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71.
Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors 总被引:8,自引:0,他引:8
Bantscheff M Eberhard D Abraham Y Bastuck S Boesche M Hobson S Mathieson T Perrin J Raida M Rau C Reader V Sweetman G Bauer A Bouwmeester T Hopf C Kruse U Neubauer G Ramsden N Rick J Kuster B Drewes G 《Nature biotechnology》2007,25(9):1035-1044
We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery. 相似文献
72.
Morvan F Meyer A Jochum A Sabin C Chevolot Y Imberty A Praly JP Vasseur JJ Souteyrand E Vidal S 《Bioconjugate chemistry》2007,18(5):1637-1643
The synthesis of propargylated pentaerythrityl phosphodiester oligomers (PePOs) was achieved using a DNA synthesizer with a bis-propargylated pentaerythritol-based phosphoramidite. An azido fucose derivative was reacted under "click" chemistry conditions activated by microwaves to construct a series of glycosylated PePOs bearing 4, 6, 8, and 10 L-fucose residues. Binding to the fucose-specific bacterial lectin (PA-IIL) was determined for the fucosylated PePOs through an enzyme-linked lectin amplification competition assay. The IC50 values measured are 10-20 times better than for monovalent l-fucose and denotate for a "macromolecular" effect rather than a "cluster" effect. 相似文献
73.
Induced parthenogenesis in mandarin for haploid production: induction procedures and genetic analysis of plantlets 总被引:1,自引:0,他引:1
Froelicher Y Bassene JB Jedidi-Neji E Dambier D Morillon R Bernardini G Costantino G Ollitrault P 《Plant cell reports》2007,26(7):937-944
This study focused on haploid induction in mandarin through in situ gynogenesis by pollination with irradiated pollen of ‘Meyer’
lemon. Pollination was carried out for three genotypes of mandarin with four levels of gamma-ray-irradiated pollen (150, 300,
600, and 900 Gy). The resulting seeds were characterised by a small size. Embryos were rescued in vitro and the ploidy level
of the plantlets was determined by flow cytometry analysis. Haploid, diploid, triploid plantlets were obtained. The haploid
parthenogenetic origin was confirmed using microsatellite marker analysis and chromosome count. Diploid and triploid plants
were the result of crosses between mandarin and lemon. The induction of gynogenetic haploids of ‘Fortune’ (Citrus clementina Hort ex Tan. × Citrus tangerina Hort ex Tan.) and ‘Ellendale’ (Citrus reticulata Blanco × Citrus sinensis L. Osb) is reported here for the first time. 相似文献
74.
75.
Legionella pneumophila, the causative agent of Legionnaires' disease, is ubiquitously found in aquatic environments, associated with free living amoebae. Trophozoite forms of the genus Acanthamoeba have been shown to support the intracellular growth of Legionella while it has been proposed that cyst forms are related to survival in harsh environments. This underlines that amoebae are of primary importance in Legionella spreading. In this study, we followed the survival of L. pneumophila Lens over 6 months in a poor medium, with or without Acanthamoeba castellanii. The results demonstrated that L. pneumophila Lens could survive for at least 6 months in association with A. castellanii and that cultivable bacteria are to be found within expelled vesicles rather than within cysts. Our findings suggest that vesicles might be further studied in order to elucidate their production and their role in the environmental spreading of Legionella. 相似文献
76.
Sébastien JD Giroux Celmar Alves-Leiva Yann Lécluse Patrick Martin Olivier Albagli Isabelle Godin 《BMC developmental biology》2007,7(1):79
Background
Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC), precursors formed earlier in the yolk sac (YS) display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. 相似文献77.
78.
Olivier Albagli-Curiel Yann Lécluse Philippe Pognonec Kim E Boulukos Patrick Martin 《BMC biotechnology》2007,7(1):85
Background
Retroviral vectors are valuable tools for gene transfer. Particularly convenient are IRES-containing retroviral vectors expressing both the protein of interest and a marker protein from a single bicistronic mRNA. This coupled expression increases the relevance of tracking and/or selection of transduced cells based on the detection of a marker protein. pAP2 is a retroviral vector containing eGFP downstream of a modified IRES element of EMCV origin, and a CMV enhancer-promoter instead of the U3 region of the 5'LTR, which increases its efficiency in transient transfection. However, pAP2 contains a limited multicloning site (MCS) and shows weak eGFP expression, which previously led us to engineer an improved version, termed pPRIG, harboring: i) the wild-type ECMV IRES sequence, thereby restoring its full activity; ii) an optimized MCS flanked by T7 and SP6 sequences; and iii) a HA tag encoding sequence 5' of the MCS (pPRIG HAa/b/c). 相似文献79.
Michal Meir Yaron Galanty Lior Kashani Michael Blank Rami Khosravi María Jesús Fernández-ávila Andrés Cruz-García Ayelet Star Lea Shochot Yann Thomas Lisa J. Garrett Daniel A. Chamovitz David M. Bodine Thimo Kurz Pablo Huertas Yael Ziv Yosef Shiloh 《Nucleic acids research》2015,43(9):4517-4530
The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways—nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection—the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability. 相似文献
80.
Yann Gibert Eric Samarut Emmanuel Pasco-Viel Laure Bernard Véronique Borday-Birraux Alexa Sadier Catherine Labbé Laurent Viriot Vincent Laudet 《Proceedings. Biological sciences / The Royal Society》2015,282(1802)
Small variations in signalling pathways have been linked to phenotypic diversity and speciation. In vertebrates, teeth represent a reservoir of adaptive morphological structures that are prone to evolutionary change. Cyprinid fish display an impressive diversity in tooth number, but the signals that generate such diversity are unknown. Here, we show that retinoic acid (RA) availability influences tooth number size in Cyprinids. Heterozygous adult zebrafish heterozygous for the cyp26b1 mutant that encodes an enzyme able to degrade RA possess an extra tooth in the ventral row. Expression analysis of pharyngeal mesenchyme markers such as dlx2a and lhx6 shows lateral, anterior and dorsal expansion of these markers in RA-treated embryos, whereas the expression of the dental epithelium markers dlx2b and dlx3b is unchanged. Our analysis suggests that changes in RA signalling play an important role in the diversification of teeth in Cyprinids. Our work illustrates that through subtle changes in the expression of rate-limiting enzymes, the RA pathway is an active player of tooth evolution in fish. 相似文献