全文获取类型
收费全文 | 764篇 |
免费 | 79篇 |
专业分类
843篇 |
出版年
2023年 | 3篇 |
2022年 | 3篇 |
2021年 | 9篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 9篇 |
2017年 | 14篇 |
2016年 | 11篇 |
2015年 | 32篇 |
2014年 | 33篇 |
2013年 | 31篇 |
2012年 | 52篇 |
2011年 | 58篇 |
2010年 | 39篇 |
2009年 | 34篇 |
2008年 | 45篇 |
2007年 | 40篇 |
2006年 | 36篇 |
2005年 | 55篇 |
2004年 | 47篇 |
2003年 | 43篇 |
2002年 | 46篇 |
2001年 | 13篇 |
2000年 | 10篇 |
1999年 | 16篇 |
1998年 | 11篇 |
1997年 | 9篇 |
1996年 | 11篇 |
1995年 | 8篇 |
1994年 | 8篇 |
1993年 | 9篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 9篇 |
1988年 | 8篇 |
1987年 | 3篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 6篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1981年 | 7篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 5篇 |
1977年 | 1篇 |
1976年 | 4篇 |
1974年 | 3篇 |
1971年 | 1篇 |
排序方式: 共有843条查询结果,搜索用时 15 毫秒
21.
Marzia Scortegagna Chelsea Ruller Surya K. De Elisa Barile Stan Krajewski Pedro Aza‐Blanc Roy Williams Anthony B. Pinkerton Michael Jackson Lynda Chin Maurizio Pellecchia Marcus Bosenberg Ze'ev A. Ronai 《Pigment cell & melanoma research》2013,26(1):136-142
To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15–20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI‐69A11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon‐ and cell death‐related genes that were associated with responsiveness of melanoma cell lines to BI‐69A11. Strikingly, the administration of BI‐69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras(Q61K)::Ink4a?/?). Biweekly administration of BI‐69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100 and 36%, respectively). BI‐69A11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI‐69A11‐resistant Nras(Q61K)::Ink4a?/? tumors exhibited increased CD45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI‐69A11 for clinical assessment. 相似文献
22.
Clay Trauernicht Brett P. Murphy Lynda D. Prior Michael J. Lawes David M. J. S. Bowman 《Ecosystems》2016,19(5):896-909
Woody plant demographics provide important insight into ecosystem state-shifts in response to changing fire regimes. In Australian tropical savannas, the switch from patchy landscape burning by Aborigines to unmanaged wildfires within the past century has been implicated in biodiversity declines including the fire-sensitive conifer, Callitris intratropica. C. intratropica commonly forms small, closed-canopy groves that exclude fire and allow recruitment of conspecifics and other fire-sensitive woody plants. C. intratropica groves provide a useful indicator of heterogeneity and fire regime change, but the mechanisms driving the species’ persistence and decline remain poorly understood. We examined the hypothesis that C. intratropica population stability depends upon a regime of frequent, low-intensity fires maintained by Aboriginal management. We combined integral projection models of C. intratropica population behaviour with an environmental state change matrix to examine how vital rates, grove dynamics and the frequency of high- and low-intensity fires contribute to population stability. Closed-canopy C. intratropica groves contributed disproportionately to population growth by promoting recruitment, whereas singleton trees accounted for a larger proportion of adult mortality. Our patch-based population model predicted population declines under current fire frequencies and that the recruitment of new groves plays a critical role in the species’ persistence. Our results also indicated that reducing fire intensity, a key outcome of Aboriginal burning, leads to C. intratropica population persistence even at high fire frequencies. These findings provide insight into the relationship between ecosystem composition and human–fire interactions and the role of fire management in sustaining the mosaics that comprise ‘natural’ systems. 相似文献
23.
24.
25.
CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex 总被引:1,自引:0,他引:1
Stuart LM Bell SA Stewart CR Silver JM Richard J Goss JL Tseng AA Zhang A El Khoury JB Moore KJ 《The Journal of biological chemistry》2007,282(37):27392-27401
The pattern recognition receptor CD36 initiates a signaling cascade that promotes microglial activation and recruitment to beta-amyloid deposits in the brain. In the present study we identify the focal adhesion-associated proteins p130Cas, Pyk2, and paxillin as novel members of the tyrosine kinase signaling pathway downstream of CD36 and show that assembly of this complex is essential for microglial migration. In primary microglia and macrophages exposed to beta-amyloid, the scaffolding protein p130Cas is rapidly tyrosine-phosphorylated and co-localizes with CD36 to membrane ruffles contemporaneous with F-actin polymerization. These beta-amyloid-stimulated events are not detected in CD36 null cells and are dependent on CD36 activation of Src family tyrosine kinases. Fyn, a Src kinase known to interact with CD36, co-precipitates with p130Cas and is an essential upstream intermediate in the signaling pathways leading to phosphorylation of the p130Cas substrate domain. Furthermore, the p130Cas-interacting kinase Pyk2 and the cytoskeletal adapter protein paxillin also demonstrate CD36-dependent phosphorylation, identifying these focal adhesion molecules as additional members of this beta-amyloid signaling cascade. Disruption of this p130Cas complex by small interfering RNA silencing inhibits p44/42 mitogen-activated protein kinase phosphorylation and microglial migration, illustrating the importance of this pathway in microglial activation and recruitment. Together, these data are the first to identify the signaling cascade that directly links CD36 to the actin cytoskeleton and, thus, implicates it in diverse processes such as cellular migration, adhesion, and phagocytosis. 相似文献
26.
Fatima Amanat Shirin Strohmeier Philip S. Meade Nicholas Dambrauskas Barbara Mühlemann Derek J. Smith Vladimir Vigdorovich D. Noah Sather Lynda Coughlan Florian Krammer 《PLoS biology》2021,19(12)
Vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have been highly efficient in protecting against Coronavirus Disease 2019 (COVID-19). However, the emergence of viral variants that are more transmissible and, in some cases, escape from neutralizing antibody responses has raised concerns. Here, we evaluated recombinant protein spike antigens derived from wild-type SARS-CoV-2 and from variants B.1.1.7, B.1.351, and P.1 for their immunogenicity and protective effect in vivo against challenge with wild-type SARS-CoV-2 in the mouse model. All proteins induced high neutralizing antibodies against the respective viruses but also induced high cross-neutralizing antibody responses. The decline in neutralizing titers between variants was moderate, with B.1.1.7-vaccinated animals having a maximum fold reduction of 4.8 against B.1.351 virus. P.1 induced the most cross-reactive antibody responses but was also the least immunogenic in terms of homologous neutralization titers. However, all antigens protected from challenge with wild-type SARS-CoV-2 in a mouse model.This study explores the immune response induced by wild type and variant SARS-CoV-2 spike proteins, and the protection that these immune responses provide against challenge with wild type virus in the mouse model. 相似文献
27.
Fabio Marra Lynda F. Bonewald Shaun Park-Snyder In-Seok Park Kathleen A. Woodruff Hanna E. Abboud 《Journal of cellular physiology》1996,166(3):537-546
Transforming growth factor-β (TGF-β) stimulates the accumulation of extracellular matrix in renal and hepatic disease. Kidney glomerular mesangial cells (GMC) and liver fat-storing cells (FSC) produce latent or inactive TGF-β. In this study, we characterized the latent TGF-β complexes secreted by these cells. Human FSC produce a single latent TGF-β complex, predominantly of the TGF-β1 isoform, whereas GMC secrete multiple complexes of latent TGF-β, containing β1 and β2 isoforms. At least four forms were identified in GMC using ion exchange chromatography, including a peak not previously described in other cell types which eluted at 0.12 M NaCl, and predominantly of the β2 isoform. Both cell types secrete the latent TGF-β1 binding protein of 190 kDa, as part of a high molecular weight TGF-β complex. Epidermal growth factor stimulates the secretion of latent TGF-β and latent TGF-β binding protein in both cell types. Secretion of the latent TGF-β in both cell types was found to be associated with secretion of decorin. This study shows that vascular pericytes from the kidney and the liver have distinctly different profiles of latent TGF-β complexes, with GMC secreting a unique form of latent TGF-β2. The regulatory effect of epidermal growth factor and platelet-derived growth factor has potential implication for the pathophysiology of liver regeneration and chronic liver and kidney diseases. © 1996 Wiley-Liss, Inc. 相似文献
28.
Identifying secretomes in people, pufferfish and pigs 总被引:1,自引:0,他引:1
29.
McDowell LM Poliks B Studelska DR O'Connor RD Beusen DD Schaefer J 《Journal of biomolecular NMR》2004,28(1):11-29
The 46-kD enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase catalyzes the condensation of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form EPSP. The reaction is inhibited by N-(phosphonomethyl)-glycine (Glp), which, in the presence of S3P, binds to EPSP synthase to form a stable ternary complex. We have used solid-state NMR and molecular modeling to characterize the EPSP synthase-S3P-Glp ternary complex. Modeling began with the crystal coordinates of the unliganded protein, published distance restraints, and information from the chemical modification and mutagenesis literature on EPSP synthase. New inter-ligand and ligand-protein distances were obtained. These measurements utilized the native (31)P in S3P and Glp, biosynthetically (13)C-labeled S3P, specifically (13)C and (15)N labeled Glp, and a variety of protein-(15)N labels. Several models were investigated and tested for accuracy using the results of both new and previously published rotational-echo double resonance (REDOR) NMR experiments. The REDOR model is compared with the recently published X-ray crystal structure of the ternary complex, PDB code 1G6S. There is general agreement between the REDOR model and the crystal structure with respect to the global folding of the two domains of EPSP synthase and the relative positioning of S3P and Glp in the binding pocket. However, some of the REDOR data are in disagreement with predictions based on the coordinates of 1G6S, particularly those of the five arginines lining the binding site. We attribute these discrepancies to substantive differences in sample preparation for REDOR and X-ray crystallography. We applied the REDOR restraints to the 1G6S coordinates and created a REDOR-refined xray structure that agrees with the NMR results. 相似文献
30.