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排序方式: 共有1671条查询结果,搜索用时 15 毫秒
101.
Steven T. Staben Timothy P. Heffron Daniel P. Sutherlin Seema R. Bhat Georgette M. Castanedo Irina S. Chuckowree Jenna Dotson Adrian J. Folkes Lori S. Friedman Leslie Lee John Lesnick Cristina Lewis Jeremy M. Murray Jim Nonomiya Alan G. Olivero Emile Plise Jodie Pang Wei Wei Prior Laurent Salphati Lionel Rouge Bing-Yan Zhu 《Bioorganic & medicinal chemistry letters》2010,20(20):6048-6051
Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model. 相似文献
102.
103.
Susana R Parathath Lori Anne Mainwaring Africa Fernandez-L Cemile G Guldal Zaher Nahle Anna Marie Kenney 《Cell cycle (Georgetown, Tex.)》2010,9(19):4013-4024
Development of the cerebellum, a brain region regulating posture and coordination, occurs post-natally and is marked by rapid proliferation of granule neuron precursors (CGNPs), stimulated by mitogenic Sonic hedgehog (Shh) signaling. β-Arrestin (βArr) proteins play important roles downstream of Smoothened, the Shh signal transducer. However, whether Shh regulates βArrs and what role it plays in Shh-driven CGNP proliferation remains to be determined. Here, we report that Shh induces βArr1 accumulation and localization to the nucleus, where it participates in enhancing expression of the cyclin dependent kinase (cdk) inhibitor p27, whose accumulation eventually drives CGNP cell cycle exit. βArr1 knockdown enhances CGNP proliferation and reduces p27 expression. Thus, Shh-mediated βArr1 induction represents a novel negative feedback loop within the Shh mitogenic pathway, such that ongoing Shh signaling, while required for CGNPs to proliferate, also sets up a cell-intrinsic clock programming their ultimate exit from the cell cycle.Key words: sonic hedgehog, cerebellum, neural precursor, β-arrestin 1, p27, differentiation 相似文献
104.
Polette-Niewold LA Manciu FS Torres B Alvarado M Chianelli RR 《Journal of inorganic biochemistry》2007,101(11-12):1958-1973
Maya Blue is an ancient blue pigment composed of palygorskite clay and indigo. It was used by the ancient Maya and provides a dramatic background for some of the most impressive murals throughout Mesoamerica. Despite exposure to acids, alkalis, and chemical solvents, the color of the Maya Blue pigment remains unaltered. The chemical interaction between palygorskite and indigo form an organic/inorganic complex with the carbonyl oxygen of the indigo bound to a surface Al(3+) in the Si-O lattice. In addition indigo will undergo an oxidation to dehydroindigo during preparation. The dehydro-indigo molecule forms a similar but stronger complex with the Al(3+). Thus, Maya Blue varies in color due to the mixed indigo/dehydroindigo complex. The above conclusions are the result of application of multiple techniques (X-ray diffraction, differential thermal analysis/thermal gravimetric analysis, high resolution transmission electron microscopy, scanning electron microscopy, infrared and Raman spectroscopy) to the characterization of the organic/inorganic complex. A picture of the bonding of the organic molecule to the palygorskite surface forming a surface complex is developed and supported by the results of density functional theory calculations. We also report that other organic molecules such as thioindigo form similar organic/inorganic complexes thus, opening an entirely new class of complex materials for future applications. 相似文献
105.
106.
Stable isotopes can be used to elucidate ecological relationships in community and trophic studies. Findings are calibrated
against baselines, e.g. from a producer or primary consumer, assumed to act as a reference to the isotopic context created
by spatio-temporal attributes such as geography, climate, nutrient, and energy sources. The ability of an organism to accurately
represent a community base depends on how, and over what time-scale, it assimilates ambient materials. Freshwater mussels
have served as references for trophic studies of freshwater communities and as indicators of change in nutrient pollution
load or source. Their suitability as reference animals has not yet been fully explored, however. We conducted a series of
studies examining the suitability of freshwater mussels as isotopic baselines, using their ability to reflect variation in
ambient nutrient loads as a case scenario. (1) We analyzed bivalve foot tissue δ15N and δ13C from 22 stream reaches in the Piedmont region of North Carolina, USA to show that compositions varied substantially among
locations. Site mean bivalve δ13C values correlated with site ambient particulate organic matter (POM) δ13C values, and site mean bivalve δ15N values correlated with site ambient water dissolved δ15N-NO3 values. (2) Similarity of results among sample types demonstrated that the minimally invasive hemolymph sample is a suitable
substitute for foot tissue in δ15N analyses, and that small sample sizes generate means representative of a larger population. Both findings can help minimize
the impact of sampling on imperiled freshwater mussel populations. (3) In a bivalve transplantation study we showed that hemolymph
δ15N compositions responded to a shift in ambient dissolved δ15N-NO3, although slowly. The tissue turnover time for bivalve hemolymph was 113 days. We conclude that bivalves serve best as biomonitors
of chronic, rather than acute, fluctuations in stream nutrient loads, and provide initial evidence of their suitability as
time-integrated isotopic baselines for community studies. 相似文献
107.
108.
Olson MM Templeton LJ Suh W Youderian P Sariaslani FS Gatenby AA Van Dyk TK 《Applied microbiology and biotechnology》2007,74(5):1031-1040
Escherichia coli K12 strains producing l-phenylalanine were converted to l-tyrosine-producing strains using a novel genetic method for gene replacement. We deleted a region of the E. coli K12 chromosome including the pheA gene encoding chorismate mutase/prephenate dehydratase, its leader peptide (pheL), and its promoter using a new polymerase chain reaction-based method that does not leave a chromosomal scar. For high level
expression of tyrA, encoding chorismate mutase/prephenate dehydrogenase, its native promoter was replaced with the strong trc promoter. The linked ΔpheLA and Ptrc-tyrA::KanR genetic modifications were moved into l-phenylalanine producing strains by generalized transduction to convert l-phenylalanine-producing strains to l-tyrosine-producing strains. Moreover, introduction of a plasmid carrying genes responsible for sucrose degradation into these
strains enabled l-tyrosine-production from sucrose. 相似文献
109.
Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells 总被引:3,自引:0,他引:3
Nazareth MR Broderick L Simpson-Abelson MR Kelleher RJ Yokota SJ Bankert RB 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(9):5552-5562
The tumor microenvironment of human non-small cell lung cancer (NSCLC) is composed largely of stromal cells, including fibroblasts, yet these cells have been the focus of few studies. In this study, we established stromal cell cultures from primary NSCLC through isolation of adherent cells. Characterization of these cells by flow cytometry demonstrated a population which expressed a human fibroblast-specific 112-kDa surface molecule, Thy1, alpha-smooth muscle actin, and fibroblast activation protein, but failed to express CD45 and CD11b, a phenotype consistent with that of an activated myofibroblast. A subset of the tumor-associated fibroblasts (TAF) was found to express B7H1 (PD-L1) and B7DC (PD-L2) constitutively, and this expression was up-regulated by IFN-gamma. Production of cytokines and chemokines, including IFN-gamma, monokine induced by IFN-gamma, IFN-gamma-inducible protein-10, RANTES, and TGF-beta1 was also demonstrated in these cells. Together, these characteristics provide multiple opportunities for the TAF to influence cellular interactions within the tumor microenvironment. To evaluate the ability of TAF to modulate tumor-associated T cell (TAT) activation, we conducted coculture experiments between autologous TAF and TAT. In five of eight tumors, TAF elicited a contact-dependent enhancement of TAT activation, even in the presence of a TGF-beta1-mediated suppressive effect. In the three other tumors, TAF had a net suppressive effect upon TAT activation, and, in one of these cases, blockade of B7H1 or B7DC was able to completely abrogate the TAF-mediated suppression. We conclude that TAF in human NSCLC are functionally and phenotypically heterogeneous and provide multiple complex regulatory signals that have the potential to enhance or suppress TAT function in the tumor microenvironment. 相似文献
110.
Lipid A is an integral component of the lipopolysaccharide (LPS) that forms the selective and protective outer monolayer of Gram-negative bacteria, and is essential for bacterial growth and viability. UDP-N-acetylglucosamine acyltransferase (LpxA) initiates lipid A biosynthesis by catalyzing the transfer of R-3-hydroxymyristic acid from acyl carrier protein to the 3'-hydroxyl group of UDP-GlcNAc. The enzyme is a homotrimer, and previous studies suggested that the active site lies within a positively charged cleft formed at the subunit-subunit interface. The crystal structure of Escherichia coli LpxA in complex with UDP-GlcNAc reveals details of the substrate-binding site, with prominent hydrophilic interactions between highly conserved clusters of residues (Asn198, Glu200, Arg204 and Arg205) with UDP, and (Asp74, His125, His144 and Gln161) with the GlcNAc moiety. These interactions serve to bind and orient the substrate for catalysis. The crystallographic model supports previous results, which suggest that acylation occurs via nucleophilic attack of deprotonated UDP-GlcNAc on the acyl donor in a general base-catalyzed mechanism involving a catalytic dyad of His125 and Asp126. His125, the general base, interacts with the 3'-hydroxyl group of UDP-GlcNAc to generate the nucleophile. The Asp126 side-chain accepts a hydrogen bond from His125 and helps orient the general base to participate in catalysis. Comparisons with an LpxA:peptide inhibitor complex indicate that the peptide competes with both nucleotide and acyl carrier protein substrates. 相似文献