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141.
Patrick D. Brandt Susi Sturzenegger Varvayanis Tracey Baas Amanda F. Bolgioni Janet Alder Kimberly A. Petrie Isabel Dominguez Abigail M. Brown C. Abigail Stayart Harinder Singh Audra Van Wart Christine S. Chow Ambika Mathur Barbara M. Schreiber David A. Fruman Brent Bowden Christopher A. Wiesen Yvonne M. Golightly Chris E. Holmquist Daniel Arneman Joshua D. Hall Linda E. Hyman Kathleen L. Gould Roger Chalkley Patrick J. Brennwald Rebekah L. Layton 《PLoS biology》2021,19(7)
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143.
In vitro compartmentalization (IVC) was employed for the first time to select for novel bacteriophage λ integrase variants displaying significantly enhanced recombination activity on a non-cognate target DNA sequence. These variants displayed up to 9-fold increased recombination activity over the parental enzyme, and one mutant recombined the chosen non-cognate substrate more efficiently than the parental enzyme recombined the wild-type DNA substrate. The in vitro specificity phenotype extended to the intracellular recombination of episomal vectors in HEK293 cells. Surprisingly, mutations conferring the strongest phenotype do not occur in the λ integrase core-binding domain, which is known to interact directly with cognate target sequences. Instead, they locate to the N-terminal domain which allosterically modulates integrase activity, highlighting a previously unknown role for this domain in directing integrase specificity. The method we describe provides a robust, completely in vitro platform for the development of novel integrase reagent tools for in vitro DNA manipulation and other biotechnological applications. 相似文献
144.
Rita Barallon Steven R. Bauer John Butler Amanda Capes-Davis Wilhelm G. Dirks Eugene Elmore Manohar Furtado Margaret C. Kline Arihiro Kohara Georgyi V. Los Roderick A. F. MacLeod John R. W. Masters Mark Nardone Roland M. Nardone Raymond W. Nims Paul J. Price Yvonne A. Reid Jaiprakash Shewale Gregory Sykes Anton F. Steuer Douglas R. Storts Jim Thomson Zenobia Taraporewala Christine Alston-Roberts Liz Kerrigan 《In vitro cellular & developmental biology. Animal》2010,46(9):727-732
Cell misidentification and cross-contamination have plagued biomedical research for as long as cells have been employed as research tools. Examples of misidentified cell lines continue to surface to this day. Efforts to eradicate the problem by raising awareness of the issue and by asking scientists voluntarily to take appropriate actions have not been successful. Unambiguous cell authentication is an essential step in the scientific process and should be an inherent consideration during peer review of papers submitted for publication or during review of grants submitted for funding. In order to facilitate proper identity testing, accurate, reliable, inexpensive, and standardized methods for authentication of cells and cell lines must be made available. To this end, an international team of scientists is, at this time, preparing a consensus standard on the authentication of human cells using short tandem repeat (STR) profiling. This standard, which will be submitted for review and approval as an American National Standard by the American National Standards Institute, will provide investigators guidance on the use of STR profiling for authenticating human cell lines. Such guidance will include methodological detail on the preparation of the DNA sample, the appropriate numbers and types of loci to be evaluated, and the interpretation and quality control of the results. Associated with the standard itself will be the establishment and maintenance of a public STR profile database under the auspices of the National Center for Biotechnology Information. The consensus standard is anticipated to be adopted by granting agencies and scientific journals as appropriate methodology for authenticating human cell lines, stem cells, and tissues. 相似文献
145.
Anis Larbi Filipe Cabreiro Henning Zelba Shiva Marthandan Emilie Combet Bertrand Friguet Isabelle Petropoulos Yvonne Barnett Graham Pawelec 《Free radical biology & medicine》2010,48(1):26-34
Cell culture and in vitro models are the basis for much biological research, especially in human immunology. Ex vivo studies of T cell physiology employ conditions attempting to mimic the in vivo situation as closely as possible. Despite improvements in controlling the cellular milieu in vitro, most of what is known about T cell behavior in vitro is derived from experiments on T cells exposed to much higher oxygen levels than are normal in vivo. In this study, we report a reduced proliferative response and increased apoptosis susceptibility after T cell activation at 2% oxygen compared to in air. To explain this observation, we tested the hypothesis of an impaired efficacy of intracellular protective mechanisms including antioxidant levels, oxidized protein repair (methionine sulfoxide reductases), and degradation (proteasome) activities. Indeed, after activation, there was a significant accumulation of intracellular oxidized proteins at more physiological oxygen levels concomitant with a reduced GSH:GSSG ratio. Proteasome and methionine sulfoxide reductase activities were also reduced. These data may explain the increased apoptotic rate observed at more physiological oxygen levels. Altogether, this study highlights the importance of controlling oxygen levels in culture when investigating oxygen-dependent phenomena such as oxidative stress. 相似文献
146.
Ian R. Ellis Sarah J. Jones Yvonne Lindsay Go Ohe Ana M. Schor Seth L. Schor Nick R. Leslie 《Cellular signalling》2010,22(11):1655-1659
The protein kinase AKT is activated strongly by many motogenic growth factors, yet has recently been shown capable of inhibiting migration in several cell types. Here we report that treatment with Migration Stimulating Factor (MSF), a truncated form of fibronectin that promotes the migration of many cell types, inhibits AKT activity in human fibroblasts and endothelial cells. In fibroblasts, treatment with either MSF or the AKT inhibitor, Akti-1/2, stimulated migration into 3D collagen gels to a similar extent and the effects of Akti-1/2 on migration could be blocked by the expression of an inhibitor-resistant mutant, AKT1 W80A. These data indicate that MSF promotes fibroblast migration, at least in part, by inhibiting the activity of AKT. 相似文献
147.
Artificial metalloenzymes result from the introduction of a catalytically competent non-native metal cofactor within a protein environment. In the present contribution, we summarize the recent achievements in the design and the optimization of such protein-based hybrid catalysts, with an emphasis on enantioselective transformations. The second part outlines the milestones required to achieve en masse production, screening and directed evolution of artificial metalloenzymes. In the spirit of Darwinian evolution, this will allow the full potential of such protein-based hybrid catalysts to be fully unraveled, thus complementing both homogeneous and enzymatic catalysis. 相似文献
148.
Craig Jamieson Robert A. Campbell Iain A. Cumming Kevin J. Gillen Jonathan Gillespie Bert Kazemier Michael Kiczun Yvonne Lamont Amanda J. Lyons John K.F. Maclean Frederic Martin Elizabeth M. Moir John A. Morrow John Pantling Zoran Rankovic Lynn Smith 《Bioorganic & medicinal chemistry letters》2010,20(20):6072-6075
Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity. 相似文献
149.
Nigel Greene Michael D. Aleo Shirley Louise-May David A. Price Yvonne Will 《Bioorganic & medicinal chemistry letters》2010,20(17):5308-5312
Recent publications have demonstrated that using calculated physiochemical properties can help in the design of compounds that have a decreased risk of significant findings in rodent toxicology studies. In this Letter, we extend this concept and incorporate results from a high throughput cytotoxicity assay to help the drug discovery community select compounds for progression into in vivo studies. The results are presented in an easily interpretable odds ratio so that teams can readily compare compounds and progress potential clinical candidates to the necessary rodent in vivo studies. 相似文献
150.
Kerstin Sander Yvonne von Coburg Jean-Claude Camelin Xavier Ligneau Oliver Rau Manfred Schubert-Zsilavecz Jean-Charles Schwartz Holger Stark 《Bioorganic & medicinal chemistry letters》2010,20(5):1581-1584
Antagonists of the human histamine H3 receptor (hH3R) often contain a second basic moiety, which is well known to boost affinity on this histamine receptor subtype. Here, we prepared compounds with acidic moieties of different pKa values to figure out that the hH3R tolerates these functionalities when added to a common pharmacophore blueprint. Depending on the acidic, electronic and steric features the designed ligands showed hH3R affinities in the nanomolar concentration range. Additionally, selected ligands were tested but failed as dual acting hH3R/hPPAR (human peroxisome proliferator-activated receptor) ligands. 相似文献