全文获取类型
收费全文 | 322篇 |
免费 | 28篇 |
国内免费 | 1篇 |
出版年
2023年 | 1篇 |
2021年 | 10篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 4篇 |
2017年 | 1篇 |
2016年 | 11篇 |
2015年 | 30篇 |
2014年 | 23篇 |
2013年 | 38篇 |
2012年 | 36篇 |
2011年 | 24篇 |
2010年 | 16篇 |
2009年 | 22篇 |
2008年 | 22篇 |
2007年 | 14篇 |
2006年 | 6篇 |
2005年 | 11篇 |
2004年 | 10篇 |
2003年 | 5篇 |
2002年 | 11篇 |
2001年 | 1篇 |
2000年 | 2篇 |
1999年 | 8篇 |
1998年 | 3篇 |
1997年 | 5篇 |
1996年 | 6篇 |
1995年 | 2篇 |
1992年 | 7篇 |
1991年 | 1篇 |
1990年 | 7篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1982年 | 1篇 |
排序方式: 共有351条查询结果,搜索用时 15 毫秒
1.
J.J.M. Meulenberg E. Sellink W.A.M. Loenen N.H. Riegman M. Van Kleef P.W. Postma 《FEMS microbiology letters》1990,71(3):337-343
We have cloned genes from Klebsiella pneumoniae which are required for pyrroloquinoline quinone (PQQ) biosynthesis. The cloned 6.7 kb fragment can complement several chromosomal pqq mutants. Escherichia coli strains are unable to synthesize PQQ but E. coli strains containing the cloned 6.7 kb K. pneumoniae fragment can synthesize PQQ in large amounts and E. coli pts mutants can be complemented on minimal glucose medium by this clone. 相似文献
2.
1. A number of compounds structurally related to GABA were tested as inhibitors of baclofen-sensitive GABAB receptor binding to membranes from mouse brain. 2. In addition to two known inhibitors--baclofen and 5-aminovaleric acid--two analogues were shown to possess inhibitory activity. These compounds were 4-aminobutyryl-DL-alanine hydrobromide (IC50 = 3 microM) and trans-2-(aminomethyl)cyclopropane carboxylic acid (IC50 = 90 microM). 3. Both drugs also exhibited affinity for GABAA binding sites. 4. Further experiments are needed to establish if these analogues exert agonist or antagonist action at the GABAB receptor. 相似文献
3.
J. J. M. Meulenberg W. A. M. Loenen E. Sellink P. W. Postma 《Molecular & general genetics : MGG》1990,220(3):481-484
Summary A generally applicable method is described for reintroduction of mutant plasmid-borne alleles to the chromosome of Klebsiella pneumoniae using bacteriophage . We, used this method to make stable chromosomal transposon insertions in genes for biosynthesis of pyrroloquinoline quinone in K. pneumoniae 相似文献
4.
5.
6.
Kristoffer von Stedingk Jan Koster Marta Piqueras Rosa Noguera Samuel Navarro Sven Påhlman Rogier Versteeg Ingrid Øra David Gisselsson David Lindgren Håkan Axelson 《Translational oncology》2013,6(4):447-IN6
Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance,most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue microarrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability. 相似文献
7.
Rogier C. J. de Jonge Marieke S. Sanders Caroline B. Terwee Martijn W. Heymans Reinoud J. B. J. Gemke Irene Koomen Lodewijk Spanjaard A. Marceline van Furth 《PloS one》2013,8(3)
Objective
This study aimed external validation of a formerly developed prediction model identifying children at risk for hearing loss after bacterial meningitis (BM). Independent risk factors included in the model are: duration of symptoms prior to admission, petechiae, cerebral spinal fluid (CSF) glucose level, Streptococcus pneumoniae and ataxia. Validation helps to evaluate whether the model has potential in clinical practice.Study design
116 Dutch school-age BM survivors were included in the validation cohort and screened for sensorineural hearing loss (>25 dB). Risk factors were obtained from medical records. The model was applied to the validation cohort and its performance was compared with the development cohort. Validation was performed by application of the model on the validation cohort and by assessment of discrimination and goodness of fit. Calibration was evaluated by testing deviations in intercept and slope. Multiple imputation techniques were used to deal with missing values.Results
Risk factors were distributed equally between both cohorts. Discriminative ability (Area Under the Curve, AUC) of the model was 0.84 in the development and 0.78 in the validation cohort. Hosmer-Lemeshow test for goodness of fit was not significant in the validation cohort, implying good fit concerning the similarity of expected and observed cases. There were no significant differences in calibration slope and intercept. Sensitivity and negative predicted value were high, while specificity and positive predicted value were low which is comparable with findings in the development cohort.Conclusions
Performance of the model remained good in the validation cohort. This prediction model might be used as a screening tool and can help to identify those children that need special attention and a long follow-up period or more frequent auditory testing. 相似文献8.
9.
Mounir Andaloussi Herman D. Lim Tiffany van der Meer Maarten Sijm Chris B.M. Poulie Iwan J.P. de Esch Rob Leurs Rogier A. Smits 《Bioorganic & medicinal chemistry letters》2013,23(9):2663-2670
In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease. 相似文献
10.
G?zde Isik Nancy P. Y. Chung Thijs van Montfort Sergey Menis Katie Matthews William R. Schief John P. Moore Rogier W. Sanders 《PloS one》2013,8(6)
Broadly neutralizing antibodies (bNAbs) that target the HIV-1 envelope glycoproteins (Env) can prevent virus acquisition, but several Env properties limit its ability to induce an antibody response that is of sufficient quantity and quality. The immunogenicity of Env can be increased by fusion to co-stimulatory molecules and here we describe novel soluble Env trimers with embedded interleukin-4 (IL-4) or interleukin-21 (IL-21) domains, designed to activate B cells that recognize Env. In particular, the chimeric EnvIL-21 molecule activated B cells efficiently and induced the differentiation of antibody secreting plasmablast-like cells. We studied whether we could increase the activity of the embedded IL-21 by designing a chimeric IL-21/IL-4 (ChimIL-21/4) molecule and by introducing amino acid substitutions in the receptor binding domain of IL-21 that were predicted to enhance its binding. In addition, we incorporated IL-21 into a cleavable Env trimer and found that insertion of IL-21 did not impair Env cleavage, while Env cleavage did not impair IL-21 activity. These studies should guide the further design of chimeric proteins and EnvIL-21 may prove useful in improving antibody responses against HIV-1. 相似文献