全文获取类型
收费全文 | 142篇 |
免费 | 6篇 |
出版年
2020年 | 1篇 |
2018年 | 1篇 |
2017年 | 1篇 |
2016年 | 3篇 |
2015年 | 6篇 |
2014年 | 11篇 |
2013年 | 7篇 |
2012年 | 9篇 |
2011年 | 6篇 |
2010年 | 11篇 |
2009年 | 7篇 |
2008年 | 8篇 |
2007年 | 12篇 |
2006年 | 6篇 |
2005年 | 3篇 |
2004年 | 3篇 |
2003年 | 4篇 |
2002年 | 1篇 |
2001年 | 1篇 |
2000年 | 5篇 |
1999年 | 4篇 |
1998年 | 6篇 |
1997年 | 2篇 |
1996年 | 3篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有148条查询结果,搜索用时 15 毫秒
31.
Juliana M Sousa-Canavez Flavio C Canavez Kátia RM Leite Luiz H Camara-Lopes 《Genetic vaccines and therapy》2008,6(1):1-7
Background
Electroporation is an established technique for enhancing plasmid delivery to many tissues in vivo, including the skin. We have previously demonstrated efficient delivery of plasmid DNA to the skin utilizing a custom-built four-plate electrode. The experiments described here further evaluate cutaneous plasmid delivery using in vivo electroporation. Plasmid expression levels are compared to those after liposome mediated delivery.Methods
Enhanced electrically-mediated delivery, and less extensively, liposome complexed delivery, of a plasmid encoding the reporter luciferase was tested in rodent skin. Expression kinetics and tissue damage were explored as well as testing in a second rodent model.Results
Experiments confirm that electroporation alone is more effective in enhancing reporter gene expression than plasmid injection alone, plasmid conjugation with liposomes followed by injection, or than the combination of liposomes and electroporation. However, with two time courses of multiple electrically-mediated plasmid deliveries, neither the levels nor duration of transgene expression are significantly increased. Tissue damage may increase following a second treatment, no further damage is observed after a third treatment. When electroporation conditions utilized in a mouse model are tested in thicker rat skin, only higher field strengths or longer pulses were as effective in plasmid delivery.Conclusion
Electroporation enhances reporter plasmid delivery to the skin to a greater extent than the liposome conjugation method tested. Multiple deliveries do not necessarily result in higher or longer term expression. In addition, some impact on tissue integrity with respect to surface damage is observed. Pulsing conditions should be optimized for the model and for the expression profile desired. 相似文献32.
33.
34.
Elliott ER Van Ziffle JA Scapini P Sullivan BM Locksley RM Lowell CA 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(8):4319-4330
The K/BxN serum transfer model of arthritis is critically dependent on FcγR signaling events mediated by spleen tyrosine kinase (Syk). However, the specific cell types in which this signaling is required are not known. We report that deletion of Syk in neutrophils, achieved using syk(f/f) MRP8-cre(+) mice, blocks disease development in serum transfer arthritis. The syk(f/f) MRP8-cre(+) mice display absent joint disease and reduced deposition of pathogenic anti-glucose-6-phosphate isomerase Abs in the joint (with a reciprocal accumulation of these Abs in the peripheral circulation). Additionally, syk(f/f) MRP8-cre(+) mice manifest poor edema formation within 3 h after formation of cutaneous immune complexes (Arthus reaction). Together, this suggests that neutrophil-dependent recognition of immune complexes contributes significantly to changes in vascular permeability during the early phases of immune complex disease. Using mixed chimeric mice, containing both wild-type and syk(f/f) MRP8-cre(+) neutrophils, we find no impairment in recruitment of Syk-deficient neutrophils to the inflamed joint, but they fail to become primed, demonstrating lower cytokine production after removal from the joint. They also display an increased apoptotic rate compared with wild-type cells in the same joint. Mast cell-deficient c-kit(sh/sh) mice developed robust arthritis after serum transfer whereas c-kit(W/Wv) mice did not, suggesting that previous conclusions concerning the central role of mast cells in this model may need to be revised. Basophil-deficient mice also responded normally to K/BxN serum transfer. These results demonstrate that Syk-dependent signaling in neutrophils alone is critically required for arthritis development in the serum transfer model. 相似文献
35.
Van Dyken SJ Garcia D Porter P Huang X Quinlan PJ Blanc PD Corry DB Locksley RM 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(5):2261-2267
Development of asthma and allergic inflammation involves innate immunity, but the environmental contributions remain incompletely defined. Analysis of dust collected from the homes of asthmatic individuals revealed that the polysaccharide chitin is environmentally widespread and associated with β-glucans, possibly from ubiquitous fungi. Cell wall preparations of Aspergillus isolated from house dust induced robust recruitment of eosinophils into mouse lung, an effect that was attenuated by enzymatic degradation of cell wall chitin and β-glucans. Mice expressing constitutively active acidic mammalian chitinase in the lungs demonstrated a significant reduction in eosinophil infiltration after fungal challenge. Conversely, chitinase inhibition prolonged the duration of tissue eosinophilia. Thus, fungal chitin derived from home environments associated with asthma induces eosinophilic allergic inflammation in the lung, and mammalian chitinases, including acidic mammalian chitinase, limit this process. 相似文献
36.
Mariana A Antunes Soraia C Abreu Fernanda F Cruz Ana Clara Teixeira Miquéias Lopes-Pacheco Elga Bandeira Priscilla C Olsen Bruno L Diaz Christina M Takyia Isalira PRG Freitas Nazareth N Rocha Vera L Capelozzi Débora G Xisto Daniel J Weiss Marcelo M Morales Patricia RM Rocco 《Respiratory research》2014,15(1)
We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2. 相似文献
37.
Tumor necrosis factors alpha and beta differ in their capacities to generate interleukin 1 release from human endothelial cells 总被引:12,自引:0,他引:12
R M Locksley F P Heinzel H M Shepard J Agosti T E Eessalu B B Aggarwal J M Harlan 《Journal of immunology (Baltimore, Md. : 1950)》1987,139(6):1891-1895
The capacity of the tumor necrosis factors, TNF-alpha and TNF-beta, products of activated macrophages and lymphocytes, respectively, to stimulate interleukin 1 (IL-1) release from endothelial cells derived from human umbilical veins was examined in vitro. Recombinant TNF-alpha caused IL-1 release by 4 hr with maximal levels of 17 U/ml by 24 hr; half-maximal stimulation occurred at approximately 80 pM. In contrast, recombinant TNF-beta was a relatively poor stimulus for IL-1 release. Even at concentrations as high as 600 pM, only 3 U of IL-1/ml were recovered; maximal IL-1 release (10 to 12 U/ml) required up to 5 nM TNF-beta. Natural, glycosated human TNF-beta was comparable in activity to recombinant TNF-beta. TNF-beta did not directly inhibit the IL-1 comitogenesis assay, nor was there evidence that TNF-beta induced the release of an IL-1 inhibitor, in that supernatants generated in the presence of TNF-beta did not inhibit thymocyte proliferation to a recombinant IL-1 standard. Binding of the recombinant TNF to endothelial monolayers was assessed by using [125I]TNF-alpha in competition studies with cold TNF-alpha and TNF-beta. Binding of TNF-alpha was half-maximal at 80 pM with an average of 664 receptors/cell and Kd = 0.043 nM. Although TNF-beta was capable of fully competing for [125I]TNF-alpha binding, half-maximal binding occurred at 800 pM TNF-beta. These data suggest that the TNF receptors on human endothelial cells may reflect the structural differences between these two homologous cytokines. 相似文献
38.
Budding yeast Rif1 binds to replication origins and protects DNA at blocked replication forks
下载免费PDF全文
![点击此处可从《EMBO reports》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Shin‐ichiro Hiraga Chandre Monerawela Yuki Katou Sophie Shaw Kate RM Clark Katsuhiko Shirahige Anne D Donaldson 《EMBO reports》2018,19(9)
Despite its evolutionarily conserved function in controlling DNA replication, the chromosomal binding sites of the budding yeast Rif1 protein are not well understood. Here, we analyse genome‐wide binding of budding yeast Rif1 by chromatin immunoprecipitation, during G1 phase and in S phase with replication progressing normally or blocked by hydroxyurea. Rif1 associates strongly with telomeres through interaction with Rap1. By comparing genomic binding of wild‐type Rif1 and truncated Rif1 lacking the Rap1‐interaction domain, we identify hundreds of Rap1‐dependent and Rap1‐independent chromosome interaction sites. Rif1 binds to centromeres, highly transcribed genes and replication origins in a Rap1‐independent manner, associating with both early and late‐initiating origins. Interestingly, Rif1 also binds around activated origins when replication progression is blocked by hydroxyurea, suggesting association with blocked forks. Using nascent DNA labelling and DNA combing techniques, we find that in cells treated with hydroxyurea, yeast Rif1 stabilises recently synthesised DNA. Our results indicate that, in addition to controlling DNA replication initiation, budding yeast Rif1 plays an ongoing role after initiation and controls events at blocked replication forks. 相似文献
39.
Evolution of eutherian cytochrome c oxidase subunit II: heterogeneous rates of protein evolution and altered interaction with cytochrome c 总被引:3,自引:1,他引:2
Cytochrome c oxidase subunit II (COII), encoded by the mitochondrial
genome, exhibits one of the most heterogeneous rates of amino acid
replacement among placental mammals. Moreover, it has been demonstrated
that cytochrome c oxidase has undergone a structural change in higher
primates which has altered its physical interaction with cytochrome c. We
collected a large data set of COII sequences from several orders of mammals
with emphasis on primates, rodents, and artiodactyls. Using phylogenetic
hypotheses based on data independent of the COII gene, we demonstrated that
an increased number of amino acid replacements are concentrated among
higher primates. Incorporating approximate divergence dates derived from
the fossil record, we find that most of the change occurred independently
along the New World monkey lineage and in a rapid burst before apes and Old
World monkeys diverged. There is some evidence that Old World monkeys have
undergone a faster rate of nonsynonymous substitution than have apes. Rates
of substitution at four-fold degenerate sites in primates are relatively
homogeneous, indicating that the rate heterogeneity is restricted to
nondegenerate sites. Excluding the rate acceleration mentioned above,
primates, rodents, and artiodactyls have remarkably similar nonsynonymous
replacement rates. A different pattern is observed for transversions at
four-fold degenerate sites, for which rodents exhibit a higher rate of
replacement than do primates and artiodactyls. Finally, we hypothesize
specific amino acid replacements which may account for much of the
structural difference in cytochrome c oxidase between higher primates and
other mammals.
相似文献
40.
Relationships among msx gene structure and function in zebrafish and other vertebrates 总被引:6,自引:2,他引:4
Ekker M; Akimenko MA; Allende ML; Smith R; Drouin G; Langille RM; Weinberg ES; Westerfield M 《Molecular biology and evolution》1997,14(10):1008-1022
The zebrafish genome contains at least five msx homeobox genes, msxA, msxB,
msxC, msxD, and the newly isolated msxE. Although these genes share
structural features common to all Msx genes, phylogenetic analyses of
protein sequences indicate that the msx genes from zebrafish are not
orthologous to the Msx1 and Msx2 genes of mammals, birds, and amphibians.
The zebrafish msxB and msxC are more closely related to each other and to
the mouse Msx3. Similarly, although the combinatorial expression of the
zebrafish msx genes in the embryonic dorsal neuroectoderm, visceral arches,
fins, and sensory organs suggests functional similarities with the Msx
genes of other vertebrates, differences in the expression patterns preclude
precise assignment of orthological relationships. Distinct duplication
events may have given rise to the msx genes of modern fish and other
vertebrate lineages whereas many aspects of msx gene functions during
embryonic development have been preserved.
相似文献