全文获取类型
收费全文 | 792篇 |
免费 | 52篇 |
专业分类
844篇 |
出版年
2023年 | 7篇 |
2022年 | 19篇 |
2021年 | 30篇 |
2020年 | 19篇 |
2019年 | 16篇 |
2018年 | 15篇 |
2017年 | 10篇 |
2016年 | 27篇 |
2015年 | 52篇 |
2014年 | 51篇 |
2013年 | 51篇 |
2012年 | 46篇 |
2011年 | 69篇 |
2010年 | 41篇 |
2009年 | 40篇 |
2008年 | 49篇 |
2007年 | 52篇 |
2006年 | 39篇 |
2005年 | 34篇 |
2004年 | 25篇 |
2003年 | 24篇 |
2002年 | 19篇 |
2001年 | 5篇 |
2000年 | 5篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1997年 | 4篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 7篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 5篇 |
1986年 | 4篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1978年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1969年 | 3篇 |
1966年 | 2篇 |
1961年 | 3篇 |
1960年 | 2篇 |
1926年 | 1篇 |
排序方式: 共有844条查询结果,搜索用时 9 毫秒
1.
2.
3.
DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps 总被引:1,自引:0,他引:1
Buchanan JT Simpson AJ Aziz RK Liu GY Kristian SA Kotb M Feramisco J Nizet V 《Current biology : CB》2006,16(4):396-400
The innate immune response plays a crucial role in satisfactory host resolution of bacterial infection. In response to chemotactic signals, neutrophils are early responding cells that migrate in large numbers to sites of infection. The recent discovery of secreted neutrophil extracellular traps (NETs) composed of DNA and histones opened a novel dimension in our understanding of the microbial killing capacity of these specialized leukocytes. M1 serotype strains of the pathogen Group A Streptococcus (GAS) are associated with invasive infections including necrotizing fasciitis (NF) and express a potent DNase (Sda1). Here we apply a molecular genetic approach of allelic replacement mutagenesis, single gene complementation, and heterologous expression to demonstrate that DNase Sda1 is both necessary and sufficient to promote GAS neutrophil resistance and virulence in a murine model of NF. Live fluorescent microscopic cell imaging and histopathological analysis are used to establish for the first time a direct linkage between NET degradation and bacterial pathogenicity. Inhibition of GAS DNase activity with G-actin enhanced neutrophil clearance of the pathogen in vitro and reduced virulence in vivo. The results demonstrate a significant role for NETs in neutrophil-mediated innate immunity, and at the same time identify a novel therapeutic target against invasive GAS infection. 相似文献
4.
Amelia A. Langston Cathryn S. Mellersh Cassandra L. Neal Kunal Ray Gregory M. Acland Mark Gibbs Gustavo D. Aguirre R.E.K. Fournier Elaine A. Ostrander 《Genomics》1997,46(3):317
We have constructed a collection of canine–rodent microcell hybrid cell lines by fusion of canine fibroblast microcell donors with immortalized rodent recipient cells. Characterization of the hybrid cell lines using a combination of fluorescencein situhybridization and PCR analysis of canine microsatellite repeat sequences allowed selection of a panel of hybrids in which most canine chromosomes are represented. Approximately 90% of genetic markers and genes that were tested could be assigned to 1 of 31 anonymous canine chromosome groups, based on common patterns of retention in the hybrid set. Many of these putative chromosome groups have now been validated by linkage analysis. This panel of cell lines provides a tool for development of genetic, physical, and comparative maps of the canine genome. 相似文献
5.
6.
Brigotti M Carnicelli D Arfilli V Rocchi L Ricci F Pagliaro P Tazzari PL Vara AG Amelia M Manoli F Monti S 《The Journal of biological chemistry》2011,286(40):34514-34521
Shiga toxins (Stx) play an important role in the pathogenesis of hemolytic uremic syndrome, a life-threatening renal sequela of human intestinal infection caused by specific Escherichia coli strains. Stx target a restricted subset of human endothelial cells that possess the globotriaosylceramide receptor, like that in renal glomeruli. The toxins, composed of five B chains and a single enzymatic A chain, by removing adenines from ribosomes and DNA, trigger apoptosis and the production of pro-inflammatory cytokines in target cells. Because bacteria are confined to the gut, the toxins move to the kidney through the circulation. Polymorphonuclear leukocytes (PMN) have been indicated as the carriers that "piggyback" shuttle toxins to the kidney. However, there is no consensus on this topic, because not all laboratories have been able to reproduce the Stx/PMN interaction. Here, we demonstrate that conformational changes of Shiga toxin 1, with reduction of α-helix content and exposition to solvent of hydrophobic tryptophan residues, cause a loss of PMN binding activity. The partially unfolded toxin was found to express both enzymatic and globotriaosylceramide binding activities being fully active in intoxicating human endothelial cells; this suggests the presence of a distinct PMN-binding domain. By reviewing functional and structural data, we suggest that A chain moieties close to Trp-203 are recognized by PMN. Our findings could help explain the conflicting results regarding Stx/PMN interactions, especially as the groups reporting positive results obtained Stx by single-step affinity chromatography, which could have preserved the correct folding of Stx with respect to more complicated multi-step purification methods. 相似文献
7.
Cerchia L D'Alessio A Amabile G Duconge F Pestourie C Tavitian B Libri D de Franciscis V 《Molecular cancer research : MCR》2006,4(7):481-488
In several neuroblastoma cell lines, retinoic acid (RA)-induced differentiation is coupled to increased expression of functional neurotrophic factor receptors, including Trk family receptors and the glial cell-derived neurotrophic factor receptor, Ret. In several cases, increased expression is dependent on signaling through TrkB. Unlike TrkA and TrkB, Ret has never been implicated as a prognostic marker for neuroblastomas. SK-N-BE(2) cells do not express any of Trk family receptors; therefore, they are a choice system to study the specific role of Ret in RA-induced differentiation. Using a 2'-fluoro-RNA aptamer and a truncated Ret protein as specific inhibitors of Ret, we show that RA-induced differentiation is mediated by a positive autocrine loop that sustains Ret downstream signaling and depends on glial cell-derived neurotrophic factor expression and release. This report shows that in SK-N-BE(2) cells, stimulation of Ret is a major upstream mechanism needed to mediate RA-induced differentiation. These results provide important insights on the molecular mechanism of RA action, which might be relevant for the development of biologically based therapeutic strategies. 相似文献
8.
Semaphorin 3B is a 1,25-Dihydroxyvitamin D3-induced gene in osteoblasts that promotes osteoclastogenesis and induces osteopenia in mice 总被引:1,自引:0,他引:1
Sutton AL Zhang X Dowd DR Kharode YP Komm BS Macdonald PN 《Molecular endocrinology (Baltimore, Md.)》2008,22(6):1370-1381
The vitamin D endocrine system is important for skeletal homeostasis. 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] impacts bone indirectly by promoting intestinal absorption of calcium and phosphate and directly by acting on osteoblasts and osteoclasts. Despite the direct actions of 1,25(OH)(2)D(3) in bone, relatively little is known of the mechanisms or target genes that are regulated by 1,25(OH)(2)D(3) in skeletal cells. Here, we identify semaphorin 3B (SEMA3B) as a 1,25(OH)(2)D(3)-stimulated gene in osteoblastic cells. Northern analysis revealed strong induction of SEMA3B mRNA by 1,25(OH)(2)D(3) in MG-63, ST-2, MC3T3, and primary osteoblastic cells. Moreover, differentiation of these osteogenic cells enhanced SEMA3B gene expression. Biological effects of SEMA3B in the skeletal system have not been reported. Here, we show that osteoblast-derived SEMA3B alters global skeletal homeostasis in intact animals and osteoblast function in cell culture. Osteoblast-targeted expression of SEMA3B in mice resulted in reduced bone mineral density and aberrant trabecular structure compared with nontransgenic littermates. Histomorphometry studies indicated that this was likely due to increased osteoclast numbers and activity. Indeed, primary osteoblasts obtained from SEMA3B transgenic mice stimulated osteoclastogenesis to a greater extent than nontransgenic osteoblasts. This study establishes that SEMA3B is a 1,25(OH)(2)D(3)-induced gene in osteoblasts and that osteoblast-derived SEMA3B impacts skeletal biology in vitro and in vivo. Collectively, these studies support a putative role for SEMA3B as an osteoblast protein that regulates bone mass and skeletal homeostasis. 相似文献
9.
10.
Amelia K. Pinto Hilario J. Ramos Xiaobo Wu Shilpa Aggarwal Bimmi Shrestha Matthew Gorman Kristin Y. Kim Mehul S. Suthar John P. Atkinson Michael Gale Jr Michael S. Diamond 《PLoS pathogens》2014,10(4)
The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar
−/− mice completely lacking type I IFN signaling. In Mavs−/−×Ifnar−/− myeloid cells and mice lacking both Ifnar and the RIG-I-like receptor adaptor gene Mavs, cytokine production was muted despite high levels of WNV infection. Thus, in myeloid cells, viral infection triggers signaling through MAVS to induce proinflammatory cytokines that can result in sepsis and organ damage. Viral pathogenesis was caused in part by massive complement activation, as liver damage was minimized in animals lacking complement components C3 or factor B or treated with neutralizing anti-C5 antibodies. Disease in Ifnar
−/− and CD11c Cre+
Ifnar
f/f mice also was facilitated by the proinflammatory cytokine TNF-α, as blocking antibodies diminished complement activation and prolonged survival without altering viral burden. Collectively, our findings establish the dominant role of type I IFN signaling in myeloid cells in restricting virus infection and controlling pathological inflammation and tissue injury. 相似文献