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81.
Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5 总被引:7,自引:0,他引:7 下载免费PDF全文
Olson WC Rabut GE Nagashima KA Tran DN Anselma DJ Monard SP Segal JP Thompson DA Kajumo F Guo Y Moore JP Maddon PJ Dragic T 《Journal of virology》1999,73(5):4145-4155
The CC-chemokine receptor CCR5 mediates fusion and entry of the most commonly transmitted human immunodeficiency virus type 1 (HIV-1) strains. We have isolated six new anti-CCR5 murine monoclonal antibodies (MAbs), designated PA8, PA9, PA10, PA11, PA12, and PA14. A panel of CCR5 alanine point mutants was used to map the epitopes of these MAbs and the previously described MAb 2D7 to specific amino acid residues in the N terminus and/or second extracellular loop regions of CCR5. This structural information was correlated with the MAbs' abilities to inhibit (i) HIV-1 entry, (ii) HIV-1 envelope glycoprotein-mediated membrane fusion, (iii) gp120 binding to CCR5, and (iv) CC-chemokine activity. Surprisingly, there was no correlation between the ability of a MAb to inhibit HIV-1 fusion-entry and its ability to inhibit either the binding of a gp120-soluble CD4 complex to CCR5 or CC-chemokine activity. MAbs PA9 to PA12, whose epitopes include residues in the CCR5 N terminus, strongly inhibited gp120 binding but only moderately inhibited HIV-1 fusion and entry and had no effect on RANTES-induced calcium mobilization. MAbs PA14 and 2D7, the most potent inhibitors of HIV-1 entry and fusion, were less effective at inhibiting gp120 binding and were variably potent at inhibiting RANTES-induced signaling. With respect to inhibiting HIV-1 entry and fusion, PA12 but not PA14 was potently synergistic when used in combination with 2D7, RANTES, and CD4-immunoglobulin G2, which inhibits HIV-1 attachment. The data support a model wherein HIV-1 entry occurs in three stages: receptor (CD4) binding, coreceptor (CCR5) binding, and coreceptor-mediated membrane fusion. The antibodies described will be useful for further dissecting these events. 相似文献
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Ruiz-Montiel C González-Hernández H Leyva J Llanderal-Cazares C Cruz-López L Rojas JC 《Journal of economic entomology》2003,96(4):1126-1131
Olfactory response of male and female Scyphophorus acupunctatus Gyllenhal (Coleoptera: Curculionidae) to volatiles released from the same or opposite conspecifics alone, or combined with host plant volatiles, was evaluated in the laboratory and field. We also evaluated the response to synthetic Rhynchophorinae pheromones in the laboratory. In laboratory tests, attraction of males and females in Y-tube olfactometer to conspecific males was greater than to females and clean air. Males and females preferred the combination males + agave over agave alone. Both sexes were significantly attracted to 2-methyl-4-heptanol and 2-methyl-4-octanol compared with hexane control. In field trials, weevils were successfully caught in the traps baited with conspecifics and plant material. These field results support those of the laboratory bioassays, showing that males attracted conspecific males and females and addition of plant material enhanced the attraction. These results further suggest that S. acupunctatus produces an aggregation pheromone. 相似文献
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Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice 总被引:8,自引:0,他引:8
Kim JY Nelson AL Algon SA Graves O Sturla LM Goumnerova LC Rowitch DH Segal RA Pomeroy SL 《Developmental biology》2003,263(1):50-66
Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/- mice. Our data show that postnatal Ptc+/- mouse granule cell precursor growth is not globally altered. However, many older Ptc+/- mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/- mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/- mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression. 相似文献
87.
Here we present the strategy that achieves the lowest possible rate of inbreeding (DeltaF) for a population with unequal numbers of sires and dams with random mating. This new strategy results in a DeltaF as much as 10% lower than previously achieved. A simple and efficient approach to reducing inbreeding in small populations with sexes of unequal census number is to impose a breeding structure where parental success is controlled in each generation. This approach led to the development of strategies for selecting replacements each generation that were based upon parentage, e.g., a son replacing its sire. This study extends these strategies to a multigeneration round robin scheme where genetic contributions of ancestors to descendants are managed to remove all uncertainties about breeding roles over generations; i.e., male descendants are distributed as equally as possible among dams. In doing so, the sampling variance of genetic contributions within each breeding category is eliminated and consequently DeltaF is minimized. Using the concept of long-term genetic contributions, the asymptotic DeltaF of the new strategy for random mating, M sires and d dams per sire, is phi/(12M), where phi = [1 + 2((1)/(4))(d)]. Predictions were validated using Monte Carlo simulations. The scheme was shown to achieve the lowest possible DeltaF using pedigree alone and showed that further reductions in DeltaF below that obtained from random mating arise from preferential mating of relatives and not from their avoidance. 相似文献
88.
Webe WM Segal A Vankeerberghen A Cassiman JJ Van Driessche W 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2001,130(3):521-531
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP sensitive Cl- channel that is defective in cystic fibrosis (CF). The most frequent mutation, namely deltaF508-CFTR, accounts for 66% of CF. Here we show that cAMP-activation of CFTR occurs via at least two distinct pathways: activation of CFTR molecules already present in the plasma membrane and protein kinase A (PKA)-mediated vesicular transport of new CFTR molecules to the plasma membrane and functional insertion into the membrane. We investigated the mechanisms that are responsible for these activation pathways using the Xenopus laevis oocytes expression system. We expressed CFTR and recorded continuously membrane current (Im), conductance (Gm) and capacitance (Cm), which is a direct measure of membrane surface area. Expression of CFTR alone did not change the plasma membrane surface area. However, activation of CFTR with cAMP increased Im, Gm and Cm while deltaF508-CFTR-expressing oocytes showed no response on cAMP. Inhibition of protein kinase A or buffering intracellular Ca2+ abolished the cAMP-induced increase in Cm while increases of Im and Gm were still present. ATP or the xanthine derivative 8-cyclopentyl-1,3-dipropylxanthine (CPX) did not further activate CFTR. Insertion of pre-formed CFTR into the plasma membrane could be prevented by compounds that interfere with intracellular transport mechanisms such as primaquine, brefeldin A, nocodazole. From these data we conclude that cAMP activates CFTR by at least two distinct pathways: activation of CFTR already present in the plasma membrane and exocytotic delivery of new CFTR molecules to the oocyte membrane and functional insertion into it. 相似文献
89.
Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain 总被引:29,自引:0,他引:29
The inhibitor of apoptosis proteins (IAPs) represent the only endogenous caspase inhibitors and are characterized by the presence of baculoviral IAP repeats (BIRs). Here, we report the crystal structure of the complex between human caspase-7 and XIAP (BIR2 and the proceeding linker). The structure surprisingly reveals that the linker is the only contacting element for the caspase, while the BIR2 domain is invisible in the crystal. The linker interacts with and blocks the substrate groove of the caspase in a backward fashion, distinct from substrate recognition. Structural analyses suggest that the linker is the energetic and specificity determinant of the interaction. Further biochemical characterizations clearly establish that the linker harbors the major energetic determinant, while the BIR2 domain serves as a regulatory element for caspase binding and Smac neutralization. 相似文献
90.
Segal E Taskar B Gasch A Friedman N Koller D 《Bioinformatics (Oxford, England)》2001,17(Z1):S243-S252
Clustering is commonly used for analyzing gene expression data. Despite their successes, clustering methods suffer from a number of limitations. First, these methods reveal similarities that exist over all of the measurements, while obscuring relationships that exist over only a subset of the data. Second, clustering methods cannot readily incorporate additional types of information, such as clinical data or known attributes of genes. To circumvent these shortcomings, we propose the use of a single coherent probabilistic model, that encompasses much of the rich structure in the genomic expression data, while incorporating additional information such as experiment type, putative binding sites, or functional information. We show how this model can be learned from the data, allowing us to discover patterns in the data and dependencies between the gene expression patterns and additional attributes. The learned model reveals context-specific relationships, that exist only over a subset of the experiments in the dataset. We demonstrate the power of our approach on synthetic data and on two real-world gene expression data sets for yeast. For example, we demonstrate a novel functionality that falls naturally out of our framework: predicting the "cluster" of the array resulting from a gene mutation based only on the gene's expression pattern in the context of other mutations. 相似文献