全文获取类型
收费全文 | 595篇 |
免费 | 53篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 15篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 17篇 |
2017年 | 4篇 |
2016年 | 14篇 |
2015年 | 23篇 |
2014年 | 38篇 |
2013年 | 39篇 |
2012年 | 47篇 |
2011年 | 45篇 |
2010年 | 17篇 |
2009年 | 22篇 |
2008年 | 32篇 |
2007年 | 42篇 |
2006年 | 23篇 |
2005年 | 43篇 |
2004年 | 33篇 |
2003年 | 33篇 |
2002年 | 32篇 |
2001年 | 6篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 8篇 |
1995年 | 5篇 |
1994年 | 4篇 |
1993年 | 7篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1988年 | 3篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 6篇 |
1972年 | 2篇 |
1969年 | 7篇 |
1966年 | 1篇 |
1965年 | 2篇 |
1962年 | 1篇 |
1958年 | 1篇 |
1934年 | 1篇 |
1919年 | 2篇 |
排序方式: 共有648条查询结果,搜索用时 359 毫秒
51.
Stern PS Yu L Choi MY Jurenka RA Becker L Rafaeli A 《Journal of insect physiology》2007,53(8):803-818
Moth sex-pheromone biosynthesis follows a circadian cycle, which is cued by the release of the neurohormone pheromone biosynthesis activating neuropeptide (PBAN) to the hemolymph. PBAN binds to a G protein-coupled receptor (GPCR), in pheromone glands, (PG) initially identified by us in Helicoverpa zea moths (HezPBAN-R). In this study, the sequences of the seven transmembrane helices of HezPBAN-R were identified, built, packed and oriented correctly after multiple sequence alignment of the HezPBAN-R and several other GPCRs using the X-ray structure of rhodopsin as a template. Molecular dynamics simulations were run on three different beta-turn types of the C-terminal hexapeptide of PBAN and the results clustered into 12 structurally distinct groups. The lowest energy conformation from each group was used for computer-simulated docking with the model of the HezPBAN-R. Highest scoring complexes were examined and putative binding sites were identified. Experimental studies, using in vitro PG, revealed lower levels of pheromonotropic activity when challenged with pyrokinin-like peptides than with HezPBAN as ligand. Thus, the Drosophila melanogaster pyrokinin-1 receptor (CG9918) was chosen to create chimera receptors by exchanging between the three extracellular loops of the HezPBAN-R and the CG9918 for in silico mutagenesis experiments. The predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells. 相似文献
52.
Appino S Pregel P Manuali E Vincenti L Rota A Carnieletto P Tiberi C Bollo E 《Animal reproduction science》2007,98(3-4):350-356
Bovine infertility is a major cause of loss in the livestock industry. In the present study bovine oviduct cell cultures were infected with a Chlamydophila abortus strain. A direct evaluation of infection was performed by means of May Grünwald-Giemsa and immunocytochemistry for chlamydial LPS, which revealed inclusion bodies and vacuolisation. SEM and TEM analysis of infected cells showed various degrees of cell damage and conglutination of microvilli. This finding suggests that cattle infertility may result from an alteration of oviduct environment caused by multiplication of C. abortus. This microorganism, among other infectious agents, could be considered a potential causative agent of bovine infertility. 相似文献
53.
Olgen S Kiliç Z Ada AO Coban T 《Journal of enzyme inhibition and medicinal chemistry》2007,22(4):457-462
We have previously reported on the synthesis of novel indole derivatives where some compounds showed significant antioxidant activity. Here, we report the synthesis of novel N-H and N-substituted indole-2- and 3-carboxamide derivatives and investigated their antioxidant role in order to identify structural characteristics responsible for activity. Although all compounds showed a strong inhibitory (95-100%) effect on superoxide anion (SOD) only compounds 4, 5 and 6 showed simliar potency for the inhibition of lipid peroxidation (81-94%) which revealed that compounds 4, 5 and 6 possessed highly potent antioxidant properties. Substitution in the 1-position of the indole ring caused the significant differences between the activity results regarding lipid peroxidation inhibition. 相似文献
54.
Krupkin M Matzov D Tang H Metz M Kalaora R Belousoff MJ Zimmerman E Bashan A Yonath A 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2011,366(1580):2972-2978
Based on the presumed capability of a prebiotic pocket-like entity to accommodate substrates whose stereochemistry enables the creation of chemical bonds, it is suggested that a universal symmetrical region identified within all contemporary ribosomes originated from an entity that we term the 'proto-ribosome'. This 'proto-ribosome' could have evolved from an earlier machine that was capable of performing essential tasks in the RNA world, called here the 'pre-proto-ribosome', which was adapted for producing proteins. 相似文献
55.
Feuerstein T Berkovitch-Luria G Nudelman A Rephaeli A Malik Z 《Photochemical & photobiological sciences》2011,10(12):1926-1933
Multi-drug resistance of breast cancer is a major obstacle in chemotherapy of cancer treatments. Recently it was suggested that photodynamic therapy (PDT) can overcome drug resistance of tumors. ALA-PDT is based on the administration of 5-aminolevulinic acid (ALA), the natural precursor for the PpIX biosynthesis, which is a potent natural photosensitizer. In the present study we used the AlaAcBu, a multifunctional ALA-prodrug for photodynamic inactivation of drug resistant MCF-7/DOX breast cancer cells. Supplementation of low doses (0.2mM) of AlaAcBu to the cells significantly increased accumulation of PpIX in both MCF-7/WT and MCF-7/DOX cells in comparison to ALA, or ALA + butyric acid (BA). In addition, our results show that MCF-7/DOX cells are capable of producing higher levels of porphyrins than MCF-7/WT cells due to low expression of the enzyme ferrochelatase, which inserts iron into the tetra-pyrrol ring to form the end product heme. Light irradiation of the AlaAcBu treated cells activated efficient photodynamic killing of MCF-7/DOX cells similar to the parent MCF-7/WT cells, depicted by low mitochondrial enzymatic activity, LDH leakage and decreased cell survival following PDT. These results indicate that the pro-drug AlaAcBu is an effective ALA derivative for PDT treatments of multidrug resistant tumors. 相似文献
56.
Triguero A Cabrera G Rodríguez M Soto J Zamora Y Pérez M Wormald MR Cremata JA 《Plant biotechnology journal》2011,9(9):1120-1130
Plant cells are able to perform most of the post-translational modifications that are required by recombinant proteins to achieve adequate bioactivity and pharmacokinetics. However, regarding N-glycosylation the processing of plant N-glycans in the Golgi apparatus displays major differences when compared with that of mammalian cells. These differences in N-glycosylation are expected to influence serum clearance rate of plant-derived monoclonal antibodies. The monoclonal antibody against the hepatitis B virus surface antigen expressed in Nicotiana tabacum leaves without KDEL endoplasmic reticulum (ER) retention signal (CB.Hep1(-)KDEL) and with a KDEL (Lys-Asp-Glu-Leu) fused to both IgG light and heavy chains (CB.Hep1(+)KDEL) were tested for in vivo stability in mice. Full characterization of N-glycosylation and aggregate formation in each monoclonal antibody batch was determined. The mouse counterpart (CB.Hep1) was used as control. Both (CB.Hep1(-)KDEL) and (CB.Hep1(+)KDEL) showed a faster initial clearance rate (first 24 h) compared with the analogous murine antibody while the terminal phase was similar in the three antibodies. Despite the differences between CB.Hep1(+)KDEL and CB.Hep1(-)KDEL N-glycans, the in vivo elimination in mice was indistinguishable from each other and higher than the murine monoclonal antibody. Molecular modelling confirmed that N-glycans linked to plantibodies were oriented away from the interdomain region, increasing the accessibility of the potential glycan epitopes by glycoprotein receptors that might be responsible for the difference in stability of these molecules. 相似文献
57.
Valeria Edefonti Francesca Bravi Katherine Turner Ettore Beghi Maria Paola Canevini Monica Ferraroni Ada Piazzini 《BMC neurology》2011,11(1):33
Background
The potential effect of age-related factors on health-related quality of life (HRQOL) of patients with epilepsy has rarely been analyzed in the literature. 相似文献58.
Gentile A Toietta G Pazzano V Tsiopoulos VD Giglio AF Crea F Pompilio G Capogrossi MC Di Rocco G 《Molecular biology of the cell》2011,22(5):581-592
Recent studies have underscored a role for the epicardium as a source of multipotent cells. Here, we investigate the myogenic potential of adult human epicardium-derived cells (EPDCs) and analyze their ability to undergo skeletal myogenesis when cultured with differentiating primary myoblasts. Results are compared to those obtained with mesenchymal stromal cells (MSCs) and with endothelial cells, another mesodermal derivative. We demonstrate that EPDCs spontaneously fuse with pre-existing myotubes with an efficiency that is significantly higher than that of other cells. Although at a low frequency, endothelial cells may also contribute to myotube formation. In all cases analyzed, after entering the myotube, nonmuscle nuclei are reprogrammed to express muscle-specific genes. The fusion competence of nonmyogenic cells in vitro parallels their ability to reconstitute dystrophin expression in mdx mice. We additionally show that vascular cell adhesion molecule 1 (VCAM1) expression levels of nonmuscle cells are modulated by soluble factors secreted by skeletal myoblasts and that VCAM1 function is required for fusion to occur. Finally, treatment with interleukin (IL)-4 or IL-13, two cytokines released by differentiating myotubes, increases VCAM1 expression and enhances the rate of fusion of EPDCs and MSCs, but not that of endothelial cells. 相似文献
59.
Quaglio E Restelli E Garofoli A Dossena S De Luigi A Tagliavacca L Imperiale D Migheli A Salmona M Sitia R Forloni G Chiesa R 《PloS one》2011,6(4):e19339
The cellular pathways activated by mutant prion protein (PrP) in genetic prion diseases, ultimately leading to neuronal dysfunction and degeneration, are not known. Several mutant PrPs misfold in the early secretory pathway and reside longer in the endoplasmic reticulum (ER) possibly stimulating ER stress-related pathogenic mechanisms. To investigate whether mutant PrP induced maladaptive responses, we checked key elements of the unfolded protein response (UPR) in transgenic mice, primary neurons and transfected cells expressing two different mutant PrPs. Because ER stress favors the formation of untranslocated PrP that might aggregate in the cytosol and impair proteasome function, we also measured the activity of the ubiquitin proteasome system (UPS). Molecular, biochemical and immunohistochemical analyses found no increase in the expression of UPR-regulated genes, such as Grp78/Bip, CHOP/GADD153, or ER stress-dependent splicing of the mRNA encoding the X-box-binding protein 1. No alterations in UPS activity were detected in mutant mouse brains and primary neurons using the Ub(G76V)-GFP reporter and a new fluorogenic peptide for monitoring proteasomal proteolytic activity in vivo. Finally, there was no loss of proteasome function in neurons in which endogenous PrP was forced to accumulate in the cytosol by inhibiting cotranslational translocation. These results indicate that neither ER stress, nor perturbation of proteasome activity plays a major pathogenic role in prion diseases. 相似文献
60.
Ada Ao Charles H. Williams Jijun Hao Charles C. Hong 《Journal of visualized experiments : JoVE》2011,(50)
Differentiation of pluripotent stem cells is tightly controlled by temporal and spatial regulation of multiple key signaling pathways. One of the hurdles to its understanding has been the varied methods in correlating changes of key signaling events to differentiation efficiency. We describe here the use of a mouse embryonic stem (ES) cell based assay to identify critical time windows for Wnt/β-catenin and BMP signal activation during cardiogenic induction. By scoring for contracting embryonic bodies (EBs) in a 96-well plate format, we can quickly quantify cardiogenic efficiency and identify crucial time windows for Wnt/β-catenin and BMP signal activation in a time course following specific modulator treatments. The principal outlined here is not limited to cardiac induction alone, and can be applied towards the study of many other cell lineages. In addition, the 96-well format has the potential to be further developed as a high throughput, automated assay to allow for the testing of more sophisticated experimental hypotheses. 相似文献