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排序方式: 共有2821条查询结果,搜索用时 15 毫秒
951.
Large JM Torr JE Raynaud FI Clarke PA Hayes A Stefano Fd Urban F Shuttleworth SJ Saghir N Sheldrake P Workman P McDonald E 《Bioorganic & medicinal chemistry》2011,19(2):836-851
Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC?? value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC?? 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols. 相似文献
952.
A solid phase approach has been used to synthesize a large branched disulphide peptide from IgG Fc, Ac-F-C*-A-K-V-N-N-K-D-L-P-A-P-I-E-K(Ac-E-L-L-G-G-P-S-V-F)-C*-I-NH2. This peptide combines the lower hinge region of IgG and a proximal beta-hairpin loop, both implicated in binding to Fc gammaRI. Solid phase Tl(tfa)3 cyclization of the linear branched peptide resulted in a poor yield of cyclic hinge-loop peptide (11%) most likely due to steric hindrance caused by the branch. However, if addition of the branch was preceded by solid phase Tl(tfa)3 cyclization of the loop, the yield was excellent at 75%. Cyclic hinge-loop peptide was active in displacing IgG2a from Fc gammaRI expressed on monocyte cell lines with an IC50 of 40 microM, whereas the linear form of this peptide was inactive. The Fc hinge-loop peptide demonstrates the potential for a non-mAb high affinity, immunomodulatory ligand for Fc gammaRI. 相似文献
953.
Alistair J.P. Brown Rudi J. Planta Fajar Restuhadi David A. Bailey Philip R. Butler Jose L. Cadahia M.Esperanza Cerdan Martine De Jonge David C.J. Gardner Manda E. Gent Andrew Hayes Carin P.A.M. Kolen Luis J. Lombardia Abdul Munir Abdul Murad Rachel A. Oliver Mark Sefton Johan M. Thevelein Helene Tournu Yvon J. van Delft Dennis J. Verbart Joris Winderickx Stephen G. Oliver 《The EMBO journal》2001,20(12):3177-3186
954.
955.
Macromolecular organization and in vitro growth characteristics of scaffold-free neocartilage grafts. 总被引:1,自引:0,他引:1
Anthony J Hayes Amanda Hall Liesbeth Brown Ross Tubo Bruce Caterson 《The journal of histochemistry and cytochemistry》2007,55(8):853-866
Recent advances in tissue engineering offer considerable promise for the repair of focal lesions in articular cartilage. Here we describe (1) the macromolecular organization of tissue-engineered neocartilage grafts at light and electron microscopic levels, (2) their in vitro development, and (3) the effect of chondrocyte dedifferentiation, induced by monolayer expansion, on their resultant structure. We show that grafts produced from primary cultures of chondrocytes are hyaline in appearance with identifiable zonal strata as evidenced by cell morphology, matrix organization, and immunohistochemical composition. Like native articular cartilage, their surface zone contains type I collagen, surface zone proteoglycan, biglycan and decorin with type II collagen, aggrecan, chondroitin sulfate, chondroitin-4-sulfate, and keratan sulfate, becoming more prominent with depth. Assessment of cell viability by Live/Dead staining and cell-cycle analysis with BrDU suggest that the in vitro tissue has a high cellular turnover and develops through both appositional and interstitial growth mechanisms. Meanwhile, cell-tracker studies with CMFDA (5-chloromethyl-fluorescein diacetate) demonstrate that cell sorting in vitro is not involved in their zonal organization. Finally, passage expansion of chondrocytes in monolayer culture causes progressive reductions in graft thickness, loss of zonal architecture, and a more fibrocartilaginous tissue histology, consistent with a dedifferentiating chondrocyte phenotype. 相似文献
956.
Nitric oxide induces vasodilation by elevating the production of cGMP, an activator of cGMP-dependent protein kinase (PKG). PKG subsequently causes smooth muscle relaxation in part via activation of myosin light chain phosphatase (MLCP). To date, the interaction between PKG and the targeting subunit of MLCP (MYPT1) is not fully understood. Earlier studies by one group of workers showed that the binding of PKG to MYPT1 is mediated by the leucine-zipper motifs at the N and C termini, respectively, of the two proteins. Another group, however, reported that binding of PKG to MYPT1 did not require the leucine-zipper motif of MYPT1. In this work we fully characterized the interaction between PKG and MYPT1 using biophysical techniques. For this purpose we constructed a recombinant PKG peptide corresponding to a predicted coiled coil region that contains the leucine-zipper motif. We further constructed various C-terminal MYPT1 peptides bearing various combinations of a predicted coiled coil region, extensions preceding this coiled coil region, and the leucine-zipper motif. Our results show, firstly, that while the leucine-zipper motif at the N terminus of PKG forms a homodimeric coiled coil, the one at the C terminus of MYPT1 is monomeric and non-helical. Secondly, the leucine-zipper motif of PKG binds to that of MYPT1 to form a heterodimer. Thirdly, when the leucine-zipper motif of MYPT1 is absent, the PKG leucine-zipper motif binds to the coiled coil region and upstream segments of MYPT1 via formation of a heterotetramer. These results provide rationalization of some of the findings by others using alternative binding analyses. 相似文献
957.
The segrosome is the nucleoprotein complex that mediates accurate segregation of bacterial plasmids. The segrosome of plasmid TP228 comprises ParF and ParG proteins that assemble on the parH centromere. ParF, which exemplifies one clade of the ubiquitous ParA superfamily of segregation proteins, polymerizes extensively in response to ATP binding. Polymerization is modulated by the ParG centromere binding factor (CBF). The segrosomes of plasmids pTAR, pVT745 and pB171 include ParA homologues of the ParF subgroup, as well as diverse homodimeric CBFs with no primary sequence similarity to ParG, or each other. Centromere binding by these analogues is largely specific. Here, we establish that the ParF homologues of pTAR and pB171 filament modestly with ATP, and that nucleotide hydrolysis is not required for this polymerization, which is more prodigious when the cognate CBF is also present. By contrast, the ParF homologue of plasmid pVT745 did not respond appreciably to ATP alone, but polymerized extensively in the presence of both its cognate CBF and ATP. The co-factors also stimulated nucleotide-independent polymerization of cognate ParF proteins. Moreover, apart from the CBF of pTAR, the disparate ParG analogues promoted polymerization of non-cognate ParF proteins suggesting that filamentation of the ParF proteins is enhanced by a common mechanism. Like ParG, the co-factors may be modular, possessing a centromere-specific interaction domain linked to a flexible region containing determinants that promiscuously stimulate ParF polymerization. The CBFs appear to function as bacterial analogues of formins, microtubule-associated proteins or related ancillary factors that regulate eucaryotic cytoskeletal dynamics. 相似文献
958.
A heterologous DNA prime-Venezuelan equine encephalitis virus replicon particle boost dengue vaccine regimen affords complete protection from virus challenge in cynomolgus macaques
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Chen L Ewing D Subramanian H Block K Rayner J Alterson KD Sedegah M Hayes C Porter K Raviprakash K 《Journal of virology》2007,81(21):11634-11639
A candidate vaccine (D1ME-VRP) expressing dengue virus type 1 premembrane and envelope proteins in a Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) system was constructed and tested in conjunction with a plasmid DNA vaccine (D1ME-DNA) expressing identical dengue virus sequences. Cynomolgus macaques were vaccinated with three doses of DNA (DDD), three doses of VRP (VVV group), or a heterologous DNA prime-VRP boost regimen (DDV) using two doses of DNA vaccine and a third dose of VRP vaccine. Four weeks after the final immunization, the DDV group produced the highest dengue virus type 1-specific immunoglobulin G antibody responses and virus-neutralizing antibody titers. Moderate T-cell responses were demonstrated only in DDD- and DDV-vaccinated animals. When vaccinated animals were challenged with live virus, all vaccination regimens showed significant protection from viremia. DDV-immunized animals were completely protected from viremia (mean time of viremia = 0 days), whereas DDD- and VVV-vaccinated animals had mean times of viremia of 0.66 and 0.75 day, respectively, compared to 6.33 days for the control group of animals. 相似文献
959.
Six barley (Hordeum vulgare L.) accessions, previously used as parents of mapping populations, were evaluated for characters potentially affecting the
location of low-temperature (LT) tolerance QTLs. Three were of winter growth habit (Kompolti Korai, Nure, and Strider), one
was facultative (Dicktoo) and two were spring (Morex and Tremois). Final leaf number (FLN) and LT50 were determined at weekly intervals from 0 to 98 days of LT acclimation/vernalization under both long day (LD) and short day
(SD) photoperiods. The point of vegetative/reproductive transition was determined from measurements of double ridge (DR) formation
and FLN. With the exception of Nure, SD delayed development by increasing leaf production. Dicktoo was extremely SD sensitive
lengthening its vegetative phase by more than 63 days relative to the LD photoperiod. SD had the opposite effect on Nure,
causing an accelerating of flowering exhibiting the characteristic of ‘short day vernalization’. All accessions except Dicktoo
and Kompolti Korai acclimated rapidly in the first 7 days of LT exposure, approaching their maximum LT tolerance in 14–21 days.
Dicktoo and Kompolti Korai continued to slowly acclimate until reproductive transition. The results emphasize two important
points: (1) the location of QTLs for LT tolerance, and as a consequence the identification of putative candidate genes, will
be a function of the genotypes sampled, the experimental conditions used, and the quality of the phenotypic data and (2) the
barley LT tolerance pathway reaches an early impediment relative to closely related more hardy members of the Triticeae such
as wheat and rye. 相似文献
960.
Hiller NL Janto B Hogg JS Boissy R Yu S Powell E Keefe R Ehrlich NE Shen K Hayes J Barbadora K Klimke W Dernovoy D Tatusova T Parkhill J Bentley SD Post JC Ehrlich GD Hu FZ 《Journal of bacteriology》2007,189(22):8186-8195
The distributed-genome hypothesis (DGH) states that pathogenic bacteria possess a supragenome that is much larger than the genome of any single bacterium and that these pathogens utilize genetic recombination and a large, noncore set of genes as a means of diversity generation. We sequenced the genomes of eight nasopharyngeal strains of Streptococcus pneumoniae isolated from pediatric patients with upper respiratory symptoms and performed quantitative genomic analyses among these and nine publicly available pneumococcal strains. Coding sequences from all strains were grouped into 3,170 orthologous gene clusters, of which 1,454 (46%) were conserved among all 17 strains. The majority of the gene clusters, 1,716 (54%), were not found in all strains. Genic differences per strain pair ranged from 35 to 629 orthologous clusters, with each strain's genome containing between 21 and 32% noncore genes. The distribution of the orthologous clusters per genome for the 17 strains was entered into the finite-supragenome model, which predicted that (i) the S. pneumoniae supragenome contains more than 5,000 orthologous clusters and (ii) 99% of the orthologous clusters (~3,000) that are represented in the S. pneumoniae population at frequencies of ≥0.1 can be identified if 33 representative genomes are sequenced. These extensive genic diversity data support the DGH and provide a basis for understanding the great differences in clinical phenotype associated with various pneumococcal strains. When these findings are taken together with previous studies that demonstrated the presence of a supragenome for Streptococcus agalactiae and Haemophilus influenzae, it appears that the possession of a distributed genome is a common host interaction strategy. 相似文献