全文获取类型
收费全文 | 205篇 |
免费 | 19篇 |
专业分类
224篇 |
出版年
2022年 | 1篇 |
2021年 | 5篇 |
2020年 | 1篇 |
2019年 | 6篇 |
2018年 | 2篇 |
2017年 | 5篇 |
2016年 | 11篇 |
2015年 | 15篇 |
2014年 | 18篇 |
2013年 | 12篇 |
2012年 | 13篇 |
2011年 | 15篇 |
2010年 | 8篇 |
2009年 | 5篇 |
2008年 | 2篇 |
2007年 | 3篇 |
2006年 | 5篇 |
2005年 | 12篇 |
2004年 | 3篇 |
2003年 | 3篇 |
2002年 | 5篇 |
2001年 | 7篇 |
2000年 | 6篇 |
1999年 | 6篇 |
1998年 | 8篇 |
1997年 | 3篇 |
1996年 | 6篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1978年 | 2篇 |
1977年 | 3篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1969年 | 1篇 |
1965年 | 1篇 |
1934年 | 1篇 |
排序方式: 共有224条查询结果,搜索用时 0 毫秒
91.
Background
Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation. Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood.This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation.Methods
Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation. Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand.Results
MMP-9 levels increased from 10.5 μg/g [1.2 to 21.1] prior to exacerbation to 17.1 μg/g [9.3 to 48.7] during exacerbation (P < 0.01). TIMP-1 levels decreased from 3.5 μg/g [0.6 to 7.8] to 1.5 μg/g [0.3 to 4.9] (P = 0.16). MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05). Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05). Macrophage numbers remained level. MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01).Conclusion
During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1. This may suggest a pathway connecting frequent exacerbations with lung function decline. 相似文献92.
In order to reconstruct phylogenetic trees from extremely dissimilar
sequences it is necessary to estimate accurately the extent of sequence
divergence. In this paper a new method of sequence analysis, Markov triple
analysis, is developed for determining the relative frequencies of
nucleotide substitutions within the three branches of a three-taxon
dendrogram. Assuming that nucleotide sites are independently and
identically distributed and assuming a Markov model for nucleotide (or
protein) evolution, it is shown that the unique Markov matrices can be
reconstructed given only the joint probability distribution relating three
taxa. (In the much simpler case involving only two taxa and two character
states, Markov matrices can also be reconstructed, provided symmetry
assumptions are placed on the elements of the matrices.) The method is
illustrated using sequence data from the combined first and second codon
positions derived from complete human, mouse, and cow mitochondrial
sequences.
相似文献
93.
M Goerig A J Habenicht W Zeh P Salbach B Kommerell D E Rothe W Nastainczyk J A Glomset 《The Journal of biological chemistry》1988,263(36):19384-19391
We used Swiss 3T3 fibroblasts stimulated with platelet-derived growth factor and HL-60 cells induced to differentiate into macrophages or neutrophils to study the regulation of prostaglandin and leukotriene synthesis. Addition of platelet-derived growth factor to quiescent 3T3 fibroblasts led within 4 h to a dramatic and preferential increase in prostacyclin synthesis from endoperoxide prostaglandin H2, and microsomal assays showed a strong platelet-derived growth factor-dependent increase in the maximal velocities (Vmax) of both prostaglandin H synthase and prostacyclin synthase. In contrast, addition of phorbol ester to HL-60 cells to induce differentiation into macrophages led within 4 h to a strong and preferential increase in thromboxane synthesis from prostaglandin H2, and microsomal assays disclosed a major rise in Vmax for both prostaglandin H synthase and thromboxane synthase. No comparable changes occurred in HL-60 cells that were differentiating into neutrophils, though upregulation of 5-lipoxygenase pathway enzymes occurred in both differentiation systems. Actinomycin D and cycloheximide prevented the appearance of all of these enzymes of eicosanoid synthesis in all three model systems. Thus, the distinctive patterns of eicosanoid synthesis that are seen in replicating fibroblasts and in differentiating macrophages and neutrophils appear to depend on a coordinate, selective upregulation of several enzymes of eicosanoid biosynthesis that is specific for each cell system. 相似文献
94.
Philip Lijnzaad Dik van Leenen Marian JA Groot Koerkamp Patrick Kemmeren Frank CP Holstege 《The EMBO journal》2017,36(3):274-290
An important distinction is frequently made between constitutively expressed housekeeping genes versus regulated genes. Although generally characterized by different DNA elements, chromatin architecture and cofactors, it is not known to what degree promoter classes strictly follow regulatability rules and which molecular mechanisms dictate such differences. We show that SAGA‐dominated/TATA‐box promoters are more responsive to changes in the amount of activator, even compared to TFIID/TATA‐like promoters that depend on the same activator Hsf1. Regulatability is therefore an inherent property of promoter class. Further analyses show that SAGA/TATA‐box promoters are more dynamic because TATA‐binding protein recruitment through SAGA is susceptible to removal by Mot1. In addition, the nucleosome configuration upon activator depletion shifts on SAGA/TATA‐box promoters and seems less amenable to preinitiation complex formation. The results explain the fundamental difference between housekeeping and regulatable genes, revealing an additional facet of combinatorial control: an activator can elicit a different response dependent on core promoter class. 相似文献
95.
Michaela Zeh Anna Paola Casazza Oliver Kreft Ute Roessner Katrin Bieberich Lothar Willmitzer Rainer Hoefgen Holger Hesse 《Plant physiology》2001,127(3):792-802
Methionine (Met) and threonine (Thr) are members of the aspartate family of amino acids. In plants, their biosynthetic pathways diverge at the level of O-phosphohomo-serine (Ser). The enzymes cystathionine gamma-synthase and Thr synthase (TS) compete for the common substrate O-phosphohomo-Ser with the notable feature that plant TS is activated through S-adenosyl-Met, a metabolite derived from Met. To investigate the regulation of this branch point, we engineered TS antisense potato (Solanum tuberosum cv Désirée) plants using the constitutive cauliflower mosaic virus 35S promoter. In leaf tissues, these transgenics exhibit a reduction of TS activity down to 6% of wild-type levels. Thr levels are reduced to 45% wild-type controls, whereas Met levels increase up to 239-fold depending on the transgenic line and environmental conditions. Increased levels of homo-Ser and homo-cysteine indicate increased carbon allocation into the aspartate pathway. In contrast to findings in Arabidopsis, increased Met content has no detectable effect on mRNA or protein levels or on the enzymatic activity of cystathionine gamma-synthase in potato. Tubers of TS antisense potato plants contain a Met level increased by a factor of 30 and no reduction in Thr. These plants offer a major biotechnological advance toward the development of crop plants with improved nutritional quality. 相似文献
96.
E C Castro JA Diaz GomezDe Ferreyra C R De Castro N D'Acosta C M De Fenos 《Biochemical and biophysical research communications》1973,50(2):337-343
There is a higher activity of ethyl morphine N-demethylase (EM-ase) and cytochrome P-450 (P-450) reductase as well as higher P-450 content in the smooth endoplasmic reticulum (SER) than in the rough endoplasmic reticulum (RER). The extent of the irreversible binding of the14C from14CCl4 to lipids and proteins, as well as the CCl4-induced destruction of P-450 is more intense in SER than in RER while the opposite was found for glucose 6-phosphatase (G6P-ase) destruction. CCl4-induced lipid peroxidation is as intense in SER as is in RER.14C from14CCl4 gets irreversibly bound to ribosomal proteins. 相似文献
97.
Daiane D Hartwig Thaís L Oliveira Fabiana K Seixas Karine M Forster Caroline Rizzi Cláudia P Hartleben Alan JA McBride Odir A Dellagostin 《Microbial cell factories》2010,9(1):98
Background
Leptospirosis, a zoonosis caused by Leptospira spp., is recognized as an emergent infectious disease. Due to the lack of adequate diagnostic tools, vaccines are an attractive intervention strategy. Recombinant proteins produced in Escherichia coli have demonstrated promising results, albeit with variable efficacy. Pichia pastoris is an alternative host with several advantages for the production of recombinant proteins. 相似文献98.
Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy. In contrast, the BH3 domain of Beclin 1 is bound to, and inhibited by Bcl-2 or Bcl-XL. This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy. Beclin 1 dysfunction has been implicated in many disorders, including cancer and neurodegeneration. Here, we summarize new findings regarding the organization and function of the Beclin 1 network in cellular homeostasis, focusing on the cross-regulation between apoptosis and autophagy. 相似文献
99.
JW Mills ADC MacKnight JA Jarrell JM Dayer DA Ausiello 《The Journal of cell biology》1981,88(3):637-643
To determine the specificity and efficacy of [(3)H]ouabain binding as a quantitative measure of the Na(+) pump (Na(+), K(+)-ATPase) and as a marker for the localization of pumps involved in transepithelial Na(+)-transport, we analyzed the interaction of [(3)H]ouabain with its receptor in pig kidney epithelial (LLC-PK(1)) cells. When these epithelial cells are depleted of Na(+) and exposed to 2 muM [(3)H]ouabain in a Na(+)-free medium, binding is reduced by 90 percent. When depleted of K(+) and incubated in a K(+)- free medium, the ouabain binding rate is increase compared with that measured at 5 mM. This increase is only demonstable when Na(+) is present. The increased rate could be attributed to the predominance of the Na(+)-stimulated phosphorylated form of the pump, as K(+) is not readily available to stimulate dephosphorylation. However, some binding in the K(+)-free medium is attributable to pump turnover (and therefore, recycling of K(+)), because analysis of K(+)-washout kinetics demonstrated that addition of 2 muM ouabain to K(+)-depleted cells increased the rate of K(+) loss. These results indicate that in intact epithelial cells, unlike isolated membrane preparations, the most favorable condition for supporting ouabain binding occurs when the Na(+), K(+)-ATPase is operating in the Na(+)-pump mode or is phosphorylated in the presence of Na(+). When LLC-PK(1) cells were exposed to ouabain at 4 degrees C, binding was reduced by 97 percent. Upon rewarming, the rate of binding was greater than that obtained on cells kept at a constant 37 degrees C. However, even at this accelerated rate, the time to reach equilibrium was beyond what is required for cells, swollen by exposure to cold, to recover normal volume. Thus, results from studies that have attempted to use ouabain to eliminate the contribution of the conventional Na(+) pump to volume recovery must be reevaluated if the exposure to ouabain was done in the cold or under conditions in which the Na(+) pump is not operating. 相似文献
100.