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51.
D W Carr Z E Hausken I D Fraser R E Stofko-Hahn J D Scott 《The Journal of biological chemistry》1992,267(19):13376-13382
The type II cAMP-dependent protein kinase (PKA) is localized to specific subcellular environments through binding of the dimeric regulatory subunit (RII) to anchoring proteins. Subcellular localization is likely to influence which substrates are most accessible to the catalytic subunit upon activation. We have previously shown that the RII-binding domains of four anchoring proteins contain sequences which exhibit a high probability of amphipathic helix formation (Carr, D. W., Stofko-Hahn, R. E., Fraser, I. D. C., Bishop, S. M., Acott, T. E., Brennan, R. G., and Scott J. D. (1991) J. Biol. Chem. 266, 14188-14192). In the present study we describe the cloning of a cDNA which encodes a 1015-amino acid segment of Ht 31. A synthetic peptide (Asp-Leu-Ile-Glu-Glu-Ala-Ala-Ser-Arg-Ile-Val-Asp-Ala-Val-Ile-Glu-Gln-Val -Lys-Ala-Ala-Tyr) representing residues 493-515 encompasses the minimum region of Ht 31 required for RII binding and blocks anchoring protein interaction with RII as detected by band-shift analysis. Structural analysis by circular dichroism suggests that this peptide can adopt an alpha-helical conformation. Both Ht 31 (493-515) peptide and its parent protein bind RII alpha or the type II PKA holoenzyme with high affinity. Equilibrium dialysis was used to calculate dissociation constants of 4.0 and 3.8 nM for Ht 31 peptide interaction with RII alpha and the type II PKA, respectively. A survey of nine different bovine tissues was conducted to identify RII binding proteins. Several bands were detected in each tissues using a 32P-RII overlay method. Addition of 0.4 microM Ht 31 (493-515) peptide to the reaction mixture blocked all RII binding. These data suggest that all anchoring proteins bind RII alpha at the same site as the Ht 31 peptide. The nanomolar affinity constant and the different patterns of RII-anchoring proteins in each tissue suggest that the type II alpha PKA holoenzyme may be specifically targeted to different locations in each type of cell. 相似文献
52.
Marie Armani-Tourret Zhicheng Zhou Romain Gasser Isabelle Staropoli Vincent Cantaloube-Ferrieu Yann Benureau Javier Garcia-Perez Mayte Prez-Olmeda Valrie Lorin Bndicte Puissant-Lubrano Lambert Assoumou Constance Delaugerre Jean-Daniel Lelivre Yves Lvy Hugo Mouquet Guillaume Martin-Blondel Jose Alcami Fernando Arenzana-Seisdedos Jacques Izopet Philippe Colin Bernard Lagane 《PLoS pathogens》2021,17(4)
HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses’ receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART. 相似文献
53.
In social environments, decisions not only determine rewards for oneself but also for others. However, individual differences in pro-social behaviors have been typically studied through self-report. We developed a decision-making paradigm in which participants chose from card decks with differing rewards for themselves and charity; some decks gave similar rewards to both, while others gave higher rewards for one or the other. We used a reinforcement-learning model that estimated each participant''s relative weighting of self versus charity reward. As shown both in choices and model parameters, individuals who showed relatively better learning of rewards for charity – compared to themselves – were more likely to engage in pro-social behavior outside of a laboratory setting indicated by self-report. Overall rates of reward learning, however, did not predict individual differences in pro-social tendencies. These results support the idea that biases toward learning about social rewards are associated with one''s altruistic tendencies. 相似文献
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55.
Ethical Considerations for Outcome‐adaptive Trial Designs: A Clinical Researcher's Perspective 下载免费PDF全文
Scott Brian Saxman 《Bioethics》2015,29(2):59-65
In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome‐adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits of outcome‐adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome‐adaptive trials. 相似文献
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To investigate changes in surface proteins of uterine cells in relation to the time of implantation, epithelial and stromal cells were isolated from rabbit endometrium and maintained in primary culture for 3 days. Surface-iodination of intact cells was carried out before and after culture, using immobilized Iodogen catalyst. The labeled proteins were analyzed by polyacrylamide gel electrophoresis, followed by autoradiography; peak areas were quantitated by scanning densitometry. Different gestational ages showed no marked qualitative differences in the surface-iodination patterns either of epithelial or stromal cells before or after culture. Quantitative differences between the surface-iodination pattern of epithelial cells from days 4 to 6.5 of pregnancy were revealed by canonical variate analysis of labeled peak areas. Values for individual rabbits clustered according to gestational age, with significant (p less than 0.05) separation of the clusters, although the discrimination was less pronounced for cultured than for freshly isolated cells. Changes involving increases in labeling of a protein of 38000 Mr in fresh cells, and decreases in a protein of 42000 Mr in cultured cells, were evident between day 4 and day 6.5. Thus changes in the surface-labeling pattern of uterine epithelial cells in relation to the time of receptivity for ovoimplantation can be distinguished. The functional significance of these changes remains to be elucidated. 相似文献
60.
Gerald Scott 《Free radical research》1988,5(3):141-147
Antioxidants and stabilisers are of critical importance in the manufacture and use of polymer artifacts. Most conventional additives are readily leached from plastics or rubbers by foodstuffs or body fluids with consequent danger associated with the potential toxicity in the body. Strategy for the development of biologically “safe” stabilisation systems for polymers are discussed and it is concluded that the attachment of the appropriate reactive functional group to the polymer backbone by “reactive processing” provides the best means of immobilising the functional group to leaching fluids without sacrificing its protective action. 相似文献