全文获取类型
收费全文 | 947篇 |
免费 | 65篇 |
国内免费 | 1篇 |
出版年
2023年 | 3篇 |
2022年 | 17篇 |
2021年 | 16篇 |
2020年 | 18篇 |
2019年 | 18篇 |
2018年 | 26篇 |
2017年 | 16篇 |
2016年 | 30篇 |
2015年 | 43篇 |
2014年 | 60篇 |
2013年 | 71篇 |
2012年 | 70篇 |
2011年 | 71篇 |
2010年 | 43篇 |
2009年 | 32篇 |
2008年 | 44篇 |
2007年 | 55篇 |
2006年 | 54篇 |
2005年 | 44篇 |
2004年 | 44篇 |
2003年 | 43篇 |
2002年 | 31篇 |
2001年 | 8篇 |
2000年 | 9篇 |
1999年 | 16篇 |
1998年 | 8篇 |
1997年 | 10篇 |
1996年 | 3篇 |
1995年 | 6篇 |
1994年 | 9篇 |
1993年 | 2篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1988年 | 7篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 4篇 |
1981年 | 6篇 |
1980年 | 3篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1975年 | 3篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1969年 | 2篇 |
1961年 | 1篇 |
1945年 | 1篇 |
排序方式: 共有1013条查询结果,搜索用时 31 毫秒
31.
32.
33.
Shefali Setia Verma Jessica N. Cooke Bailey Anastasia Lucas Yuki Bradford James G. Linneman Michael A. Hauser Louis R. Pasquale Peggy L. Peissig Murray H. Brilliant Catherine A. McCarty Jonathan L. Haines Janey L. Wiggs Tamara R. Vrabec Gerard Tromp Marylyn D. Ritchie eMERGE Network NEIGHBOR Consortium 《PLoS genetics》2016,12(9)
Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies. 相似文献
34.
Roberta De Grandi Pasquale Capaccio Alessandro Bidossi Marta Bottagisio Lorenzo Drago Sara Torretta Lorenzo Pignataro Elena De Vecchi 《Microbes and infection / Institut Pasteur》2019,21(2):109-112
Sialolithiasis represents the most common disorders of salivary glands in middle-aged patients. It has been hypothesized that the retrograde migration of bacteria from the oral cavity to gland ducts may facilitate the formation of stones. Thus, in the present study, a microbiome characterization of salivary calculi was performed to evaluate the abundance and the potential correlations between microorganisms constituting the salivary calculi microbiota. Our data supported the presence of a core microbiota of sialoliths constituted principally by Streptococcus spp., Fusobacterium spp. and Eikenella spp., along with the presence of important pathogens commonly involved in infective sialoadenitis. 相似文献
35.
Pasquale D'Acunzo Tal Hargash Monika Pawlik Chris N. Goulbourne Rocío Prez‐Gonzlez Efrat Levy 《Developmental neurobiology》2019,79(7):656-663
Down syndrome (DS) is a human genetic disease caused by trisomy of chromosome 21 and characterized by early developmental brain abnormalities. Dysfunctional endosomal pathway in neurons is an early event of DS and Alzheimer's disease. Recently, we have demonstrated that exosome secretion is upregulated in human DS postmortem brains, in the brain of the trisomic mouse model Ts[Rb(12.1716)]2Cje (Ts2) and by DS fibroblasts as compared with disomic controls. High levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Partially blocking exosome secretion by DS fibroblasts exacerbated a pre‐existing early endosomal pathology. We thus hypothesized that enhanced CD63 expression induces generation of intraluminal vesicles (ILVs) in late endosomes/multivesicular bodies (MVBs), increasing exosome release as an endogenous mechanism to mitigate endosomal abnormalities in DS. Herein, we show a high‐resolution electron microscopy analysis of MVBs in neurons of the frontal cortex of 12‐month‐old Ts2 mice and littermate diploid controls. Our quantitative analysis revealed that Ts2 MVBs are larger, more abundant, and contain a higher number of ILVs per neuron compared to controls. These findings were further corroborated biochemically by Western blot analysis of purified endosomal fractions showing higher levels of ILVs proteins in the same fractions containing endosomal markers in the brain of Ts2 mice compared to controls. These data suggest that upregulation of ILVs production may be a key homeostatic mechanism to alleviate endosomal dysregulation via the endosomal–exosomal pathway. 相似文献
36.
Evidence for contributions of airway smooth muscle (ASM) to the hyperresponsiveness of newborn and juvenile airways continues to accumulate. In our laboratory, 3 novel paradigms of hyperresponsiveness of newborn and young ASM have recently emerged using a guinea pig model of maturation in 3 age groups: 1 week (newborn), 3 weeks (juvenile), and 2-3 months (adult). The first paradigm includes evidence for a natural decline after newborn and juvenile life of the velocity of ASM shortening associated with a decrease in regulatory myosin light chain phosphorylation and a parallel decline in the content of myosin light chain kinase. Associated with the decrease in ASM shortening with age is an increase in the internal resistance to shortening. Dynamic stiffness is shown to relate inversely to the expression of myosin light chain kinase. This suggests that developmental changes in shortening relate inversely to the stiffness of the ASM early in shortening, suggesting a dynamic role for the cytoskeleton in facilitating and opposing ASM shortening. This relationship can be approximated as (dP/dt)max approximately (dP/dL)passive x (dL/dt)max (the maximal rate of increase of active stress generation approximately to the passive stiffness x the maximal shortening velocity). The second paradigm demonstrates that newborn ASM, unlike that in adults, does not relax during prolonged electric field stimulation. The impaired relaxation is related to changes in prostanoid synthesis and acetylcholinesterase function. The third paradigm demonstrates that, whereas oscillatory strain serves to transiently relax adult ASM, in newborns it induces (after the initial relaxation) a sustained potentiation of active stress. This is related to developmental changes in the prostanoid release. Together, these paradigms demonstrate that ASM contributes by multiple mechanisms to the natural hyperresponsiveness of newborn and juvenile airways. Future studies will elaborate the mechanisms and extend these paradigms to ASM hyperresponsiveness following sensitization in early life. 相似文献
37.
38.
Functional and structural aspects of poplar cytosolic and plastidial type a methionine sulfoxide reductases 总被引:1,自引:0,他引:1
Rouhier N Kauffmann B Tete-Favier F Palladino P Gans P Branlant G Jacquot JP Boschi-Muller S 《The Journal of biological chemistry》2007,282(5):3367-3378
The genome of Populus trichocarpa contains five methionine sulfoxide reductase A genes. Here, both cytosolic (cMsrA) and plastidial (pMsrA) poplar MsrAs were analyzed. The two recombinant enzymes are active in the reduction of methionine sulfoxide with either dithiothreitol or poplar thioredoxin as a reductant. In both enzymes, five cysteines, at positions 46, 81, 100, 196, and 202, are conserved. Biochemical and enzymatic analyses of the cysteine-mutated MsrAs support a catalytic mechanism involving three cysteines at positions 46, 196, and 202. Cys(46) is the catalytic cysteine, and the two C-terminal cysteines, Cys(196) and Cys(202), are implicated in the thioredoxin-dependent recycling mechanism. Inspection of the pMsrA x-ray three-dimensional structure, which has been determined in this study, strongly suggests that contrary to bacterial and Bos taurus MsrAs, which also contain three essential Cys, the last C-terminal Cys(202), but not Cys(196), is the first recycling cysteine that forms a disulfide bond with the catalytic Cys(46). Then Cys(202) forms a disulfide bond with the second recycling cysteine Cys(196) that is preferentially reduced by thioredoxin. In agreement with this assumption, Cys(202) is located closer to Cys(46) compared with Cys(196) and is included in a (202)CYG(204) signature specific for most plant MsrAs. The tyrosine residue corresponds to the one described to be involved in substrate binding in bacterial and B. taurus MsrAs. In these MsrAs, the tyrosine residue belongs to a similar signature as found in plant MsrAs but with the first C-terminal cysteine instead of the last C-terminal cysteine. 相似文献
39.
Yin Chun-yu Lu Hong-zhou Jiang Wei-ming Maria Pia De Pasquale Hu Yue-kai Pan Xiao-zhang Weng Xin-hua Richard T. D’Aquila Tang Yi-Wei 《中国病毒学》2007,22(3):212-217
Illegally paid blood donation was a risk factor for HIV acquisition exclusively in Henan and Hubei Provinces of China, and
not in Shanghai. Nucleotide sequences in the gag and env genes of HIV-1 were compared between isolates from Henan and Shanghai regions of China to test whether an expected higher
degree of a common source of infections from this unique blood donation transmission risk would be evident as decreased variation
among Henan isolates in an exploratory cross-sectional analysis. Among 38 isolates studied, 23 of 23 (100%) from Henan and
8 of 15 (54%) from Shanghai were subtype B. In addition, fewer sequence differences were found in gp41 of subtype B isolates
from Henan than from Shanghai isolates. Further studies with additional controls are therefore warranted to confirm the role
of the degree of a common source of infections in differences in HIV variation across populations.
Fundation items: The Vanderbilt-Meharry Center for AIDS Research (P30 AI 54999); R.T.D (R01 AI 29193); Start Fund of Ministry
of Education of China (for Hong-zhou LU, 2004BA719A10). 相似文献
40.