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排序方式: 共有1805条查询结果,搜索用时 15 毫秒
91.
Bryan T. Mayer Allan C. deCamp Yunda Huang Joshua T. Schiffer Raphael Gottardo Peter B. Gilbert Daniel B. Reeves 《PLoS computational biology》2022,18(4)
Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV’s extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10–1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies. 相似文献
92.
Spermatogenesis is inhibited in Balb/C mice as a result of oxyradical insult. However, mammalian spermatocytes and synaptonemal complexes retain their structure and function after oxyradical insult due to protection afforded by the antioxidant vitamin E. Control groups were compared with experimental groups which were fed various vitamin E-deficient diets and subjected to varying times in an humidified 100% oxygen (hyperoxia) chamber. Measurements were made of sex body volume (SBV), nuclear envelope aberrations (NEA), and synaptonemal complex structure in spermatocytes during pachytene of meiosis prophase I. Changes in the volume of the sex body were positively correlated with increased oxyradical insult. The structure of the synaptonemal complex was not altered in any of the experimental groups which is a significant observation. It is suggested that vitamin E affords antioxidant protection and inhibits the alteration of membranes and sex chromosomes in mice during meiosis. 相似文献
93.
Urvater JA Hickman H Dzuris JL Prilliman K Allen TM Schwartz KJ Lorentzen D Shufflebotham C Collins EJ Neiffer DL Raphael B Hildebrand W Sette A Watkins DI 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(5):3334-3344
The human MHC class I gene, HLA-B27, is a strong risk factor for susceptibility to a group of disorders termed spondyloarthropathies (SpAs). HLA-B27-transgenic rodents develop SpAs, implicating HLA-B27 in the etiology of these disorders. Several nonhuman primates, including gorillas, develop signs of SpAs indistinguishable from clinical signs of humans with SpAs. To determine whether SpAs in gorillas have a similar HLA-B27-related etiology, we analyzed the MHC class I molecules expressed in four affected gorillas. Gogo-B01, isolated from three of the animals, has only limited similarity to HLA-B27 at the end of the alpha1 domain. It differs by several residues in the B pocket, including differences at positions 45 and 67. However, the molecular model of Gogo-B*0101 is consistent with a requirement for positively charged residues at the second amino acid of peptides bound by the MHC class I molecule. Indeed, the peptide binding motif and sequence of individual ligands eluted from Gogo-B*0101 demonstrate that, like HLA-B27, this gorilla MHC class I molecule binds peptides with arginine at the second amino acid position of peptides bound by the MHC class I molecule. Furthermore, live cell binding assays show that Gogo-B*0101 can bind HLA-B27 ligands. Therefore, although most gorillas that develop SpAs express an MHC class I molecule with striking differences to HLA-B27, this molecule binds peptides similar to those bound by HLA-B27. 相似文献
94.
Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis 总被引:107,自引:0,他引:107
Yang J Mani SA Donaher JL Ramaswamy S Itzykson RA Come C Savagner P Gitelman I Richardson A Weinberg RA 《Cell》2004,117(7):927-939
95.
da Silva AJ Coelho AL Simas AB Moraes RA Pinheiro DA Fernandes FF Arruda EZ Costa PR Melo PA 《Bioorganic & medicinal chemistry letters》2004,14(2):431-435
Edunol (3), a pterocarpan isolated from Harpalyce brasiliana, a plant used in the northeast of Brazil against snakebites, was obtained by synthesis and showed antimyotoxic, antiproteolytic and PLA2 inhibitor properties. These proprieties could be improved through the synthesis of a bioisoster (5), where the prenyl group was replaced by the benzyl group. 相似文献
96.
97.
Backbone dynamics of the human MIA protein studied by (15)N NMR relaxation: implications for extended interactions of SH3 domains 总被引:1,自引:0,他引:1
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Stoll R Renner C Buettner R Voelter W Bosserhoff AK Holak TA 《Protein science : a publication of the Protein Society》2003,12(3):510-519
The melanoma inhibitory activity (MIA) protein is a clinically valuable marker in patients with malignant melanoma as enhanced values diagnose metastatic melanoma stages III and IV. Here, we report the backbone dynamics of human MIA studied by (15)N NMR relaxation experiments. The folded core of human MIA is found to be rigid, but several loops connecting beta-sheets, such as the RT-loop for example, display increased mobility on picosecond to nanosecond time scales. One of the most important dynamic features is the pronounced flexibility of the distal loop, comprising residues Asp 68 to Ala 75, where motions on time scales up to milliseconds occur. Further, significant exchange contributions are observed for residues of the canonical binding site of SH3 domains including the RT-loop, the n-Src loop, for the loop comprising residues 13 to 19, which we refer to as the"disulfide loop", in part for the distal loop, and the carboxyl terminus of human MIA. The functional importance of this dynamic behavior is discussed with respect to the biological activity of several point mutations of human MIA. The results of this study suggest that the MIA protein and the recently identified highly homologous fibrocyte-derived protein (FDP)/MIA-like (MIAL) constitute a new family of secreted proteins that adopt an SH3 domain-like fold in solution with expanded ligand interactions. 相似文献
98.
Izbicki G Breuer R 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(6):2767-8; author reply 2768
99.
Falk R 《Journal of the history of biology》2003,36(1):87-117
Genetics was established on a strictparticulate conception of heredity. Geneticlinkage, the deviation from independentsegregation of Mendelian factors, was conceivedas a function of the material allocation of thefactors to the chromosomes, rather than to themultiple effects (pleiotropy) of discretefactors. Although linkage maps wereabstractions they provided strong support forthe chromosomal theory of inheritance. DirectCytogenetic evidence was scarce until X-rayinduced major chromosomal rearrangementsallowed direct correlation of genetic andcytological rearrangements. Only with thediscovery of the polytenic giant chromosomes inDrosophila larvae in the 1930s were thevirtual maps backed up by physical maps of thegenetic loci. Genetic linkage became a pivotalexperimental tool for the examination of theintegration of genetic functions in developmentand in evolution. Genetic mapping has remaineda hallmark of genetic analysis. The location ofgenes in DNA is a modern extension of thenotion of genetic linkage. 相似文献
100.
Among the various hematopoi;etic cells, platelets are critical for maintaining the integrity of the vascular system. They must be rapidly activated by sequential and coordinated mechanisms in order to efficiently prevent haemorrhage upon vascular injury. Several signal transduction pathways lead to platelet activation in vitro and in vivo, among them, several are initiated via receptors or co-receptors containing immuno-receptor tyrosine-based activation motifs (ITAM) which trigger downstream signalling like the immune receptors in lymphocytes. However, in contrast to immune cells for which the role of lipid rafts in signalling has largely been described, the involvement of laterally segregated membrane microdomains in platelet activation has been investigated only recently. The results obtained until now strongly suggest that early steps of platelet activation via the collagen receptor GpVI or via FcgammaRIIa occur preferentially in these microdomains where specific proteins efficiently organize key downstream signalling pathways. In addition, lipid rafts also contribute to platelet activation via heterotrimeric G-protein-coupled receptors. They are sites where the phosphoinositide (PI) metabolism is highly active, leading to a local generation of lipid second messengers such as phosphatidylinositol 3,4,5-trisphosphate. Here, evidence is accumulating that cholesterol-enriched membrane microdomains are part of a general process that contributes to the efficiency and the coordination of platelet activation mechanisms. Here we will discuss the biochemical and functional characterizations of human platelet rafts and their potential impact in platelet physiopathology. 相似文献