全文获取类型
收费全文 | 437篇 |
免费 | 56篇 |
出版年
2022年 | 1篇 |
2021年 | 3篇 |
2020年 | 6篇 |
2019年 | 4篇 |
2018年 | 6篇 |
2017年 | 8篇 |
2016年 | 9篇 |
2015年 | 19篇 |
2014年 | 23篇 |
2013年 | 31篇 |
2012年 | 32篇 |
2011年 | 29篇 |
2010年 | 35篇 |
2009年 | 19篇 |
2008年 | 34篇 |
2007年 | 34篇 |
2006年 | 22篇 |
2005年 | 36篇 |
2004年 | 25篇 |
2003年 | 35篇 |
2002年 | 24篇 |
2001年 | 4篇 |
2000年 | 4篇 |
1999年 | 8篇 |
1998年 | 5篇 |
1997年 | 1篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 1篇 |
1993年 | 4篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1978年 | 2篇 |
1975年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有493条查询结果,搜索用时 15 毫秒
11.
Rajkumar Dorajoo Ruoying Li Mohammad Kamran Ikram Jianjun Liu Philippe Froguel Jeannette Lee Xueling Sim Rick Twee-Hee Ong Wan Ting Tay Chen Peng Terri L. Young Alexandra I. F. Blakemore Ching Yu Cheng Tin Aung Paul Mitchell Jie Jin Wang Caroline C. Klaver Eric Boerwinkle Ronald Klein David S. Siscovick Richard A. Jensen Vilmundur Gudnason Albert Vernon Smith Yik Ying Teo Tien Yin Wong E-Shyong Tai Chew-Kiat Heng Yechiel Friedlander 《PloS one》2013,8(7)
Introduction
C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.Methods
Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.Results
Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10−8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).Conclusions
Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease. 相似文献12.
13.
Mateusz Siedlinski Dustin Tingley Peter J. Lipman Michael H. Cho Augusto A. Litonjua David Sparrow Per Bakke Amund Gulsvik David A. Lomas Wayne Anderson Xiangyang Kong Stephen I. Rennard Terri H. Beaty John E. Hokanson James D. Crapo Christoph Lange Edwin K. Silverman 《Human genetics》2013,132(4):431-441
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r 2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking. 相似文献
14.
15.
Eukaryotic translation elongation factor 2 (eEF2) facilitates the movement of the peptidyl tRNA-mRNA complex from the A site of the ribosome to the P site during protein synthesis. ADP-ribosylation (ADPR) of eEF2 by bacterial toxins on a unique diphthamide residue inhibits its translocation activity, but the mechanism is unclear. We have employed a hormone-inducible diphtheria toxin (DT) expression system in Saccharomyces cerevisiae which allows for the rapid induction of ADPR-eEF2 to examine the effects of DT in vivo. ADPR of eEF2 resulted in a decrease in total protein synthesis consistent with a defect in translation elongation. Association of eEF2 with polyribosomes, however, was unchanged upon expression of DT. Upon prolonged exposure to DT, cells with an abnormal morphology and increased DNA content accumulated. This observation was specific to DT expression and was not observed when translation elongation was inhibited by other methods. Examination of these cells by electron microscopy indicated a defect in cell separation following mitosis. These results suggest that expression of proteins late in the cell cycle is particularly sensitive to inhibition by ADPR-eEF2. 相似文献
16.
Imane Sabaouni Ahmed Moussa Brigitte Vannier Oussama Semlali Terri A Pietka Nada A Abumrad Azeddine Ibrahimi 《Bioinformation》2013,9(17):849-852
We have previously shown that CD36 is a membrane protein that facilitates long chain fatty acid (FA) transport by muscle tissues.
We also documented the significant impact of muscle CD36 expression on heart function, skeletal muscle insulin sensitivity as well
as on overall metabolism. To identify a comprehensive set of genes that are differentially regulated by CD36 expression in the
heart, we used two microarray technologies (Affymetrix and Agilent) to compare gene expression in heart tissues from CD36
KnocK-Out (KO-CD36) versus wild type (WT-CD36) mice. The obtained results using the two technologies were similar with
around 35 genes differentially expressed using both technologies. Absence of CD36 led to down-regulation of the expression of
three groups of genes involved in pathways of FA metabolism, angiogenesis/apoptosis and structure. These data are consistent
with the fact that the CD36 protein binds FA and thrombospondin 1 invoved respectively in lipid metabolism and anti-angiogenic
activities. In conclusion, our findings led to validate our data analysis workflow and identify specific pathways, possibly
underlying the phenotypic abnormalities in CD36 Knock -Out hearts. 相似文献
17.
Eleanor Burnett Tenneth Dalipanda Divi Ogaoga Jenny Gaiofa Gregory Jilini Alison Halpin Vance Dietz Kashmira Date Eric Mintz Terri Hyde Kathleen Wannemuehler Catherine Yen 《PLoS neglected tropical diseases》2016,10(8)
BackgroundIn response to a 2011 cholera outbreak in Papua New Guinea, the Government of the Solomon Islands initiated a cholera prevention program which included cholera disease prevention and treatment messaging, community meetings, and a pre-emptive cholera vaccination campaign targeting 11,000 children aged 1–15 years in selected communities in Choiseul and Western Provinces.ConclusionsThis pre-emptive OCV campaign in a cholera-naïve community provided a unique opportunity to assess household-level knowledge, attitudes, and practices regarding diarrhea, cholera, and water, sanitation, and hygiene (WASH). Our findings suggest that education provided during the vaccination campaign may have reinforced earlier mass messaging about cholera and diarrheal disease in vaccinated communities. 相似文献
18.
Ortaldo JR Mason A Willette-Brown J Ruscetti FW Wine J Back T Stull T Bere EW Feigenbaum L Winkler-Pickett R Young HA 《Cellular immunology》2007,249(1):8-19
Analysis of the NK cell developmental pathway suggests that CD2 expression may be important in regulating NK maturation. To test this hypothesis, we developed mice containing only an inhibitory CD2 molecule by linking the extracellular domain of CD2 to an intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) motif. Mice containing the CD2 Tg(ITIM) transgene, introduced into a CD2 KO background, have no morphologically detectable lymph nodes, although development of the thymus appears normal. In addition, these mice had major loss of both NK and NKT subsets in peripheral organs, while T and B cell frequencies were intact. Expression of CD2 was low on T cells and lacking on B cells and functional defects were observed in these populations. NKT cells expressing CD4 were absent, while the CD8+ and double negative NKT cells were retained. Small subsets of NK cells were detected but expression of CD2 on these cells was very low or absent, and their maturation was impaired. Based on the phenotype described here, we believe that these mice represent a unique model to study lymphoid organ and lymphocyte development. 相似文献
19.
Lead resistance and sensitivity in Staphylococcus aureus 总被引:1,自引:0,他引:1
Hillel S. Levinson Inga Mahler Patricia Blackwelder Terri Hood 《FEMS microbiology letters》1996,145(3):421-425
Abstract Five lead-resistant strains of Staphylococcus aureus were isolated. Plasmid-free lead-sensitive variants were obtained from the three plasmid-bearing strains. Lead-resistant strains tolerated an approximately 600 × higher Pb(NO3 )2 concentration than lead-sensitive strains. Both types of strains initially bound lead, but only the resistant strains accumulated the metal as an intracellular lead-phosphate. 相似文献
20.
Schlatt S Zhengwei Y Meehan T de Kretser DM Loveland KL 《Cell and tissue research》1999,298(2):335-343
The extent of Sertoli cell proliferation during fetal and neonatal development determines the final adult testis size and potential for sperm output. To gain further knowledge of the factors that regulate Sertoli cell proliferation, the present study used a new approach to analyse changes in morphology and proliferation in the postnatal testis by combining organ culture with morphometric analysis. Fragments of rat testes from days 0 to 10 postpartum were cultured in contact with DMEM for 6 h or 72 h and fixed. The effects of ovine follicle-stimulating hormone (FSH) and activin were studied in an additional 72-h organ culture experiment using day 9 testes. Bromodeoxyuridine (BrdU) was added for the last 6 h of culture to mark proliferating cells. Two-microm sections of the fragments were analysed for morphological changes of the seminiferous cords, and the proportion of BrdU-labelled Sertoli and germ cells was determined. Assessment of 6-h samples revealed growth characteristics consistent with those observed in vivo during days 1-10 of postnatal development. From day 2 onwards, the volume fraction of seminiferous cords began to increase, while significant growth in cross-sectional area of the cords occurred only after day 6. In these culture conditions, germ cell proliferation and testicular architecture was consistent with that expected for the age of the tissue at time of explant. The proportion of dividing Sertoli cells declined from 15-20% at days 0-4 postpartum to below % at day 10 postpartum in the 6-h culture, and it was low or abolished in the 3-day culture at all time points. Activin and FSH together, but not singly, stimulated Sertoli cell proliferation in the 72-h culture. This paper presents a new approach to analysis of in vitro testis development. The combination of fragment culture and stereological analysis permits rigorous and detailed assessment of developmental changes in the postnatal testis. 相似文献