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51.
Kerstin Sander Yvonne von Coburg Jean-Claude Camelin Xavier Ligneau Oliver Rau Manfred Schubert-Zsilavecz Jean-Charles Schwartz Holger Stark 《Bioorganic & medicinal chemistry letters》2010,20(5):1581-1584
Antagonists of the human histamine H3 receptor (hH3R) often contain a second basic moiety, which is well known to boost affinity on this histamine receptor subtype. Here, we prepared compounds with acidic moieties of different pKa values to figure out that the hH3R tolerates these functionalities when added to a common pharmacophore blueprint. Depending on the acidic, electronic and steric features the designed ligands showed hH3R affinities in the nanomolar concentration range. Additionally, selected ligands were tested but failed as dual acting hH3R/hPPAR (human peroxisome proliferator-activated receptor) ligands. 相似文献
52.
S. A. Angioi D. Rau G. Attene L. Nanni E. Bellucci G. Logozzo V. Negri P. L. Spagnoletti Zeuli R. Papa 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,121(5):829-843
This study focuses on the expansion of Phaseolus vulgaris in Europe. The pathways of distribution of beans into and across Europe were very complex, with several introductions from
the New World that were combined with direct exchanges between European and other Mediterranean countries. We have analyzed
here six chloroplast microsatellite (cpSSR) loci and two unlinked nuclear loci (for phaseolin types and Pv-shatterproof1). We have assessed the genetic structure and level of diversity of a large collection of European landraces of P. vulgaris (307) in comparison to 94 genotypes from the Americas that are representative of the Andean and Mesoamerican gene pools.
First, we show that most of the European common bean landraces (67%) are of Andean origin, and that there are no strong differences
across European regions for the proportions of the Andean and Mesoamerican gene pools. Moreover, cytoplasmic diversity is
evenly distributed across European regions. Secondly, the cytoplasmic bottleneck that was due to the introduction of P. vulgaris into the Old World was very weak or nearly absent. This is in contrast to evidence from nuclear analyses that have suggested
a bottleneck of greater intensity. Finally, we estimate that a relatively high proportion of the European bean germplasm (about
44%) was derived from hybridization between the Andean and Mesoamerican gene pools. Moreover, although hybrids are present
everywhere in Europe, they show an uneven distribution, with high frequencies in central Europe, and low frequencies in Spain
and Italy. On the basis of these data, we suggest that the entire European continent and not only some of the countries therein
can be regarded as a secondary diversification center for P. vulgaris. Finally, we outline the relevance of these inter-gene pool hybrids for plant breeding. 相似文献
53.
Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors 总被引:8,自引:0,他引:8
Bantscheff M Eberhard D Abraham Y Bastuck S Boesche M Hobson S Mathieson T Perrin J Raida M Rau C Reader V Sweetman G Bauer A Bouwmeester T Hopf C Kruse U Neubauer G Ramsden N Rick J Kuster B Drewes G 《Nature biotechnology》2007,25(9):1035-1044
We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery. 相似文献
54.
van der Heijde D Landewé R Boonen A Einstein S Herborn G Rau R Wassenberg S Weissman BN Winalski CS Sharp JT 《Arthritis research & therapy》2007,9(4):R62
The objective of the present study was to test the hypothesis that experts recognize repair of erosions and, if so, to determine
which, if any, morphologic features permitted them to recognize the repair. We also tested whether scoring by a standard method
detected repair. Seven experienced readers of radiographs in rheumatoid arthritis were presented with 64 sets of single joints-of-interest
at two time points, randomized and blinded for the correct sequence. The readers assessed which joint was better, and recorded
whether any of six specific features were seen. Two independent readers, experienced in scoring by the van der Heijde-modified
Sharp method who were not on the expert panel, then scored the complete films that included the joint-of-interest. The panel
agreed very well on which of two joints was better, and, even though they did not know the true sequence, the panel accurately
assigned a sequence slightly better than chance alone (58%) but worse than their agreement on which image was 'better or worse'
(78%). The readers therefore indirectly assigned repair by choosing the second film as the best. Putative repair features
were seen in cases of both repair and progression, and were not discriminatory. Similar results were obtained when the experts
were presented with the entire hand or foot containing the joint-of-interest. In the third repair exercise, two independent
readers who scored whole hands and feet using a standard method found a mean negative score in 22/60 joints-of-interest. All
22 joints were also scored as repair by the panel. Repair was detected reliably by a majority of the panel on viewing paired
images based on a better/worse decision and assigning sequence in a set of images that were blinded for sequence by an independent
project manager. In this test set of images, repair was manifested by a reduction in the size of erosion in many cases. Size
was one feature that aided the experts to detect repair but cannot be the only one; the experts had to find other features
to determine whether a smaller erosion was the first in a sequence of radiographs in a patient with progressive damage or
was the second film in a patient exhibiting repair. The change in size of erosion was also picked up by independent readers
applying the van der Heijde-modified Sharp scoring method and was reflected in their scores. 相似文献
55.
In this paper new mitochondrial COI sequences of Common Barn Owl Tyto
alba (Scopoli, 1769) and Short-eared Owl Asio
flammeus (Pontoppidan, 1763) from southern Chile are reported and compared with sequences from other parts of the World. The intraspecific genetic divergence (mean p-distance) was 4.6 to 5.5% for the Common Barn Owl in comparison with specimens from northern Europe and Australasia and 3.1% for the Short-eared Owl with respect to samples from north America, northern Europe and northern Asia. Phylogenetic analyses revealed three distinctive groups for the Common Barn Owl: (i) South America (Chile and Argentina) plus Central and North America, (ii) northern Europe and (iii) Australasia, and two distinctive groups for the Short-eared Owl: (i) South America (Chile and Argentina) and (ii) north America plus northern Europe and northern Asia. The level of genetic divergence observed in both species exceeds the upper limit of intraspecific comparisons reported previously for Strigiformes. Therefore, this suggests that further research is needed to assess the taxonomic status, particularly for the Chilean populations that, to date, have been identified as belonging to these species through traditional taxonomy. 相似文献
56.
57.
Rau U Nguyen LA Schulz S Wray V Nimtz M Roeper H Koch H Lang S 《Applied microbiology and biotechnology》2005,66(5):551-559
Pseudozyma aphidis DSM 70725 was found to be a novel producer of mannosylerythritol lipids (MELs). The MELs were quantified by HPLC. Glucose as carbon source for precultivation supported growth well. By contrast, at concentrations >30 g l–1 in preculture, subsequent MEL formation in the main culture with soybean oil as sole carbon source was reduced. The type of substrate supply considerably influenced MEL formation. High concentrations of soybean oil (80 ml l–1) at init favored the production process when compared to a stepwise (20 ml l–1) addition. Mannose or erythritol were suitable second carbon sources that enhanced the MEL yield with soybean oil as preferred primary substrate. After 10 days, a maximum yield of 75 g l–1 was attained during shake-flask cultivation. Biofuel (rapeseed oil methyl ester) also resulted in high yields of MEL, but glucose reduced the MEL yield. Analysis by GC-MS showed that all fatty acids contained in MEL and derived from soybean oil or related methyl ester were degraded by C2-units to differing extents. The surface (water/air) and interfacial (water/hexadecane) tension of the MELs produced from different carbon sources were reduced to a minimum of 26.2 mN m–1 and 1 mN m–1, respectively. 相似文献
58.
Sugar conjugation of biooactive peptides has been shown to be a powerful tool to modulate peptide pharmacokinetics. In the case of radiolabeled somatostatin analogues developed for in vivo scintigraphy of somatostatin receptor (sst) expressing tumors, it generally led to tracers with predominant renal excretion and low uptake in nontarget organs, and in some cases also with enhanced tumor accumulation. Especially with respect to endoradiotherapeutic applicability of these tracers, however, understanding the structural requirements for minimal kidney accumulation and maximal tumor uptake is important. The aim of this study was therefore the evaluation of the potential of specific glycoside structures in combination with reduced peptide net charge to reduce kidney accumulation without affecting tumor accumulation. Three glyco analogues of radioiodinated Tyr(3)-octreotate (TOCA) with z = 0 were evaluated in a comparative study using [(125)I]Mtr-TOCA (z = +1), the maltotriose-Amadori analogue of [(125)I]TOCA, as a reference, [(125)I]Glucuron-TOCA, the Amadori conjugate with glucuronic acid, and [(125)I]Gluc-S- and [(125)I]Gal-S-TOCA, the coupling products with glucosyl- and mannosyl-mercaptopropionate. In cells transfected with sst(1)-sst(5), all three new analogues show sst-subtype binding profiles similar to I-Mtr-TOCA with high, but somewhat reduced, affinity for sst(2). In contrast, internalization into sst(2)-expressing cells (in % of [(125)I]Tyr(3)-octreotide ([(125)I]TOC)) as well as the EC(50,R) of unlabeled TOC for internalization determined in dual-tracer experiments are substantially enhanced for [(123)I]Gal-S-TOCA and [(123)I]Gluc-S-TOCA (internalization, 190% +/- 12% and 265% +/- 20%, respectively, vs 168% +/- 6% of [(125)I]TOC for [(123)I]Mtr-TOCA; EC(50,R), 2.62 +/- 0.07 and 2.96 +/- 0.14, respectively, vs 1.81 +/- 0.07 for [(123)I]Mtr-TOCA). The tumor accumulation of [(125)I]Gal-S-TOCA and [(125)I]Gluc-S-TOCA in AR42J tumor-bearing nude mice 1 h p.i. is consequently very high (22.6 +/- 2.2 and 26.2 +/- 5.6%ID/g) and comparable to that of [(125)I]Mtr-TOCA (25.1 +/- 4.4%ID/g). [(125)I]Glucuron-TOCA showed lower uptake in sst-expressing tissues than did [(125)I]Mtr-TOCA, but considerably enhanced accumulation in nontarget organs such as liver, intestine, and kidney. Due to increased lipophilicity, hepatic and intestinal uptake 1 and 4 h p.i. of [(125)I]Gal-S-TOCA and [(125)I]Gluc-S-TOCA was also slightly higher than that of [(125)I]Mtr-TOCA. Kidney accumulation, however, was reduced by approximately 50% for both compounds (2.6 +/- 0.3 and 2.2 +/- 0.4, respectively, vs 4.0 +/- 0.7%ID/g at 1 h p.i.). Because no sugar-specific effect was detected in the latter case, it is concluded that general ligand pharmacokinetics and especially kidney accumulation of the tracers investigated are mainly determined by physicochemical characteristics such as lipophilicity, net charge, and also charge distribution ([(125)I]Glucuron-TOCA vs [(125)I]Gal-S- and [(125)I]Gluc-S-TOCA). With respect to receptor targeting, however, the structure of the carbohydrate moiety plays an important role, leading to dramatically enhanced ligand internalization, especially in the case of [(123)I]Gluc-S-TOCA. Taking into account the combined effects of the Gluc-S-moiety both on kidney and on tumor accumulation, this group seems to be a promising synthon for the synthesis of other radiolabeled peptide analogues with improved pharmacokinetics. 相似文献
59.
Incomplete ion dissociation underlies the weakened attraction between DNA helices at high spermidine concentrations
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We have investigated the salt sensitivity of the hexagonal-to-cholesteric phase transition of spermidine-condensed DNA. This transition precedes the resolubilization of precipitated DNA that occurs at high spermidine concentration. The sensitivity of the critical spermidine concentration at the transition point to the anion species and the NaCl concentration indicates that ion pairing of this trivalent ion underlies this unusual transition. Osmotic pressure measurements of spermidine salt solutions are consistent with this interpretation. Spermidine salts are not fully dissociated at higher concentrations. The competition for DNA binding among the fully charged trivalent ion and the lesser charged complex species at higher concentrations significantly weakens attraction between DNA helices in the condensed state. This is contrary to the suggestion that the binding of spermidine at higher concentrations causes DNA overcharging and consequent electrostatic repulsion. 相似文献
60.
Sialylation of glycoconjugates is essential for mammalian cells. Sialic acid is synthesized in the cytosol from N-acetylmannosamine by several consecutive steps. Using N-propanoylmannosamine, a novel precursor of sialic acid, we are able to incorporate unnatural sialic acids with a prolonged N-acyl side chain (e.g., N-propanoylneuraminic acid) into glycoconjugates taking advance of the cellular sialylation machinery. Here, we report that unnatural sialylation of HL60-cells leads to an increased release of intracellular calcium after application of thapsigargin, an inhibitor of SERCA Ca2+-ATPases. Furthermore, this increased intracellular calcium concentration leads to an increased adhesion to fibronectin. Finally, we observed an increase of the lectin galectin-3, a marker of monocytic differentiation of HL60-cells. 相似文献