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91.
Polyploidy or whole-genome duplication is a frequent phenomenon within the plant kingdom and has been associated with the occurrence of evolutionary novelty and increase in biological complexity. Because genome-wide duplication events duplicate whole molecular networks it is of interest to investigate how these networks evolve subsequent to such events. Although genome duplications are generally followed by massive gene loss, at least part of the network is usually retained in duplicate and can rewire to execute novel functions. Alternatively, the network can remain largely redundant and as such confer robustness against mutations. The increasing availability of high-throughput data makes it possible to study evolution following whole genome duplication events at the network level. Here we discuss how the use of 'omics' data in network analysis can provide novel insights on network redundancy and rewiring and conclude with some directions for future research. 相似文献
92.
ER–mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem‐like cells 下载免费PDF全文
Valentina Chiusolo Guillaume Jacquemin Emma Boydell Sebastian Zamorano Cristina Riccadonna Serena Pellegatta Nicolas Hulo Valérie Dutoit Madiha Derouazi Pierre Yves Dietrich Paul R Walker Denis Martinvalet 《The EMBO journal》2017,36(11):1493-1512
Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem‐like cells (GSC) being more sensitive to cytotoxic lymphocyte‐mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER–mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER–mitochondria contacts compared to GDCs. Forced ER–mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER–mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. 相似文献
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Moisy D Avilov SV Jacob Y Laoide BM Ge X Baudin F Naffakh N Jestin JL 《Journal of virology》2012,86(17):9122-9133
Influenza virus has evolved replication strategies that hijack host cell pathways. To uncover interactions between viral macromolecules and host proteins, we applied a phage display strategy. A library of human cDNA expression products displayed on filamentous phages was submitted to affinity selection for influenza viral ribonucleoproteins (vRNPs). High-mobility-group box (HMGB) proteins were found to bind to the nucleoprotein (NP) component of vRNPs. HMGB1 and HMGB2 bind directly to the purified NP in the absence of viral RNA, and the HMG box A domain is sufficient to bind the NP. We show that HMGB1 associates with the viral NP in the nuclei of infected cells, promotes viral growth, and enhances the activity of the viral polymerase. The presence of a functional HMGB1 DNA-binding site is required to enhance influenza virus replication. Glycyrrhizin, which reduces HMGB1 binding to DNA, inhibits influenza virus polymerase activity. Our data show that the HMGB1 protein can play a significant role in intranuclear replication of influenza viruses, thus extending previous findings on the bornavirus and on a number of DNA viruses. 相似文献
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Hombrouck A De Rijck J Hendrix J Vandekerckhove L Voet A De Maeyer M Witvrouw M Engelborghs Y Christ F Gijsbers R Debyser Z 《PLoS pathogens》2007,3(3):e47
Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T-cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75-integrase interface provides in vivo evidence for previously reported crystallographic data. Moreover, the complementary inhibition by LEDGF/p75 knockdown and mutagenesis at the integrase-LEDGF/p75 interface points to the incapability of HIV to circumvent LEDGF/p75 function during proviral integration. Altogether, the data provide a striking example of the power of viral molecular evolution. The results underline the importance of the LEDGF/p75 HIV-1 interplay as target for innovative antiviral therapy. Moreover, the role of LEDGF/p75 in targeting integration will stimulate research on strategies to direct gene therapy vectors into safe landing sites. 相似文献
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Granich R Kahn JG Bennett R Holmes CB Garg N Serenata C Sabin ML Makhlouf-Obermeyer C De Filippo Mack C Williams P Jones L Smyth C Kutch KA Ying-Ru L Vitoria M Souteyrand Y Crowley S Korenromp EL Williams BG 《PloS one》2012,7(2):e30216
Background
Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa.Methods
We model a best case scenario of 90% annual HIV testing coverage in adults 15–49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm3 (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011–2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses.Results
Expanding ART to CD4 count <350 cells/mm3 prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9–194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%.Conclusion
Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated. 相似文献99.
Identification and characterization of the Arabidopsis PHO1 gene involved in phosphate loading to the xylem 总被引:19,自引:0,他引:19 下载免费PDF全文
Hamburger D Rezzonico E MacDonald-Comber Petétot J Somerville C Poirier Y 《The Plant cell》2002,14(4):889-902
The Arabidopsis mutant pho1 is deficient in the transfer of Pi from root epidermal and cortical cells to the xylem. The PHO1 gene was identified by a map-based cloning strategy. The N-terminal half of PHO1 is mainly hydrophilic, whereas the C-terminal half has six potential membrane-spanning domains. PHO1 shows no homology with any characterized solute transporter, including the family of H(+)-Pi cotransporters identified in plants and fungi. PHO1 shows highest homology with the Rcm1 mammalian receptor for xenotropic murine leukemia retroviruses and with the Saccharomyces cerevisiae Syg1 protein involved in the mating pheromone signal transduction pathway. PHO1 is expressed predominantly in the roots and is upregulated weakly under Pi stress. Studies with PHO1 promoter-beta-glucuronidase constructs reveal predominant expression of the PHO1 promoter in the stelar cells of the root and the lower part of the hypocotyl. There also is beta-glucuronidase staining of endodermal cells that are adjacent to the protoxylem vessels. The Arabidopsis genome contains 10 additional genes showing homology with PHO1. Thus, PHO1 defines a novel class of proteins involved in ion transport in plants. 相似文献
100.
Marsault E Hoveyda HR Gagnon R Peterson ML Vézina M Saint-Louis C Landry A Pinault JF Ouellet L Beauchemin S Beaubien S Mathieu A Benakli K Wang Z Brassard M Lonergan D Bilodeau F Ramaseshan M Fortin N Lan R Li S Galaud F Plourde V Champagne M Doucet A Bhérer P Gauthier M Olsen G Villeneuve G Bhat S Foucher L Fortin D Peng X Bernard S Drouin A Déziel R Berthiaume G Dory YL Fraser GL Deslongchamps P 《Bioorganic & medicinal chemistry letters》2008,18(16):4731-4735
A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported. 相似文献