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11.
Stability of therapeutic IgG preparations is an important issue as adequate efficacy and safety has to be ensured throughout a long shelf life. To this end, denaturation and aggregation have to be avoided. In many cases sugars are applied for stabilizing IgG in relatively high concentration (5-10%). However, certain sugars (sucrose, maltose) are responsible for adverse effects including renal failure. In this work we reassessed the effect of pH and stabilizers to optimize the solvent environment and minimize the amount of additives without endangering quality and stability. Since both biological function and aggregation depend on the conformational properties of individual IgG molecules, two sensitive and rapid physical methods were introduced to assess conformational changes and structural stability as a function of pH and addition of standard stabilizers. It was observed that the conformational stability decreases with decreasing pH, while the resistance against aggregation improves. The optimum pH range for storage is 5.0-6.0, as a compromise between conformational stability and the tendency for oligomerization. Intriguingly, additives in physiologically acceptable concentration have no effect on the thermal stability of IgG. On the other hand, glucose or sorbitol, even at a concentration as low as 1%, have significant effect on the tertiary structure as revealed by near-UV-CD spectroscopy, reflecting changes in the environment of aromatic side-chains. Although, 0.3% leucine does not increase conformational stability, it decreases the aggregation tendency even more efficiently than 1% glucose or sorbitol. Both pH and storage temperature are decisive factors for the long-term stability of IgG solutions. An increase in the dimer content was observed upon storage at 5 degrees C which was partly reverted upon incubation at 37 degrees C. Storage at temperatures higher than 5 degrees C may help to maintain an optimal proportion of dimers. Regarding the known side effects, and their limited stabilizing capacity at low concentration, it is advisable to omit sugars at intravenous immunoglobulin (IVIG) formulation. Hydrophobic amino acids give promising alternatives. 相似文献
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Michael J. Domingue Zoltán Imrei Jonathan P. Lelito József Muskovits Gergely Janik György Csóka Victor C. Mastro Thomas C. Baker 《Entomologia Experimentalis et Applicata》2013,148(2):116-129
Trapping approaches developed for the emerald ash borer (EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), were adapted for trapping several European oak buprestid species. These approaches included the use of natural leaf surfaces as well as green and purple plastic in sticky trap designs. Plastic surfaces were incorporated into novel ‘branch‐trap’ designs that each presented two 5 × 9‐cm2 rectangular surfaces on a cardboard structure wrapped around the leaves of a branch. We used visual adult Agrilus decoys in an attempt to evoke male mating approaches toward the traps. Our first experiment compared the attractiveness of visual characteristics of the surfaces of branch‐traps. The second looked at the effect on trap captures of adding semiochemical lures, including manuka oil, (Z)‐3‐hexen‐1‐ol, and (Z)‐9‐tricosene. In total, 1 962 buprestid specimens including 14 species from the genus Agrilus were caught on 178 traps in a 22‐day time‐span. Overall, the green plastic‐covered branch‐traps significantly out‐performed the other trap designs. We further found that the presence of an EAB visual decoy placed on the trap surface often increased captures on these green traps, but this effect was stronger for certain Agrilus species than for others. The visual decoy was particularly important for the most serious pest detected, Agrilus biguttatus Fabricius, which was captured 13 times on traps with decoys, but only once without a decoy. There were some small but significant effects of odor treatment on the capture of buprestids of two common species, Agrilus angustulus Illiger and Agrilus sulcicollis Lacordaire. There were also 141 Elateridae specimens on these traps, which were not influenced by trap type or decoys. The results suggest that small branch‐traps of this nature can provide a useful new tool for monitoring of buprestids, which have the potential to be further optimized with respect to visual and olfactory cues. 相似文献
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László Kékesi Anna Sipos Gábor Németh János Pató Nóra Breza Ferenc Baska László Őrfi György Kéri 《Bioorganic & medicinal chemistry letters》2013,23(22):6152-6155
A series of novel pyrido[2,3-b]pyrazines were synthesized as potential antitumor agents for erlotinib-resistant tumors. Known signal inhibitor compounds from our Nested Chemical Library were tested in phenotypic assays on erlotinib-sensitive PC9 and erlotinib-resistant PC9-ER cell lines to find a compound class to be active on erlotinib resistant cell lines. Based on the screening data, novel pyrido[2,3-b]pyrazines were designed and synthesized. The effect of the substituent position of the heteroaromatic moiety in position 7 and the importance of unsubstituted position 2 of the pyridopyrazine core were explored. Compound 7n had an IC50 value of 0.09 μM for the inhibition of PC9 and 0.15 μM for the inhibition of PC9-ER. We found that some lead compounds of these structures overcome erlotinib-resistance which might become promising drug candidates to fight against NSCLC with EGFR T790M mutation. The signaling network(s) involved in the mechanism(s) of action of these novel compounds in overcoming erlotinib resistance remain to be elucidated. 相似文献
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Daniella Takács Orsolya Egyed László Drahos Pál Szabó Katalin Jemnitz Mónika Szabó Zsuzsa Veres Júlia Visy József Molnár Zsuzsanna Riedl György Hajós 《Bioorganic & medicinal chemistry》2013,21(13):3760-3779
Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration–oxidation of dienes followed by Buchwald–Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity. 相似文献
17.
Gy?rgy Abrusán 《Genetics》2013,195(4):1407-1417
It has been recently discovered that new genes can originate de novo from noncoding DNA, and several biological traits including expression or sequence composition form a continuum from noncoding sequences to conserved genes. In this article, using yeast genes I test whether the integration of new genes into cellular networks and their structural maturation shows such a continuum by analyzing their changes with gene age. I show that 1) The number of regulatory, protein–protein, and genetic interactions increases continuously with gene age, although with very different rates. New regulatory interactions emerge rapidly within a few million years, while the number of protein–protein and genetic interactions increases slowly, with a rate of 2–2.25 × 10−8/year and 4.8 × 10−8/year, respectively. 2) Gene essentiality evolves relatively quickly: the youngest essential genes appear in proto-genes ∼14 MY old. 3) In contrast to interactions, the secondary structure of proteins and their robustness to mutations indicate that new genes face a bottleneck in their evolution: proto-genes are characterized by high β-strand content, high aggregation propensity, and low robustness against mutations, while conserved genes are characterized by lower strand content and higher stability, most likely due to the higher probability of gene loss among young genes and accumulation of neutral mutations. 相似文献
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In the last decade, optimized treatment for non-small cell lung cancer had lead to improved prognosis, but the overall survival is still very short. To further understand the molecular basis of the disease we have to identify biomarkers related to survival. Here we present the development of an online tool suitable for the real-time meta-analysis of published lung cancer microarray datasets to identify biomarkers related to survival. We searched the caBIG, GEO and TCGA repositories to identify samples with published gene expression data and survival information. Univariate and multivariate Cox regression analysis, Kaplan-Meier survival plot with hazard ratio and logrank P value are calculated and plotted in R. The complete analysis tool can be accessed online at: www.kmplot.com/lung. All together 1,715 samples of ten independent datasets were integrated into the system. As a demonstration, we used the tool to validate 21 previously published survival associated biomarkers. Of these, survival was best predicted by CDK1 (p<1E-16), CD24 (p<1E-16) and CADM1 (p = 7E-12) in adenocarcinomas and by CCNE1 (p = 2.3E-09) and VEGF (p = 3.3E-10) in all NSCLC patients. Additional genes significantly correlated to survival include RAD51, CDKN2A, OPN, EZH2, ANXA3, ADAM28 and ERCC1. In summary, we established an integrated database and an online tool capable of uni- and multivariate analysis for in silico validation of new biomarker candidates in non-small cell lung cancer. 相似文献
20.
Margit Keresztes Tamás Horváth Imre Ocsovszki Imre F?ldesi Gy?ngyi Serf?z? Krisztina Boda Imre Ungi 《PloS one》2013,8(8)