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Joe Rainger Margaret Keighren Douglas R. Keene Noe L. Charbonneau Jacqueline K. Rainger Malcolm Fisher Sebastien Mella Jeffrey T-J. Huang Lorraine Rose Rob van't Hof Lynne Y. Sakai Ian J. Jackson David R. FitzPatrick 《PLoS genetics》2013,9(12)
Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1Mp) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2
Mp) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1–2646, exons 1–62) lacking the C-terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe eye malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2Mp forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM – known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp “worse-than-null” eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing. 相似文献
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Laura M. Riley Joel T. Weadge Perrin Baker Howard Robinson Jeroen D. C. Codée Peter A. Tipton Dennis E. Ohman P. Lynne Howell 《The Journal of biological chemistry》2013,288(31):22299-22314
The exopolysaccharide alginate, produced by mucoid Pseudomonas aeruginosa in the lungs of cystic fibrosis patients, undergoes two different chemical modifications as it is synthesized that alter the properties of the polymer and hence the biofilm. One modification, acetylation, causes the cells in the biofilm to adhere better to lung epithelium, form microcolonies, and resist the effects of the host immune system and/or antibiotics. Alginate biosynthesis requires 12 proteins encoded by the algD operon, including AlgX, and although this protein is essential for polymer production, its exact role is unknown. In this study, we present the X-ray crystal structure of AlgX at 2.15 Å resolution. The structure reveals that AlgX is a two-domain protein, with an N-terminal domain with structural homology to members of the SGNH hydrolase superfamily and a C-terminal carbohydrate-binding module. A number of residues in the carbohydrate-binding module form a substrate recognition “pinch point” that we propose aids in alginate binding and orientation. Although the topology of the N-terminal domain deviates from canonical SGNH hydrolases, the residues that constitute the Ser-His-Asp catalytic triad characteristic of this family are structurally conserved. In vivo studies reveal that site-specific mutation of these residues results in non-acetylated alginate. This catalytic triad is also required for acetylesterase activity in vitro. Our data suggest that not only does AlgX protect the polymer as it passages through the periplasm but that it also plays a role in alginate acetylation. Our results provide the first structural insight for a wide group of closely related bacterial polysaccharide acetyltransferases. 相似文献
994.
Christopher A. Haiman Yesha M. Patel Daniel O. Stram Steven G. Carmella Menglan Chen Lynne R. Wilkens Loic Le Marchand Stephen S. Hecht 《PloS one》2016,11(3)
Research from the Multiethnic Cohort (MEC) demonstrated that, for the same quantity of cigarette smoking, African Americans and Native Hawaiians have a higher lung cancer risk than Whites, while Latinos and Japanese Americans are less susceptible. We collected urine samples from 2,239 cigarette smokers from five different ethnic groups in the MEC and analyzed each sample for S-phenylmercapturic acid (SPMA), a specific biomarker of benzene uptake. African Americans had significantly higher (geometric mean [SE] 3.69 [0.2], p<0.005) SPMA/ml urine than Whites (2.67 [0.13]) while Japanese Americans had significantly lower levels than Whites (1.65 [0.07], p<0.005). SPMA levels in Native Hawaiians and Latinos were not significantly different from those of Whites. We also conducted a genome-wide association study in search of genetic risk factors related to benzene exposure. The glutathione S-transferase T1 (GSTT1) deletion explained between 14.2–31.6% (p = 5.4x10-157) and the GSTM1 deletion explained between 0.2%-2.4% of the variance (p = 1.1x10-9) of SPMA levels in these populations. Ethnic differences in levels of SPMA remained strong even after controlling for the effects of these two deletions. These results demonstrate the powerful effect of GSTT1 status on SPMA levels in urine and show that uptake of benzene in African American, White, and Japanese American cigarette smokers is consistent with their lung cancer risk in the MEC. While benzene is not generally considered a cause of lung cancer, its metabolite SPMA could be a biomarker for other volatile lung carcinogens in cigarette smoke. 相似文献
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Heat and drought adaptive QTL in a wheat population designed to minimize confounding agronomic effects 总被引:3,自引:0,他引:3
R. Suzuky Pinto Matthew P. Reynolds Ky L. Mathews C. Lynne McIntyre Juan-Jose Olivares-Villegas Scott C. Chapman 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2010,121(6):1001-1021
A restricted range in height and phenology of the elite Seri/Babax recombinant inbred line (RIL) population makes it ideal
for physiological and genetic studies. Previous research has shown differential expression for yield under water deficit associated
with canopy temperature (CT). In the current study, 167 RILs plus parents were phenotyped under drought (DRT), hot irrigated
(HOT), and temperate irrigated (IRR) environments to identify the genomic regions associated with stress-adaptive traits.
In total, 104 QTL were identified across a combination of 115 traits × 3 environments × 2 years, of which 14, 16, and 10 QTL
were associated exclusively with DRT, HOT, and IRR, respectively. Six genomic regions were related to a large number of traits,
namely 1B-a, 2B-a, 3B-b, 4A-a, 4A-b, and 5A-a. A yield QTL located on 4A-a explained 27 and 17% of variation under drought
and heat stress, respectively. At the same location, a QTL explained 28% of the variation in CT under heat, while 14% of CT
variation under drought was explained by a QTL on 3B-b. The T1BL.1RS (rye) translocation donated by the Seri parent was associated
with decreased yield in this population. There was no co-location of consistent yield and phenology or height-related QTL,
highlighting the utility of using a population with a restricted range in anthesis to facilitate QTL studies. Common QTL for
drought and heat stress traits were identified on 1B-a, 2B-a, 3B-b, 4A-a, 4B-b, and 7A-a confirming their generic value across
stresses. Yield QTL were shown to be associated with components of other traits, supporting the prospects for dissecting crop
performance into its physiological and genetic components in order to facilitate a more strategic approach to breeding. 相似文献