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231.
232.
Alexandra S. Solovyova Jonathan A. Pointon Paul R. Race Wendy D. Smith Michael A. Kehoe Mark J. Banfield 《European biophysics journal : EBJ》2010,39(3):469-480
Adhesion of the serotype M1 Streptococcus pyogenes strain SF370 to human tonsil explants and cultured keratinocytes requires extended polymeric surface structures called pili.
In this important human pathogen, pili are assembled from three protein subunits: Spy0125, Spy0128 and Spy0130 through the
action of sortase enzymes. For this study, the structural properties of these pili proteins have been investigated in solution.
Spy0125 and Spy0128 display characteristics of globular, folded proteins. Circular dichroism suggests a largely β-sheet composition
for Spy0128 and Spy0125; Spy0130 appears to contain little secondary structure. Each of the proteins adopts a monodisperse,
monomeric state in solution as assessed by analytical ultracentrifugation. Further, small-angle X-ray scattering curves for
Spy0125, Spy0128 and Spy0130 suggest each protein adopts an elongated shape, likely comprised of two domains, with similar
maximal dimensions. Based on the scattering data, dummy atom models of each of the pili subunits have been reconstructed ab
initio. This study provides the first insights into the structure of Streptococcus pyogenes minor pili subunits, and possible implications for protein function are discussed. 相似文献
233.
Melissa M.B. Morrow Wendy J. Hurd Kenton R. Kaufman Kai-Nan An 《Journal of electromyography and kinesiology》2010,20(1):61-67
ObjectiveInvestigate shoulder joint kinetics over a range of daily activity and mobility tasks associated with manual wheelchair propulsion to characterize demands placed on the shoulder during the daily activity of manual wheelchair users.DesignCase series.SubjectsTwelve individuals who were experienced manual wheelchair users.MethodsUpper extremity kinematics and handrim wheelchair kinetics were measured over level propulsion, ramp propulsion, start and stop over level terrain, and a weight relief maneuver. Shoulder intersegmental forces and moments were calculated from inverse dynamics for all conditions.ResultsWeight relief resulted in significantly higher forces and ramp propulsion resulted in significantly higher moments than the other conditions. Surprisingly, the start condition resulted in large intersegmental moments about the shoulder equivalent with that of the ramp propulsion, while the demand imparted by the stop condition was shown to be equivalent to level propulsion across all forces and moments.ConclusionsThis study provides characterization of daily living and mobility activities associated with manual wheelchair propulsion not previously reported and identifies activities that result in higher shoulder kinetics when compared to standard level propulsion. 相似文献
234.
Phosphatidylinositol 3-kinase (PI3K) mediates receptor tyrosine kinase and G protein coupled receptor (GPCR) signaling by phosphorylating phosphoinositides to elicit various biological responses. Gαq has previously been shown to inhibit class IA PI3K by interacting with the p110α subunit. However, it is not known if PI3Ks can associate with other Gαq family members such as Gα16. Here, we demonstrated that class IA PI3Ks, p85/p110α and p85/p110β, could form stable complexes with wild type Gα16 and its constitutively active mutant (Gα16QL) in HEK293 cells. In contrast, no interaction between Gα16 and class IB PI3K was observed. The Gα16/p110α signaling complex could be detected in hematopoietic cells that endogenously express Gα16. Overexpression of class I PI3Ks did not inhibit Gα16QL-induced IP3 production and, unlike p63RhoGEF, class IA PI3Ks did not attenuate the binding of PLCβ2 to Gα16QL. On the contrary, the function of class IA PI3Ks was suppressed by Gα16QL as revealed by diminished production of PIP3 as well as inhibition of EGF-induced Akt phosphorylation. Taken together, these results suggest that Gα16 can bind to class IA PI3Ks and inhibit the PI3K signaling pathway. 相似文献
235.
Ozyamak E Black SS Walker CA Maclean MJ Bartlett W Miller S Booth IR 《Molecular microbiology》2010,78(6):1577-1590
Survival of exposure to methylglyoxal (MG) in Gram-negative pathogens is largely dependent upon the operation of the glutathione-dependent glyoxalase system, consisting of two enzymes, GlxI (gloA) and GlxII (gloB). In addition, the activation of the KefGB potassium efflux system is maintained closed by glutathione (GSH) and is activated by S-lactoylGSH (SLG), the intermediate formed by GlxI and destroyed by GlxII. Escherichia coli mutants lacking GlxI are known to be extremely sensitive to MG. In this study we demonstrate that a ΔgloB mutant is as tolerant of MG as the parent, despite having the same degree of inhibition of MG detoxification as a ΔgloA strain. Increased expression of GlxII from a multicopy plasmid sensitizes E. coli to MG. Measurement of SLG pools, KefGB activity and cytoplasmic pH shows these parameters to be linked and to be very sensitive to changes in the activity of GlxI and GlxII. The SLG pool determines the activity of KefGB and the degree of acidification of the cytoplasm, which is a major determinant of the sensitivity to electrophiles. The data are discussed in terms of how cell fate is determined by the relative abundance of the enzymes and KefGB. 相似文献
236.
Kevin K.-C. Liu Bruce A. Lefker Mark A. Dombroski Phoebe Chiang Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen P. Gibbons Ravi Marala Janice A. Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Craig Giragossian Hou Chen Steven B. Coffey 《Bioorganic & medicinal chemistry letters》2010,20(7):2365-2369
Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered. 相似文献
237.
Kevin K.-C. Liu Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen Gibbons Tristan S. Maurer Ravi Marala Janice Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Chandra Vage 《Bioorganic & medicinal chemistry letters》2010,20(1):266-271
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure–activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose–responsive in vivo efficacy in our pre-clinical food intake model. 相似文献
238.
Jacob A. Kaizerman Wade Aaron Songzhu An Richard Austin Matt Brown Angela Chong Tom Huang Randall Hungate Ben Jiang Michael G. Johnson Gary Lee Brian S. Lucas Jessica Orf Minqing Rong Maria M. Toteva Dineli Wickramasinghe Guifen Xu Qiuping Ye Wendy Zhong Dustin L. McMinn 《Bioorganic & medicinal chemistry letters》2010,20(15):4607-4610
Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model. 相似文献
239.
Gaudet MM Kirchhoff T Green T Vijai J Korn JM Guiducci C Segrè AV McGee K McGuffog L Kartsonaki C Morrison J Healey S Sinilnikova OM Stoppa-Lyonnet D Mazoyer S Gauthier-Villars M Sobol H Longy M Frenay M GEMO Study Collaborators Hogervorst FB Rookus MA Collée JM Hoogerbrugge N van Roozendaal KE;HEBON Study Collaborators Piedmonte M Rubinstein W Nerenstone S Van Le L Blank SV Caldés T de la Hoya M Nevanlinna H Aittomäki K Lazaro C Blanco I Arason A Johannsson OT Barkardottir RB Devilee P 《PLoS genetics》2010,6(10):e1001183
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer. 相似文献
240.