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251.
The dark staining of human sperm heads by Diff Quik is significantly correlated with abnormal sperm head morphology (r=0.51, p<0.0001), but is not associated with changes in sperm chromatin detected by a sperm chromatin structure assay (SCSA; r=0.18, p>0.09). Whilst valuable in the assessment of head morphology, it is concluded that Diff Quik staining is not a useful substitute for the SCSA to assess human sperm chromatin. 相似文献
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Anthony Shock Linda Burkly Ian Wakefield Christopher Peters Ellen Garber Janine Ferrant Frederick R. Taylor Lihe Su Yen-Ming Hsu David Hutto Ali Amirkhosravi Todd Meyer John Francis Sarah Malcolm Martyn Robinson Derek Brown Stevan Shaw Roland Foulkes Alastair Lawson Olivier Harari Timothy Bourne Alison Maloney Neil Weir 《Arthritis research & therapy》2015,17(1)
IntroductionCD40 ligand (CD40L) blockade has demonstrated efficacy in experimental autoimmune models. However, clinical trials of hu5c8, an anti-human CD40L IgG1 antibody, in systemic lupus erythematosus (SLE) were halted due to an increased incidence of thrombotic events. This study evaluated CDP7657, a high affinity PEGylated monovalent Fab'' anti-CD40L antibody fragment, to assess whether an Fc-deficient molecule retains efficacy while avoiding the increased risk of thrombotic events observed with hu5c8.MethodsThe potency and cross-reactivity of CDP7657 was assessed in in vitro assays employing human and non-human primate leukocytes, and the capacity of different antibody formats to activate platelets in vitro was assessed using aggregometry and dense granule release assays. Given the important role CD40L plays in regulating humoral immunity, in vivo efficacy was assessed by investigating the capacity of Cynomolgus monkeys to generate immune responses to the tetanus toxoid antigen while the potential to induce thrombotic events in vivo was evaluated after repeat dosing of antibodies to Rhesus monkeys. A PEGylated anti-mouse CD40L was generated to assess efficacy in the New Zealand Black/White (NZB/W) mouse model of SLE.ResultsCDP7657 dose-dependently inhibited antigen-specific immune responses to tetanus toxoid in Cynomolgus monkeys, and in contrast to hu5c8, there was no evidence of pulmonary thrombovasculopathy in Rhesus monkeys. Aglycosyl hu5c8, which lacks Fc receptor binding function, also failed to induce thrombotic events in Rhesus monkeys. In vitro experiments confirmed that antibody constructs lacking an Fc, including CDP7657, did not induce human or monkey platelet activation. A PEGylated monovalent Fab'' anti-mouse CD40L antibody also inhibited disease activity in the NZB/W mouse model of SLE after administration using a therapeutic dosing regimen where mice received antibodies only after they had displayed severe proteinuria.ConclusionsThese findings demonstrate for the first time that anti-CD40L antibodies lacking a functional Fc region do not induce thrombotic events in Rhesus monkeys and fail to activate platelets in vitro but, nevertheless retain pharmacological activity and support the investigation of CDP7657 as a potential therapy for systemic lupus erythematosus and other autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0757-4) contains supplementary material, which is available to authorized users. 相似文献254.
Li J Wakefield BD Ruble JC Stiff CM Romero DL Marotti KR Sweeney MT Zurenko GE Rohrer DC Thorarensen A 《Bioorganic & medicinal chemistry letters》2007,17(8):2347-2350
Discovery of novel antibacterial agents is a significant challenge. We have recently reported on our discovery of novel antibacterial agents in which we have rapidly optimized potency utilizing a parallel chemistry approach. These advanced leads suffer from high affinity for human serum albumin (HSA). In an effort to decrease the affinity for HSA we have prepared a series of heterocyclic analogs, which retained antibacterial activity and demonstrated reduced affinity for HSA. 相似文献
255.
Thorarensen A Wakefield BD Romero DL Marotti KR Sweeney MT Zurenko GE Rohrer DC Han F Bryant GL 《Bioorganic & medicinal chemistry letters》2007,17(10):2823-2827
In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity. 相似文献
256.
黄檗丛枝菌根真菌鉴定 总被引:1,自引:0,他引:1
目的:利用形态学特征与Nested-PCR技术鉴定黄檗丛枝菌根真菌。方法:采用酸性品红染色法挑选黄檗丛枝菌根。同时,利用湿筛法获得AM真菌孢子,进行形态学鉴定。运用Nested-PCR技术,对黄檗粗提DNA进行特异性扩增,采用blastn进行序列相似性比较。并构建系统进化树,确定侵染黄檗根系的AM真菌。结果:编号为HDAM-1的AM真菌孢子,形态特征与G.intraradices的特征描述一致。Nested-PCR检测到约455bp的目的片段,其序列与G.intraradices(DQ469118)相似性最高,达97.8%,有11个碱基的差异。系统进化树显示该序列在基于25S rDNA的进化树中与G.intraradices(DQ469118.1)处于同一分支,确定G.intraradices侵染黄檗根系。结论:将形态学特征与Nested-PCR技术相结合鉴定AM真菌,不仅简易、经济,而且能够提高研究结果的可靠性。 相似文献
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Statistical Analysis of Environmental Space‐Time Processes (N. D. Le and J. V. Zidek) Jon Wakefield Computer‐Intensive Methods of Data Analysis in Biology (D. A. Roff) A. W. Kemp Randomization, Bootstrap, and Monte Carlo Methods in Biology (3rd Edition) (B. F. J. Manly) A. W. Kemp Applied Mixed Models in Medicine, 2nd edition (H. Brown and R. Prescott) Matthew J. Gurka Stochastic Modeling for Systems Biology (D. J. Wilkinson) Olaf Wolkenhauer Knowledge Discovery in Proteomics (I. Jurisica and D. Wigle) Zhen Zhang Computational Genome Analysis: An Introduction (R. C. Deonier, S. Tavaré, and M. S. Waterman) Marc Suling Stochastic Orders (M. Shaked and J. G. Shantikumar) Subhash Kochar Brief Reports by the Editor Measurement Error in Nonlinear Models: A Modern Perspective, 2nd edition (R. J. Carroll, D. Ruppert, L. A. Stefansky, and C. M. Crainiceanu) Basic Statistics and Pharmaceutical Statistical Applications, 2nd edition (J. E. De Muth) A Handbook of Statistical Analyses Using Stata, 4th edition (S. Rabe‐Hesketh and B. S. Everitt) Introduction to Randomized Controlled Clinical Trials, 2nd edition (J. N. S. Matthews) Survival and Event History Analysis (P. K. Andersen and N. Keiding, editors) A Pocket Guide to Epidemiology (D. G. Kleinbaum, K. M. Sullivan, and N. D. Barker) 相似文献
259.
Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness 总被引:35,自引:0,他引:35
A H Rook J H Kehrl L M Wakefield A B Roberts M B Sporn D B Burlington H C Lane A S Fauci 《Journal of immunology (Baltimore, Md. : 1950)》1986,136(10):3916-3920
Type beta transforming growth factor (TGF-beta) is a unique polypeptide that has been isolated from a number of different tissues and can induce the phenotypic transformation of non-neoplastic fibroblasts as measured by the stimulation of their growth in soft agar. Recently, TGF-beta has been demonstrated to exert profound inhibitory effects on T and B lymphocyte proliferation. In this study, the effects of TGF-beta on natural killer (NK) cell function were investigated. After 20 hr of culture in the presence of TGF-beta, the NK activity of peripheral blood lymphocytes (PBL) was significantly reduced compared with PBL cultured in medium alone. Similarly, TGF-beta produced a significant depression in the cytolytic activity of highly enriched large granular lymphocytes (LGL). This effect of TGF-beta appeared to be mediated directly on the effector cells, because cultivation of the K562 target cells in TGF-beta did not affect target cell susceptibility to lysis. Binding studies with 125I-TGF-beta indicated that LGL possess approximately 1400 high-affinity (Kd = 1PM) receptors/cell, which represents a considerably higher affinity receptor for TGF-beta than that found on fibroblasts. Culturing of PBL and LGL in TGF-beta resulted in a marked blunting of the boosting of NK cytolysis by interferon-alpha but not by interleukin 2, which suggested that TGF-beta may down-regulate interferon-alpha receptors on NK cells. These results, indicate that in addition to inhibitory effects on T and B cells, TGF-beta also inhibits NK cell function. Although the in vivo role of TGF-beta is presently undefined, it may be an important immunoregulatory protein that has a negative influence on lymphocyte activation. 相似文献
260.