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91.
92.
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
93.
Apocalyptic views on the natural order, chimeras and genetic engineering should not detract from the fact that medical research, similar to the promotion of health, is a public good. Genomics crosses all species, thereby requiring a global approach that respects human rights and public health priorities. Public trust and public participation in research demand clear stewardship as well as transparent and accountable oversight. Characterizing fundamental genomic data as a public resource might counterbalance the current overemphasis on individual rights but this will not be simple. It is only through an attachment to justice and solidarity that the dignity and well-being of persons, both as humans and as citizens, can truly be fostered. 相似文献
94.
Friedlein G El Hage F Vergnon I Richon C Saulnier P Lécluse Y Caignard A Boumsell L Bismuth G Chouaib S Mami-Chouaib F 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(11):6821-6827
We previously characterized several tumor-specific T cell clones from PBL and tumor-infiltrating lymphocytes of a lung cancer patient with identical TCR rearrangements and similar lytic potential, but with different antitumor response. A role of the TCR inhibitory molecule CD5 to impair reactivity of peripheral T cells against the tumor was found to be involved in this process. In this report, we demonstrate that CD5 also controls the susceptibility of specific T cells to activation-induced cell death (AICD) triggered by the tumor. Using a panel of tumor-infiltrating lymphocytes and PBL-derived clones expressing different levels of CD5, our results indicate that T lymphocyte AICD in response to the cognate tumor is inversely proportional to the surface expression level of CD5. They also suggest a direct involvement of CD5 in this process, as revealed by an increase in tumor-mediated T lymphocyte AICD following neutralization of the molecule with specific mAb. Mechanistically, our data indicate that down-regulation of FasL expression and subsequent inhibition of caspase-8 activation are involved in CD5-induced T cell survival. These results provide evidence for a role of CD5 in the fate of peripheral tumor-specific T cells and further suggest its contribution to regulate the extension of CTL response against tumor. 相似文献
95.
Transmembrane domains of hepatitis C virus envelope glycoproteins: residues involved in E1E2 heterodimerization and involvement of these domains in virus entry 下载免费PDF全文
The transmembrane (TM) domains of hepatitis C virus (HCV) envelope glycoproteins E1 and E2 have been shown to play multiple roles during the biogenesis of the E1E2 heterodimer. By using alanine scanning insertion mutagenesis within the TM domains of HCV envelope glycoproteins, we have previously shown that the central regions of these domains as well as the N-terminal part of the TM domain of E1 are involved in heterodimerization. Here, we used a tryptophan replacement scan of these regions to identify individual residues that participate in those interactions. Our mutagenesis study identified at least four residues involved in heterodimerization: Gly 354, Gly 358, Lys 370, and Asp 728. Interestingly, Gly 354 and Gly 358 belong to a GXXXG oligomerization motif. Our tryptophan mutants were also used to generate retrovirus-based, HCV-pseudotyped particles (HCVpp) in order to analyze the effects of these mutations on virus entry. Surprisingly, two mutants consistently displayed higher infectivity compared to that of the wild type. In contrast, HCVpp infectivity was strongly affected for many mutants, despite normal E1E2 heterodimerization and normal levels of incorporation of HCV glycoproteins into HCVpp. The characterization of some of these HCVpp mutants in the recently developed in vitro fusion assay using fluorescent-labeled liposomes indicated that mutations reducing HCVpp infectivity without altering E1E2 heterodimerization affected the fusion properties of HCV envelope glycoproteins. In conclusion, this mutational analysis identified residues involved in E1E2 heterodimerization and revealed that the TM domains of HCV envelope glycoproteins play a major role in the fusion properties of these proteins. 相似文献
96.
Hue-Beauvais C Péchoux C Bouguyon E Chat S Truchet S Pauloin A Le Gouar Y Ollivier-Bousquet M 《Cell and tissue research》2007,328(3):521-536
Caveolins, components of caveolae, are expressed in mammary tissue. In order to determine whether caveolins are present in
different mammary cell types and whether their localisation depends on the physiological stage or species, cav-1 and cav-2
were characterised by immunoblotting in mammary tissues from the mouse, ewe and rabbit and localised, by immunofluorescence
and electron microscopy, in mammary tissues from the mouse and ewe. At all the physiological stages studied, cav-1 and cav-2
were present in endothelial and myoepithelial cells in which flask-shaped caveolae were abundant. However, labelling of cav-1
and cav-2 associated with small vesiculo-tubular structures (including those close to lipid droplets) was low in epithelial
cells. To study the possible association of cav-1 with lipid droplets, lactating ewe mammary fragments were treated in vitro
with brefeldin A. This treatment did not modify the association of cav-1-labelled structures with lipid droplets. Finally,
HC11 and MCF-10A mammary cell lines were treated with oleic acid. The total quantity of cav-1 was little affected by the treatment,
although the lipid droplet labelling of cav-1 was amplified in MCF-10A cells. Thus, the synthesis and localisation of caveolins
are mostly dependent upon the cell types of mammary tissue and upon their state of differentiation. 相似文献
97.
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
98.
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
99.
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
100.