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排序方式: 共有355条查询结果,搜索用时 31 毫秒
291.
Elena K. Schneider Johnny X. Huang Vincenzo Carbone Mark Baker Mohammad A. K. Azad Matthew A. Cooper Jian Li Tony Velkov 《Journal of molecular recognition : JMR》2015,28(6):339-348
Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR‐protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co‐administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co‐administered CF drugs for human serum albumin (HSA) and α1‐acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site‐selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug–drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug–drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug–drug interactions of ivacaftor with co‐administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
292.
Nitric Oxide Mediates Bleomycin‐induced Angiogenesis and Pulmonary Fibrosis via Regulation of VEGF
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293.
Litterman N Ikeuchi Y Gallardo G O'Connell BC Sowa ME Gygi SP Harper JW Bonni A 《PLoS biology》2011,9(5):e1001060
The elaboration of dendrites in neurons requires secretory trafficking through the Golgi apparatus, but the mechanisms that govern Golgi function in neuronal morphogenesis in the brain have remained largely unexplored. Here, we report that the E3 ubiquitin ligase Cul7(Fbxw8) localizes to the Golgi complex in mammalian brain neurons. Inhibition of Cul7(Fbxw8) by independent approaches including Fbxw8 knockdown reveals that Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo. Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons. Using an immunoprecipitation/mass spectrometry screening approach, we also uncover the cytoskeletal adaptor protein OBSL1 as a critical regulator of Cul7(Fbxw8) in Golgi morphogenesis and dendrite elaboration. OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus. Accordingly, OBSL1 is required for the morphogenesis of the Golgi apparatus and the elaboration of dendrites. Finally, we identify the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cul7(Fbxw8) in the control of Golgi and dendrite morphogenesis in neurons. Collectively, these findings define a novel OBSL1-regulated Cul7(Fbxw8) ubiquitin signaling mechanism that orchestrates the morphogenesis of the Golgi apparatus and patterning of dendrites, with fundamental implications for our understanding of brain development. 相似文献
294.
Gayen Srimonta Hossain Munshi Azad Sen Soumitra K. 《Journal of plant biochemistry and biotechnology.》2012,21(1):128-133
The potential of insecticidal Vip3Aa toxin peptide of Bacillus thuringiensis (Bt) as a resource for development of lepidopteran insect resistant transgenic crop plants has not yet been fully fathomed. The single mode of protection offered by the insecticidal Vip3Aa toxin against a broad spectrum of lepidopteran insect pests that invade crop field as secondary insect pests, carry definitive significance. However, lack of diversity amongst insecticidal Vip3A toxin towards toxicity for lepidopteran insects is often considered as disadvantage. In order to bring in improvement at this front, search for diversity and protein engineering of the toxin molecule for creation of diversity require to be undertaken in future. In that context, identification of the bioactive core component of Vip3BR toxin peptide of Bt an analogue of Vip3Aa toxin has been accomplished. The core component was found to contain enhanced potency of the insecticidal property 2–3 folds more than the native toxin against four major crop pests. 相似文献
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296.
The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showed recently that post-translational modifications are important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constituting an initial step in the BAK activation process. We now show that dephosphorylation of serine 117 (S117), located in the BAK hydrophobic groove, is also critical for BAK activation to proceed to completion. Phosphorylation of BAK at S117 has two important regulatory functions: first, it occludes the binding of BH3-containing peptides that bind to BAK causing activation and cytochrome c release from mitochondria; second, it prevents BAK-BH3:BAK-Groove interactions that nucleate dimer formation for subsequent multimerization. Hence, BH3-mediated BAK conformational change and subsequent BAK multimerization for cytochrome c release and cell death is intimately linked to, and dependent on, dephosphorylation at S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governing the process of BAK activation in commitment to cell death and how they are regulated. 相似文献
297.
Azad Teimori Tanja Schulz‐Mirbach Hamid R. Esmaeili Bettina Reichenbacher 《Journal of Zoological Systematics and Evolutionary Research》2012,50(4):289-304
The Arabian cyprinodontid Aphanius dispar (Rüppell, 1829) is known to show considerable morphological variation. It has remained unknown, however, whether this variation is a result of environmental differences or allopatric divergence owing to geographical isolation. In this study, 11 populations of A. dispar from three geographically separated basins were analysed, that is, the Makran Basin (I, one river system), the Hormuzgan Basin (II, five rivers and three hot springs) and the Helleh Basin (III, two hot springs) in southern Iran. Statistical analyses do not indicate significant differences between the fishes from river and hot spring habitats (T‐test, p < 0.05), which is also supported by the Canonical Discriminant Analysis (CDA). Nevertheless, morphometric and meristic characters of the fishes, as well as otolith morphology and morphometry, demonstrate that six phenotypic characters discriminate the A. dispar populations of the three basins, that is, (1) predorsal distance (Prdd.SL), (2) head length (HL.SL), (3) pelvic fin length (Lplf.SL), (4) number of pelvic fin rays, as well as relative length of both the (5) medial part and (6) rostrum of the otolith. In addition, these characters display a consistent pattern of variation, thus providing support for the assumption that the phenotypically different A. dispar populations are a result of geographical isolation and not related to environmental differences. It is likely that the geological history of the drainage systems caused isolation event(s) that may date back to the Pleistocene (1.8 million years before present). The high phenotypic differences might suggest that the A. dispar populations from the three studied basins represent separate subspecies or even species. 相似文献
298.
Mishra M Byrd MS Sergeant S Azad AK Parsek MR McPhail L Schlesinger LS Wozniak DJ 《Cellular microbiology》2012,14(1):95-106
Pseudomonas aeruginosa causes chronic lung infections in the airways of cystic fibrosis (CF) patients. Psl is an extracellular polysaccharide expressed by non-mucoid P. aeruginosa strains, which are believed to be initial colonizers. We hypothesized that Psl protects P. aeruginosa from host defences within the CF lung prior to their conversion to the mucoid phenotype. We discovered that serum opsonization significantly increased the production of reactive oxygen species (ROS) by neutrophils exposed to a psl-deficient mutant, compared with wild-type (WT) and Psl overexpressing strains (Psl(++)). Psl-deficient P. aeruginosa were internalized and killed by neutrophils and macrophages more efficiently than WT and Psl(++) variants. Deposition of complement components C3, C5 and C7 was significantly higher on psl-deficient strains compared with WT and Psl(++) bacteria. In an in vivo pulmonary competition assay, there was a 4.5-fold fitness advantage for WT over psl-deficient P. aeruginosa. Together, these data show that Psl inhibits efficient opsonization, resulting in reduced neutrophil ROS production, and decreased killing by phagocytes. This provides a survival advantage in vivo. Since phagocytes are critical in early recognition and control of infection, therapies aimed at Psl could improve the quality of life for patients colonized with P. aeruginosa. 相似文献
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