全文获取类型
收费全文 | 4003篇 |
免费 | 505篇 |
国内免费 | 10篇 |
专业分类
4518篇 |
出版年
2021年 | 48篇 |
2019年 | 45篇 |
2018年 | 50篇 |
2017年 | 34篇 |
2016年 | 69篇 |
2015年 | 95篇 |
2014年 | 119篇 |
2013年 | 181篇 |
2012年 | 198篇 |
2011年 | 201篇 |
2010年 | 121篇 |
2009年 | 102篇 |
2008年 | 157篇 |
2007年 | 154篇 |
2006年 | 142篇 |
2005年 | 139篇 |
2004年 | 155篇 |
2003年 | 144篇 |
2002年 | 120篇 |
2001年 | 115篇 |
2000年 | 129篇 |
1999年 | 121篇 |
1998年 | 62篇 |
1997年 | 58篇 |
1996年 | 64篇 |
1995年 | 50篇 |
1994年 | 55篇 |
1993年 | 43篇 |
1992年 | 89篇 |
1991年 | 105篇 |
1990年 | 83篇 |
1989年 | 84篇 |
1988年 | 90篇 |
1987年 | 83篇 |
1986年 | 71篇 |
1985年 | 76篇 |
1984年 | 60篇 |
1983年 | 53篇 |
1982年 | 34篇 |
1981年 | 29篇 |
1979年 | 43篇 |
1978年 | 32篇 |
1977年 | 31篇 |
1976年 | 31篇 |
1975年 | 36篇 |
1974年 | 54篇 |
1973年 | 45篇 |
1972年 | 39篇 |
1969年 | 28篇 |
1968年 | 36篇 |
排序方式: 共有4518条查询结果,搜索用时 11 毫秒
161.
Page TH D'Souza Z Nakanishi S Serikawa T Pusey CD Aitman TJ Cook HT Behmoaras J 《The Journal of biological chemistry》2012,287(8):5710-5719
Crescentic glomerulonephritis (Crgn) is a complex disease where the initial insult is often the glomerular deposition of antibodies against intrinsic or deposited antigens in the glomerulus. The role of Fc receptors in the induction and progression of Crgn is increasingly recognized, and our previous studies have shown that copy number variation in Fcgr3 partially explains the genetic susceptibility of the Wistar-Kyoto (WKY) rat to nephrotoxic nephritis, a rat model of Crgn. The Fcgr3-related sequence (Fcgr3-rs) is a novel rat-specific Fc receptor with a cytoplasmic domain 6 amino acids longer than its paralogue, Fcgr3. The Fcgr3-rs gene is deleted from the WKY rat genome, and this deletion is associated with enhanced macrophage activity in this strain. Here, we investigated the mechanism by which the deletion of Fcgr3-rs in the WKY strain leads to increased macrophage activation. By lentivirus-mediated gene delivery, we generated stably transduced U937 cells expressing either Fcgr3-rs or Fcgr3. In these cells, which lack endogenous Fcgr3 receptors, we show that Fcgr3-rs interacts with the common Fc-γ chain but that Fc receptor-mediated phagocytosis and signaling are defective. Furthermore, in primary macrophages, expression of Fcgr3-rs inhibits Fc receptor-mediated functions, because WKY bone marrow-derived macrophages transduced with Fcgr3-rs had significantly reduced phagocytic activity. This inhibitory effect on phagocytosis was mediated by the novel cytoplasmic domain of Fcgr3-rs. These results suggest that Fcgr3-rs may act to inhibit Fcgr3-mediated signaling and phagocytosis and could be considered as a novel mechanism in the modulation of Fc receptor-mediated cell activation in autoimmune diseases. 相似文献
162.
The clinicopathological and gene expression patterns associated with ulceration of primary melanoma 下载免费PDF全文
Rosalyn Jewell Faye Elliott Jonathan Laye Jérémie Nsengimana John Davies Christy Walker Caroline Conway Angana Mitra Mark Harland Martin G. Cook Andy Boon Sarah Storr Sabreena Safuan Stewart G. Martin Karin Jirström Håkan Olsson Christian Ingvar Martin Lauss Tim Bishop Göran Jönsson Julia Newton‐Bishop 《Pigment cell & melanoma research》2015,28(1):94-104
Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinicopathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502‐gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion, and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up‐regulation of pro‐inflammatory cytokines suggests that ulceration is associated with tumor‐related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signaling pathways involved in inflammation. 相似文献
163.
目的建立心脏特异表达LMNAE82K转基因小鼠,为研究LMNAE82K与心肌病发病机制的关系提供工具动物。方法把LMNAE82K基因插入α-MHC启动子下游,构建转基因表达载体,显微注射法建立C57BL/6JLMNAE82K转基因小鼠,PCR鉴定转基因小鼠的基因型,采用Western Blot鉴定LMNAE82K在心脏组织中的表达,H&E染色和超声检测转基因小鼠心脏的病理改变。结果建立了2个心脏组织特异表达LMNAE82K的转基因小鼠品系。超声检查显示转基因小鼠心室壁变薄,收缩期容积和舒张期容积增加,射血分数及短轴缩短率降低。结论LMNAE82K转基因小鼠具有LMNAE82K引起的家族性扩心病有类似的病理变化,为研究LMNAE82K与心肌病发病机制的关系的研究提供了有价值的疾病动物模型。 相似文献
164.
165.
Li Peng Kimberly Cook Linda Xu Li Cheng Melissa Damschroder Changshou Gao 《MABS-AUSTIN》2016,8(8):1598-1605
Inhibitors of tumor necrosis factor-α converting enzyme (TACE) have potential as therapeutics for various diseases. Many small molecule inhibitors, however, exhibit poor specificity profiles because they target the highly conserved catalytic cleft of TACE. We report for the first time the molecular interaction of a highly specific anti-TACE antagonistic antibody (MEDI3622). We characterized the binding of MEDI3622 using mutagenesis, as well as structural modeling and docking approaches. We show that MEDI3622 recognizes a unique surface loop of sIVa-sIVb β-hairpin on TACE M-domain, but does not interact with the conserved catalytic cleft or its nearby regions. The exquisite specificity of MEDI3622 is mediated by this distinct structural feature on the TACE M-domain. These findings may aid the design of antibody therapies against TACE. 相似文献
166.
Greg G. Sass Thad R. Cook Kevin S. Irons Michael A. McClelland Nerissa N. Michaels T. Matthew O’Hara Matthew R. Stroub 《Biological invasions》2010,12(3):433-436
Invasive silver carp (Hypophthalmichthys molitrix) populations have expanded greatly in the Upper Mississippi River System (UMRS) since their introduction in the early 1970s.
We conducted a Chapman-modified, continuous Schnabel mark-recapture population and biomass estimate for silver carp (106–901 mm)
in the La Grange reach, Illinois River during 2007–2008. We estimated a total of 328,192 (95% CI 231,226–484,474) silver carp
(2,544 per river km 1,792–3,756) comprising 705 (95% CI; 496–1,040) metric tons of biomass (5.5 metric tons per river km 3.8–8.1).
Long Term Resource Monitoring Program (LTRMP) data from the La Grange reach showed an exponential increase in silver carp
catches since 1998, with an intrinsic rate of increase approaching 84%. In 2008, silver carp comprised about 51% of the total
LTRMP annual fish collection. To our knowledge, this large river reach may contain the greatest ambient densities of wild
silver carp in the world. Our findings provide a target for reduction efforts and also emphasize the importance of the La
Grange reach as a source population for potential expansion of the species to the Laurentian Great Lakes. 相似文献
167.
This review summarises recent information on beneficial roles that soil nematodes play in the cycling of carbon and other
plant nutrients in grassland ecosystems. In particular, we focus on the role of the two dominant functional groups of nematodes,
namely the microbial- and root-feeders, and how their activities may enhance soil ecosystem-level processes of nutrient cycling
and, ultimately, plant productivity in managed and unmanaged grassland ecosystems. We report recent experiments which show
that low amounts of root herbivory by nematodes can increase the allocation of photoassimilate carbon to roots, leading to
increased root exudation and microbial activity in the rhizosphere. The effects of these interactions on soil nutrient cycling
and plant productivity are discussed. Evidence is presented to show that the feeding activities of microbial-feeding nematodes
can enhance nutrient mineralization and plant nutrient uptake in grasslands, but that these responses are highly species-specific
and appear to be strongly regulated by higher trophic groups of fauna (top-down regulation). We recommend that future studies
of the roles of nematodes in grasslands ecosystems should consider these more complex trophic interactions and also the effects
of species diversity of nematodes on soil ecosystem-level processes.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
168.
David A. Scott Kirsten J. Bell Cheryl T. Campbell Donald J. Cook Les A. Dakin David J. Del Valle Lisa Drew Thomas W. Gero Maureen M. Hattersley Charles A. Omer Boris Tyurin Xiaolan Zheng 《Bioorganic & medicinal chemistry letters》2009,19(3):701-705
The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified. 相似文献
169.
Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression 下载免费PDF全文
Braden WA Lenihan JM Lan Z Luce KS Zagorski W Bosco E Reed MF Cook JG Knudsen ES 《Molecular and cellular biology》2006,26(20):7667-7681
The retinoblastoma (RB) and p16ink4a tumor suppressors are believed to function in a linear pathway that is functionally inactivated in a large fraction of human cancers. Recent studies have shown that RB plays a critical role in regulating S phase as a means for suppressing aberrant proliferation and controlling genome stability. Here, we demonstrate a novel role for p16ink4a in replication control that is distinct from that of RB. Specifically, p16ink4a disrupts prereplication complex assembly by inhibiting mini-chromosome maintenance (MCM) protein loading in G1, while RB was found to disrupt replication in S phase through attenuation of PCNA function. This influence of p16ink4a on the prereplication complex was dependent on the presence of RB and the downregulation of cyclin-dependent kinase (CDK) activity. Strikingly, the inhibition of CDK2 activity was not sufficient to prevent the loading of MCM proteins onto chromatin, which supports a model wherein the composite action of multiple G1 CDK complexes regulates prereplication complex assembly. Additionally, p16ink4a attenuated the levels of the assembly factors Cdt1 and Cdc6. The enforced expression of these two licensing factors was sufficient to restore the assembly of the prereplication complex yet failed to promote S-phase progression due to the continued absence of PCNA function. Combined, these data reveal that RB and p16ink4a function through distinct pathways to inhibit the replication machinery and provide evidence that stepwise regulation of CDK activity interfaces with the replication machinery at two discrete execution points. 相似文献
170.
A series of oligonucleotides containing biotin-11-dUMP at various positions were synthesized and compared in quantitative, colorimetric hybridization-detection studies. A deoxyuridine phosphoramidite containing a protected allylamino sidearm was synthesized and used in standard, automated synthesis cycles to prepare oligonucleotides with allylamino residues at various positions within a standard 17-base sequence. Biotin substituents were subsequently attached to the allylamino sidearms by reaction with N-biotinyl-6-aminocaproic acid N-hydroxysuccinimide ester. These oligomers were hybridized to target DNA immobilized on microtiter wells (ELISA plates), and were detected with a streptavidin-biotinylated horseradish peroxidase complex using hydrogen peroxide as substrate and o-phenylenediamine as chromogen. We found that the sensitivity of detection of target DNA by biotin-labeled oligonucleotide probes was strongly dependent upon the position of the biotin label. Oligonucleotides containing biotin labels near or off the ends of the hybridizing sequence were more effective probes than oligonucleotides containing internal biotin labels. An additive effect of increasing numbers of biotin-dUMP residues was found for some labeling configurations. 相似文献