全文获取类型
收费全文 | 165篇 |
免费 | 25篇 |
出版年
2021年 | 2篇 |
2020年 | 1篇 |
2019年 | 1篇 |
2017年 | 1篇 |
2016年 | 6篇 |
2015年 | 7篇 |
2014年 | 8篇 |
2013年 | 5篇 |
2012年 | 9篇 |
2011年 | 9篇 |
2010年 | 7篇 |
2009年 | 7篇 |
2008年 | 9篇 |
2007年 | 10篇 |
2006年 | 6篇 |
2005年 | 8篇 |
2004年 | 9篇 |
2003年 | 7篇 |
2002年 | 8篇 |
2001年 | 6篇 |
2000年 | 13篇 |
1999年 | 9篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1964年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有190条查询结果,搜索用时 31 毫秒
81.
Krejci P Aklian A Kaucka M Sevcikova E Prochazkova J Masek JK Mikolka P Pospisilova T Spoustova T Weis M Paznekas WA Wolf JH Gutkind JS Wilcox WR Kozubik A Jabs EW Bryja V Salazar L Vesela I Balek L 《PloS one》2012,7(4):e35826
Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling. 相似文献
82.
R Szabo K Uzzun Sales P Kosa NA Shylo S Godiksen KK Hansen S Friis JS Gutkind LK Vogel E Hummler E Camerer TH Bugge 《PLoS genetics》2012,8(8):e1002937
Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent. 相似文献
83.
84.
85.
Binding of Wnt to Frizzled, and either of two members of the low-density-lipoprotein receptor-related protein family, LRP5/6, leads to beta-catenin activation by a poorly understood mechanism. LRP5/6 exhibit five highly conserved PPPS/TP motifs in their intracellular region, among which the first PPPS/TP site is rapidly phosphorylated upon Wnt stimulation. By the use of full-length LRP6 mutants harboring multiple mutations involving the five PPPS/TP motifs, we found that this first PPPS/TP phosphoacceptor site is alone not sufficient or strictly necessary for beta-catenin activation. Instead, we show that each LRP6 PPPS/TP motif contributes in a combinatorial fashion to activate the canonical Wnt-beta-catenin pathway. 相似文献
86.
Yamaza T Miura Y Bi Y Liu Y Akiyama K Sonoyama W Patel V Gutkind S Young M Gronthos S Le A Wang CY Chen W Shi S 《PloS one》2008,3(7):e2615
Background
Osteoporosis is the most prevalent skeletal disorder, characterized by a low bone mineral density (BMD) and bone structural deterioration, leading to bone fragility fractures. Accelerated bone resorption by osteoclasts has been established as a principal mechanism in osteoporosis. However, recent experimental evidences suggest that inappropriate apoptosis of osteoblasts/osteocytes accounts for, at least in part, the imbalance in bone remodeling as occurs in osteoporosis. The aim of this study is to examine whether aspirin, which has been reported as an effective drug improving bone mineral density in human epidemiology studies, regulates the balance between bone resorption and bone formation at stem cell levels.Methods and Findings
We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studies revealed that T cell-mediated BMMSC impairment was mainly attributed to the apoptosis of BMMSCs via the Fas/Fas ligand pathway. To explore potential of using pharmacologic stem cell based intervention as an approach for osteoporosis treatment, we selected ovariectomy (OVX)-induced ostoeporosis mouse model to examine feasibility and mechanism of aspirin-mediated therapy for osteoporosis. We found that aspirin can inhibit T cell activation and Fas ligand induced BMMSC apoptosis in vitro. Further, we revealed that aspirin increases osteogenesis of BMMSCs by aiming at telomerase activity and inhibits osteoclast activity in OVX mice, leading to ameliorating bone density.Conclusion
Our findings have revealed a novel osteoporosis mechanism in which activated T cells induce BMMSC apoptosis via Fas/Fas ligand pathway and suggested that pharmacologic stem cell based intervention by aspirin may be a new alternative in osteoporosis treatment including activated osteoblasts and inhibited osteoclasts. 相似文献87.
88.
Sacha AFT van Hijum Richard JS Baerends Aldert L Zomer Harma A Karsens Victoria Martin-Requena Oswaldo Trelles Jan Kok Oscar P Kuipers 《BMC bioinformatics》2008,9(1):1-10
Background
Visualising the evolutionary history of a set of sequences is a challenge for molecular phylogenetics. One approach is to use undirected graphs, such as median networks, to visualise phylogenies where reticulate relationships such as recombination or homoplasy are displayed as cycles. Median networks contain binary representations of sequences as nodes, with edges connecting those sequences differing at one character; hypothetical ancestral nodes are invoked to generate a connected network which contains all most parsimonious trees. Quasi-median networks are a generalisation of median networks which are not restricted to binary data, although phylogenetic information contained within the multistate positions can be lost during the preprocessing of data. Where the history of a set of samples contain frequent homoplasies or recombination events quasi-median networks will have a complex topology. Graph reduction or pruning methods have been used to reduce network complexity but some of these methods are inapplicable to datasets in which recombination has occurred and others are procedurally complex and/or result in disconnected networks.Results
We address the problems inherent in construction and reduction of quasi-median networks. We describe a novel method of generating quasi-median networks that uses all characters, both binary and multistate, without imposing an arbitrary ordering of the multistate partitions. We also describe a pruning mechanism which maintains at least one shortest path between observed sequences, displaying the underlying relations between all pairs of sequences while maintaining a connected graph.Conclusion
Application of this approach to 5S rDNA sequence data from sea beet produced a pruned network within which genetic isolation between populations by distance was evident, demonstrating the value of this approach for exploration of evolutionary relationships. 相似文献89.
JS Agerholm O Andersen MB Almskou C Bendixen J Arnbjerg GP Aamand US Nielsen F Panitz AH Petersen 《Acta veterinaria Scandinavica》2004,45(3):133
To investigate the congenital complex vertebral malformation syndrome (CVM) in Holstein calves, two breeding studies were
performed including 262 and 363 cows, respectively. Cows were selected from the Danish Cattle Database based on pedigree and
insemination records. Selected cows were progeny of sires with an established heterozygous CVM genotype and pregnant after
insemination with semen from another sire with heterozygous CVM genotype. Following calving the breeders should state, if
the calf was normal and was requested to submit dead calves for necropsy. In both studies, significantly fewer CVM affected
calves than expected were obtained; a finding probably reflecting extensive intrauterine mortality in CVM affected foetuses.
The findings illustrate increased intrauterine mortality as a major potential bias in observational studies of inherited disorders. 相似文献
90.