全文获取类型
收费全文 | 345篇 |
免费 | 21篇 |
出版年
2022年 | 4篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 5篇 |
2015年 | 14篇 |
2014年 | 12篇 |
2013年 | 6篇 |
2012年 | 15篇 |
2011年 | 17篇 |
2010年 | 7篇 |
2009年 | 8篇 |
2008年 | 6篇 |
2007年 | 19篇 |
2006年 | 12篇 |
2005年 | 12篇 |
2004年 | 14篇 |
2003年 | 8篇 |
2002年 | 11篇 |
2001年 | 15篇 |
2000年 | 5篇 |
1999年 | 5篇 |
1998年 | 12篇 |
1997年 | 13篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 2篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 3篇 |
1983年 | 6篇 |
1982年 | 7篇 |
1979年 | 5篇 |
1978年 | 3篇 |
1977年 | 9篇 |
1976年 | 7篇 |
1975年 | 5篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 3篇 |
1971年 | 4篇 |
1968年 | 2篇 |
1937年 | 2篇 |
排序方式: 共有366条查询结果,搜索用时 15 毫秒
31.
Combs TP Nagajyothi Mukherjee S de Almeida CJ Jelicks LA Schubert W Lin Y Jayabalan DS Zhao D Braunstein VL Landskroner-Eiger S Cordero A Factor SM Weiss LM Lisanti MP Tanowitz HB Scherer PE 《The Journal of biological chemistry》2005,280(25):24085-24094
Adipose tissue plays an active role in normal metabolic homeostasis as well as in the development of human disease. Beyond its obvious role as a depot for triglycerides, adipose tissue controls energy expenditure through secretion of several factors. Little attention has been given to the role of adipocytes in the pathogenesis of Chagas disease and the associated metabolic alterations. Our previous studies have indicated that hyperglycemia significantly increases parasitemia and mortality in mice infected with Trypanosoma cruzi. We determined the consequences of adipocyte infection in vitro and in vivo. Cultured 3T3-L1 adipocytes can be infected with high efficiency. Electron micrographs of infected cells revealed a large number of intracellular parasites that cluster around lipid droplets. Furthermore, infected adipocytes exhibited changes in expression levels of a number of different adipocyte-specific or adipocyte-enriched proteins. The adipocyte is therefore an important target cell during acute Chagas disease. Infection of adipocytes by T. cruzi profoundly influences the pattern of adipokines. During chronic infection, adipocytes may represent an important long-term reservoir for parasites from which relapse of infection can occur. We have demonstrated that acute infection has a unique metabolic profile with a high degree of local inflammation in adipose tissue, hypoadiponectinemia, hypoglycemia, and hypoinsulinemia but with relatively normal glucose disposal during an oral glucose tolerance test. 相似文献
32.
Background
It has been argued that multibreed animal models should include a heterogeneous covariance structure. However, the estimation of the (co)variance components is not an easy task, because these parameters can not be factored out from the inverse of the additive genetic covariance matrix. An alternative model, based on the decomposition of the genetic covariance matrix by source of variability, provides a much simpler formulation. In this study, we formalize the equivalence between this alternative model and the one derived from the quantitative genetic theory. Further, we extend the model to include maternal effects and, in order to estimate the (co)variance components, we describe a hierarchical Bayes implementation. Finally, we implement the model to weaning weight data from an Angus × Hereford crossbred experiment.Methods
Our argument is based on redefining the vectors of breeding values by breed origin such that they do not include individuals with null contributions. Next, we define matrices that retrieve the null-row and the null-column pattern and, by means of appropriate algebraic operations, we demonstrate the equivalence. The extension to include maternal effects and the estimation of the (co)variance components through the hierarchical Bayes analysis are then straightforward. A FORTRAN 90 Gibbs sampler was specifically programmed and executed to estimate the (co)variance components of the Angus × Hereford population.Results
In general, genetic (co)variance components showed marginal posterior densities with a high degree of symmetry, except for the segregation components. Angus and Hereford breeds contributed with 50.26% and 41.73% of the total direct additive variance, and with 23.59% and 59.65% of the total maternal additive variance. In turn, the contribution of the segregation variance was not significant in either case, which suggests that the allelic frequencies in the two parental breeds were similar.Conclusion
The multibreed maternal animal model introduced in this study simplifies the problem of estimating (co)variance components in the framework of a hierarchical Bayes analysis. Using this approach, we obtained for the first time estimates of the full set of genetic (co)variance components. It would be interesting to assess the performance of the procedure with field data, especially when interbreed information is limited. 相似文献33.
Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons and a substantial decrease in
the neurotransmitter dopamine in the nigro-striatal region of the brain. Increased markers of oxidative stress, activated
microglias and elevated levels of pro-inflammatory cytokines have been identified in the brains of patients with PD. Although
the precise mechanism of loss of neurons in PD remains unclear, these findings suggest that microglial activation may contribute
directly to loss of dopaminergic neurons in PD patients. In the present study, we tested the hypothesis that activated microglia
induces nitric oxide-dependent oxidative stress which subsequently causes death of dopaminergic neuronal cells in culture.
We employed lipopolysaccharide (LPS) stimulated mouse macrophage cells (RAW 264.7) as a reactive microglial model and SH-SY5Y
cells as a model for human dopaminergic neurons. LPS stimulation of macrophages led to increased production of nitric oxide
in a time and dose dependent manner as well as subsequent generation of other reactive nitrogen species such as peroxynitrite
anions. In co-culture conditions, reactive macrophages stimulated SH-SY5Y cell death characterized by increased peroxynitrite
concentrations and nitration of alpha-synuclein within SH-SY5Y cells. Importantly 1400W, an inhibitor of the inducible nitric
oxide synthase provided protection from cell death via decreasing the levels of nitrated alpha-synuclein. These results suggest
that reactive microglias could induce oxidative stress in dopaminergic neurons and such oxidative stress may finally lead
to nitration of alpha-synuclein and death of dopaminergic neurons in PD. 相似文献
34.
Ala PJ Gonneville L Hillman M Becker-Pasha M Yue EW Douty B Wayland B Polam P Crawley ML McLaughlin E Sparks RB Glass B Takvorian A Combs AP Burn TC Hollis GF Wynn R 《The Journal of biological chemistry》2006,281(49):38013-38021
Structural analyses of the protein-tyrosine phosphatase 1B (PTP1B) active site and inhibitor complexes have aided in optimization of a peptide inhibitor containing the novel (S)-isothiazolidinone (IZD) phosphonate mimetic. Potency and permeability were simultaneously improved by replacing the polar peptidic backbone of the inhibitor with nonpeptidic moieties. The C-terminal primary amide was replaced with a benzimidazole ring, which hydrogen bonds to the carboxylate of Asp(48), and the N terminus of the peptide was replaced with an aryl sulfonamide, which hydrogen bonds to Asp(48) and the backbone NH of Arg(47) via a water molecule. Although both substituents retain the favorable hydrogen bonding network of the peptide scaffold, their aryl rings interact weakly with the protein. The aryl ring of benzimidazole is partially solvent exposed and only participates in van der Waals interactions with Phe(182) of the flap. The aryl ring of aryl sulfonamide adopts an unexpected conformation and only participates in intramolecular pi-stacking interactions with the benzimidazole ring. These results explain the flat SAR for substitutions on both rings and the reason why unsubstituted moieties were selected as candidates. Finally, substituents ortho to the IZD heterocycle on the aryl ring of the IZD-phenyl moiety bind in a small narrow site adjacent to the primary phosphate binding pocket. The crystal structure of an o-chloro derivative reveals that chlorine interacts extensively with residues in the small site. The structural insights that have led to the discovery of potent benzimidazole aryl sulfonamide o-substituted derivatives are discussed in detail. 相似文献
35.
RP Tucker K Drabikowski JF Hess J Ferralli R Chiquet-Ehrismann JC Adams 《BMC evolutionary biology》2006,6(1):60-17
Background
Tenascins are a family of glycoproteins found primarily in the extracellular matrix of embryos where they help to regulate cell proliferation, adhesion and migration. In order to learn more about their origins and relationships to each other, as well as to clarify the nomenclature used to describe them, the tenascin genes of the urochordate Ciona intestinalis, the pufferfish Tetraodon nigroviridis and Takifugu rubripes and the frog Xenopus tropicalis were identified and their gene organization and predicted protein products compared with the previously characterized tenascins of amniotes. 相似文献36.
Lopatin DE Jaramillo E Edwards CA Van Poperin N Combs A Shelburne CE 《FEMS microbiology letters》1999,181(1):9-16
We previously reported an association between elevated serum antibody titers to the 90-kDa human heat shock protein (Hsp90), periodontal health and colonization by Porphyromonas gingivalis. In this study, we examined the cellular localization of the Hsp90 homologue of P. gingivalis. Cultures of P. gingivalis were heat-stressed (45 degrees C) and examined for localization of the Hsp90 homologue. Heat stress induced a 4-5-fold increase in anti-Hsp90 antibody reactivity over that of the unstressed controls. Western blot analysis revealed two bands (44 and 68 kDa) that reacted with anti-Hsp90 antibodies. The 68-kDa band was heat-inducible, while the 44-kDa band was not. Immunogold staining revealed that the Hsp90 homologue localized principally to the membrane and extracellular vesicles. Subcellular fractionation confirmed that the Hsp90 homologue was primarily membrane-associated. 相似文献
37.
Tagscherer KE Fassl A Sinkovic T Combs SE Roth W 《Apoptosis : an international journal on programmed cell death》2012,17(2):187-199
Treatment with the Bcl-2/Bcl-XL inhibitor ABT-737 is a promising novel strategy to therapeutically induce apoptotic cell death
in malignant tumors such as glioblastomas. Although many studies have demonstrated that ABT-737 acts synergistically with
chemotherapeutic drugs, the possibility of a combined treatment with ionizing radiation (IR) and ABT-737 has not yet been
thoroughly investigated. Similarly, the relationship between p53 function and the pro-apoptotic effects of ABT-737 are still
obscure. Here, we demonstrate that IR and ABT-737 synergistically induce apoptosis in glioblastoma cells. The sensitivity
to ABT-737-mediated cell death is significantly increased by the IR-dependent accumulation of cells in the G2/M cell cycle
phase. Wild type p53 function inhibits the efficacy of a combined IR and ABT-737 treatment via a p21-dependent G1 cell cycle
arrest. Moreover, mutant as well as wild type p53 counteract the pro-apoptotic activity of ABT-737 by maintaining the expression
levels of the Mcl-1 protein. Thus, p53 regulates the sensitivity to ABT-737 of glioblastoma cells. Our results warrant a further
evaluation of a novel combination therapy using IR and ABT-737. The efficacy of such a therapy could be substantially enhanced
by Mcl-1-lowering strategies. 相似文献
38.
39.
40.