the t-SNARE syntaxin 4 has been localized to the basolateral membrane, the v-SNARE operative in the AP-1B pathway remained unknown. We show that the ubiquitously expressed v-SNARE cellubrevin localizes to the basolateral membrane and to recycling endosomes, where it colocalizes with AP-1B. Furthermore, we demonstrate that cellubrevin coimmunoprecipitates preferentially with syntaxin 4, implicating this v-SNARE in basolateral fusion events. Cleavage of cellubrevin with tetanus neurotoxin (TeNT) results in scattering of AP-1B localization and missorting of AP-1B-dependent cargos, such as transferrin receptor and a truncated low-density lipoprotein receptor, LDLR-CT27. These data suggest that cellubrevin and AP-1B cooperate in basolateral membrane trafficking. 相似文献
996.
Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3(+) T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3(+) T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4(+) T cells as well as unique to the FoxP3(+) cell lineage. In the thymus, precursors of FoxP3(+) cells undergo the first trafficking receptor switch (CCR8/CCR9-->CXCR4-->CCR7), generating mostly homogeneous CD62L(+)CCR7(+)CXCR4(low)FoxP3(+) T cells. CXCR4 expression is regained in FoxP3(+) thymic emigrants in the periphery. Consistent with this switch, recent FoxP3(+) thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3(+) thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3(+) T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3(+) and FoxP3(-) T cell populations is that FoxP3(+) T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3(-) T cells, generating FoxP3(+) T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues. 相似文献
997.
The phylogenic relationships existing among 14 parasitic Platyhelminthes in the Republic of Korea were investigated via the use of the partial 28S ribosomal DNA (rDNA) D1 region and the partial mitochondrial cytochrome c oxidase subunit 1 (mCOI) DNA sequences. The nucleotide sequences were analyzed by length, G + C %, nucleotide differences and gaps in order to determine the analyzed phylogenic relationships. The phylogenic patterns of the 28S rDNA D1 and mCOI regions were closely related within the same class and order as analyzed by the PAUP 4.0 program, with the exception of a few species. These findings indicate that the 28S rDNA gene sequence is more highly conserved than are the mCOI gene sequences. The 28S rDNA gene may prove useful in studies of the systematics and population genetic structures of parasitic Platyhelminthes. 相似文献
998.
Kang MA Jeoung NH Kim JY Lee JE Jung UJ Choi MS Lee WH Kwon OS Lee H Park YB 《Life sciences》2007,80(5):460-467
Changes in the expression level of the skeletal muscle LIM protein 1 (SLIM1) in cultured A10 cells were monitored in response to 25-hydroxycholesterol (25-HC), an oxidized form of cholesterol present in the oxidized low-density lipoproteins. The level of SLIM1 mRNA was elevated in a time- and concentration-dependent manner by treatment of 25-HC. Expressions of smooth muscle (SM) alpha-actin and calponin-1 (CNN-1), early markers for SMC differentiation, were also increased by the 25-HC treatments. Expressions of all three genes (SLIM1, SM alpha-actin and CNN-1) were simultaneously elevated in the cells treated with 9-cis retinoic acid (RA). On the other hand, the SLIM1 expression induced by the 25-HC or 9-cis RA (as well as SM alpha-actin and CNN-1) was decreased by the treatment of 15d-PGJ2. Since the 25-HC, 9-cis RA and 15d-PGJ2 were ligands for the LXR, RXRalpha and PPARgamma respectively, there might be a functional positive cross-talk between LXR and RXRalpha pathways and a negative cross-talk between PPARgamma and LXR and/or RXRalpha pathways in the regulation of SLIM1 expression. The cells stably transfected with the expressional vector for SLIM1 also showed an elevation in the levels of SM alpha-actin and CNN-1. In addition, an over-production of SLIM1 in the cells resulted in a change in the cell-shape into a spindle-like form, which is identical to that observed after a prolonged treatment of the cells with cholesterol. 相似文献
999.
Yu S Yin S Li C Wong P Chang B Xiao F Kang SC Yan H Xiao G Tien P Sy MS 《The Biochemical journal》2007,403(2):343-351
Mutation in the prion gene, PRNP, accounts for approx. 10-15% of human prion diseases. However, little is known about the mechanisms by which a mutant prion protein (PrP) causes disease. We compared the biochemical properties of a wild-type human prion protein, rPrP(C) (recombinant wild-type PrP), which has five octapeptide-repeats, with two recombinant human prion proteins with insertion mutations, one with three more octapeptide repeats, rPrP(8OR), and the other with five more octapeptide repeats, rPrP(10OR). We found that the insertion mutant proteins are more prone to aggregate, and the degree and kinetics of aggregation are proportional to the number of inserts. The octapeptide-repeat and alpha-helix 1 regions are important in aggregate formation, because aggregation is inhibited with monoclonal antibodies that are specific for epitopes in these regions. We also showed that a small amount of mutant protein could enhance the formation of mixed aggregates that are composed of mutant protein and wild-type rPrP(C). Accordingly, rPrP(10OR) is also more efficient in promoting the aggregation of rPrP(C) than rPrP(8OR). These findings provide a biochemical explanation for the clinical observations that the severity of the disease in patients with insertion mutations is proportional to the number of inserts, and thus have implications for the pathogenesis of inherited human prion disease. 相似文献
1000.
Li C Wong P Pan T Xiao F Yin S Chang B Kang SC Ironside J Sy MS 《The Biochemical journal》2007,406(2):333-341
The normal PrP(C) (cellular prion protein) contains sLe(X) [sialyl-Le(X) (Lewis X)] and Le(X). sLe(X) is a ligand of selectins. To examine whether PrP(C) is a ligand of selectins, we generated three human PrP(C)-Ig fusion proteins: one with Le(X), one with sLe(X), and the other with neither Le(X) nor sLe(X). Only Le(X)-PrP(C)-Ig binds E-, L- and P-selectins. Binding is Ca(2+)-dependent and occurs with nanomolar affinity. Removal of sialic acid on sLe(X)-PrP(C)-Ig enables the fusion protein to bind all selectins. These findings were confirmed with brain-derived PrP(C). The selectins precipitated PrP(C) in human brain in a Ca(2+)-dependent manner. Treatment of brain homogenates with neuraminidase increased the amounts of PrP(C) precipitated. Therefore the presence of sialic acid prevents the binding of PrP(C) in human brain to selectins. Hence, human brain PrP(C) interacts with selectins in a manner that is distinct from interactions in peripheral tissues. Alternations in these interactions may have pathological consequences. 相似文献