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Berger-Wolf TY Sheikh SI DasGupta B Ashley MV Caballero IC Chaovalitwongse W Putrevu SL 《Bioinformatics (Oxford, England)》2007,23(13):i49-i56
Reconstruction of sibling relationships from genetic data is an important component of many biological applications. In particular, the growing application of molecular markers (microsatellites) to study wild populations of plant and animals has created the need for new computational methods of establishing pedigree relationships, such as sibgroups, among individuals in these populations. Most current methods for sibship reconstruction from microsatellite data use statistical and heuristic techniques that rely on a priori knowledge about various parameter distributions. Moreover, these methods are designed for data with large number of sampled loci and small family groups, both of which typically do not hold for wild populations. We present a deterministic technique that parsimoniously reconstructs sibling groups using only Mendelian laws of inheritance. We validate our approach using both simulated and real biological data and compare it to other methods. Our method is highly accurate on real data and compares favorably with other methods on simulated data with few loci and large family groups. It is the only method that does not rely on a priori knowledge about the population under study. Thus, our method is particularly appropriate for reconstructing sibling groups in wild populations. 相似文献
156.
Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex 总被引:1,自引:0,他引:1
Yoon SI Logsdon NJ Sheikh F Donnelly RP Walter MR 《The Journal of biological chemistry》2006,281(46):35088-35096
Interleukin-10 receptor 2 (IL-10R2) is a critical component of the IL-10.IL-10R1.IL-10R2 complex which regulates IL-10-mediated immunomodulatory responses. The ternary IL-10 signaling complex is assembled in a sequential order with the IL-10.IL-10R1 interaction occurring first followed by engagement of the IL-10R2 chain. In this study we map the IL-10R2 binding site on IL-10 using surface plasmon resonance and cell-based assays. Critical IL-10R2 binding residues are located in helix A adjacent to the previously identified IL-10R1 recognition surface. Interestingly, IL-10R2 binding residues located in the N-terminal end of helix A exhibit large structural differences between unbound cIL-10 and cIL-10.IL-10R1 crystal structures. This suggests IL-10R1-induced conformational changes regulate IL-10R2 binding and assembly of the ternary IL-10.IL-10R1.IL-10R2 complex. The basic mechanistic features of the assembly process are likely shared by six additional class-2 cytokines (viral IL-10s, IL-22, IL-26, IL-28A, IL28B, and IL-29) to promote IL-10R2 binding to six additional receptor complexes. These studies highlight the importance of structure in regulating low affinity protein-protein interactions and IL-10 signal transduction. 相似文献
157.
We investigated capture and activation of flowing human neutrophils through their Fc-receptors, FcRgammaIIIB (CD16) and FcRgammaIIA (CD32). Immobilised platelets bearing murine monoclonal antibody against glycoprotein IIbIIIA were able to capture and activate flowing neutrophils. The activation response was inhibited by antibody blockade of neutrophil CD32. However, capture only occurred efficiently at wall shear stress below 0.1 Pa if platelet P-selectin was blocked. If neutrophils were perfused over immobilised human IgG, many adhered at 0.025 or 0.05 Pa, but not at 0.1 Pa. Adhesion was reduced by blockade of CD16 or CD32, but blockade of CD16 had the greater effect. When neutrophils were perfused over a combination of purified P-selectin and IgG, blockade of CD16 and CD32 inhibited activation of captured cells. Immunoglobulin deposited in tissue could capture and activate slow-flowing neutrophils. It might also potentiate inflammatory responses at higher stress if presented along with selectins. The dominant FcR for capture of neutrophils was CD16, but with murine antibody, CD32 played a greater role. 相似文献
158.
Smajilovic S Hansen JL Christoffersen TE Lewin E Sheikh SP Terwilliger EF Brown EM Haunso S Tfelt-Hansen J 《Biochemical and biophysical research communications》2006,348(4):1215-1223
Extracellular calcium (Ca(2+)(o)) can act as a first messenger in many cell types through a G protein-coupled receptor, calcium-sensing receptor (CaR). It is still debated whether the CaR is expressed in vascular smooth muscle cells (VSMCs). Here, we report the expression of CaR mRNA and protein in rat aortic VSMCs and show that Ca(2+)(o) stimulates proliferation of the cells. The effects of Ca(2+)(o) were attenuated by pre-treatment with MAPK kinase 1 (MEK1) inhibitor, as well as an allosteric modulator, NPS 2390. Furthermore, stimulation of the VSMCs with Ca(2+)(o)-induced phosphorylation of ERK1/2, but surprisingly did not cause inositol phosphate accumulation. We were not able to conclusively state that the CaR mediates Ca(2+)(o)-induced cell proliferation. Rather, an additional calcium-sensing mechanism may exist. Our findings may be of importance with regard to atherosclerosis, an inflammatory disease characterized by abnormal proliferation of VSMCs and high local levels of calcium. 相似文献
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Tfelt-Hansen J Hansen JL Smajilovic S Terwilliger EF Haunso S Sheikh SP 《American journal of physiology. Heart and circulatory physiology》2006,290(3):H1165-H1171
Both intra- and extracellular calcium play multiple roles in the physiology and pathophysiology of cardiomyocytes, especially in stimulus-contraction coupling. The intracellular calcium level is closely controlled through the concerted actions of calcium channels, exchangers, and pumps; however, the expression and function(s) of the so-called calcium-sensing receptor (CaR) in the heart remain less well characterized. The CaR is a seven-transmembrane receptor, which, in response to noncovalent binding of extracellular calcium, activates intracellular effectors, including G proteins and extracellular signal-regulated kinases (ERK1/2). We have shown that cultured neonatal cardiomyocytes express the CaR messenger RNA and the CaR protein. Furthermore, increasing concentrations of extracellular calcium and a type II CaR activator "calcimimetic" caused inositol phosphate (IP) accumulation, downregulated tritiated thymidine incorporation, and supported ERK1/2 phosphorylation, suggesting that the CaR protein is functionally active. Interestingly, the calcimimetic induced a more rapid ERK1/2 phosphorylation than calcium and left-shifted the IP concentration-response curve for extracellular calcium, supporting the hypothesis that CaR is functionally expressed in cardiac myocytes. This notion was underscored by studies using a virus containing a dominant-negative CaR construct, because this protein blunted the calcium-induced IP response. In conclusion, we have shown that the CaR is functionally expressed in neonatal ventricular cardiomyocytes and that the receptor activates second messenger pathways, including IP and ERK, and decreases DNA synthesis. A specific calcium-sensing receptor on cardiac myocytes could play a role in regulating cardiac development, function, and homeostasis. 相似文献