全文获取类型
收费全文 | 8206篇 |
免费 | 726篇 |
专业分类
8932篇 |
出版年
2024年 | 9篇 |
2023年 | 89篇 |
2022年 | 179篇 |
2021年 | 323篇 |
2020年 | 187篇 |
2019年 | 237篇 |
2018年 | 272篇 |
2017年 | 230篇 |
2016年 | 366篇 |
2015年 | 562篇 |
2014年 | 544篇 |
2013年 | 660篇 |
2012年 | 776篇 |
2011年 | 716篇 |
2010年 | 457篇 |
2009年 | 348篇 |
2008年 | 486篇 |
2007年 | 424篇 |
2006年 | 374篇 |
2005年 | 329篇 |
2004年 | 306篇 |
2003年 | 264篇 |
2002年 | 232篇 |
2001年 | 36篇 |
2000年 | 23篇 |
1999年 | 37篇 |
1998年 | 59篇 |
1997年 | 33篇 |
1996年 | 29篇 |
1995年 | 25篇 |
1994年 | 23篇 |
1993年 | 25篇 |
1992年 | 9篇 |
1991年 | 18篇 |
1990年 | 12篇 |
1989年 | 10篇 |
1988年 | 11篇 |
1987年 | 17篇 |
1986年 | 11篇 |
1985年 | 18篇 |
1984年 | 19篇 |
1983年 | 17篇 |
1982年 | 17篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 13篇 |
1978年 | 8篇 |
1977年 | 7篇 |
1976年 | 7篇 |
1972年 | 8篇 |
排序方式: 共有8932条查询结果,搜索用时 15 毫秒
91.
Etienne Morel Sara Ghezzal Géraldine Lucchi Caroline Truntzer Jean-Paul Pais de Barros Françoise Simon-Plas Sylvie Demignot Chieko Mineo Philip W. Shaul Armelle Leturque Monique Rousset Véronique Carrière 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2018,1863(2):199-211
Scavenger receptor Class B type 1 (SR-B1) is a lipid transporter and sensor. In intestinal epithelial cells, SR-B1-dependent lipid sensing is associated with SR-B1 recruitment in raft-like/ detergent-resistant membrane domains and interaction of its C-terminal transmembrane domain with plasma membrane cholesterol. To clarify the initiating events occurring during lipid sensing by SR-B1, we analyzed cholesterol trafficking and raft-like domain composition in intestinal epithelial cells expressing wild-type SR-B1 or the mutated form SR-B1-Q445A, defective in membrane cholesterol binding and signal initiation. These features of SR-B1 were found to influence both apical cholesterol efflux and intracellular cholesterol trafficking from plasma membrane to lipid droplets, and the lipid composition of raft-like domains. Lipidomic analysis revealed likely participation of d18:0/16:0 sphingomyelin and 16:0/0:0 lysophosphatidylethanolamine in lipid sensing by SR-B1. Proteomic analysis identified proteins, whose abundance changed in raft-like domains during lipid sensing, and these included molecules linked to lipid raft dynamics and signal transduction. These findings provide new insights into the role of SR-B1 in cellular cholesterol homeostasis and suggest molecular links between SR-B1-dependent lipid sensing and cell cholesterol and lipid droplet dynamics. 相似文献
92.
93.
Jennifer L. Jacobi Bo Yang Xu Li Anna K. Menze Sara M. Laurentz Elsa M. Janle Mario G. Ferruzzi George P. McCabe Clint Chapple Ann L. Kirchmaier 《PloS one》2016,11(2)
The plant secondary metabolite and common food additive dihydrocoumarin (DHC) is an inhibitor of the Sirtuin family of NAD+-dependent deacetylases. Sirtuins are key regulators of epigenetic processes that maintain silent chromatin in yeast and have been linked to gene expression, metabolism, apoptosis, tumorogenesis and age-related processes in multiple organisms, including humans. Here we report that exposure to the polyphenol DHC led to defects in several Sirtuin-regulated processes in budding yeast including the establishment and maintenance of Sir2p-dependent silencing by causing disassembly of silent chromatin, Hst1p-dependent repression of meiotic-specific genes during the mitotic cell cycle. As both transient and prolonged exposure to environmental and dietary factors have the potential to lead to heritable alterations in epigenetic states and to modulate additional Sirtuin-dependent phenotypes, we examined the bioavailability and digestive stability of DHC using an in vivo rat model and in vitro digestive simulator. Our analyses revealed that DHC was unstable during digestion and could be converted to melilotic acid (MA), which also caused epigenetic defects, albeit less efficiently. Upon ingestion, DHC was observed primarily in intestinal tissues, but did not accumulate over time and was readily cleared from the animals. MA displayed a wider tissue distribution and, in contrast to DHC, was also detected in the blood plasma, interstitial fluid, and urine, implying that the conversion of DHC to the less bioactive compound, MA, occurred efficiently in vivo. 相似文献
94.
Lydia Feinstein Sara Ferrando-Martínez Manuel Leal Xuan Zhou Gregory D. Sempowski Derek E. Wildman 《Biodemography and social biology》2016,62(2):208-221
The thymus is critical for mounting an effective immune response and maintaining health. However, epidemiologic studies characterizing thymic function in the population setting are lacking. Using data from 263 adults in the Detroit Neighborhood Health Study, we examined thymic function as measured by the number of signal joint T-cell receptor excision circles (sjTREC) and assessed associations with established indicators of physiological health. Overall, increasing age and male gender were significantly associated with reduced thymic function. Adjusting for covariates, individuals with elevated levels of the pro-inflammatory biomarkers C-reactive protein (β: ?0.50 [95% CI: ?0.82, ?0.18] for moderate elevation, β: ?0.29 [95% CI: ?0.59, 0.00] for high elevation) and interleukin-6 (β: ?0.60 [95% CI: ?0.92, ?0.28] for moderate elevation, β: ?0.43 [95% CI: ?0.77, ?0.08] for severe elevation) also had lower thymic function. Compared to individuals with a BMI < 25, individuals who were overweight (β: 0.36 [95% CI: 0.07, 0.64]) or obese (β: 0.27 [95% CI: ?0.03, 0.56]) had higher thymic function. Differences by self-rated health were not statistically significant. Our findings underscore demographic- and health-related gradients in thymic function among adult residents of Detroit, suggesting thymic function may be an important biomarker of health status in adults at the population level. 相似文献
95.
The genome sequence of avian pathogenic Escherichia coli strain O1:K1:H7 shares strong similarities with human extraintestinal pathogenic E. coli genomes 下载免费PDF全文
Johnson TJ Kariyawasam S Wannemuehler Y Mangiamele P Johnson SJ Doetkott C Skyberg JA Lynne AM Johnson JR Nolan LK 《Journal of bacteriology》2007,189(8):3228-3236
Escherichia coli strains that cause disease outside the intestine are known as extraintestinal pathogenic E. coli (ExPEC) and include human uropathogenic E. coli (UPEC) and avian pathogenic E. coli (APEC). Regardless of host of origin, ExPEC strains share many traits. It has been suggested that these commonalities may enable APEC to cause disease in humans. Here, we begin to test the hypothesis that certain APEC strains possess potential to cause human urinary tract infection through virulence genotyping of 1,000 APEC and UPEC strains, generation of the first complete genomic sequence of an APEC (APEC O1:K1:H7) strain, and comparison of this genome to all available human ExPEC genomic sequences. The genomes of APEC O1 and three human UPEC strains were found to be remarkably similar, with only 4.5% of APEC O1's genome not found in other sequenced ExPEC genomes. Also, use of multilocus sequence typing showed that some of the sequenced human ExPEC strains were more like APEC O1 than other human ExPEC strains. This work provides evidence that at least some human and avian ExPEC strains are highly similar to one another, and it supports the possibility that a food-borne link between some APEC and UPEC strains exists. Future studies are necessary to assess the ability of APEC to overcome the hurdles necessary for such a food-borne transmission, and epidemiological studies are required to confirm that such a phenomenon actually occurs. 相似文献
96.
Genetic isolation between two recently diverged populations of a symbiotic fungus 总被引:1,自引:0,他引:1 下载免费PDF全文
Sara Branco Pierre Gladieux Christopher E. Ellison Alan Kuo Kurt LaButti Anna Lipzen Igor V. Grigoriev Hui‐Ling Liao Rytas Vilgalys Kabir G. Peay John W. Taylor Thomas D. Bruns 《Molecular ecology》2015,24(11):2747-2758
Fungi are an omnipresent and highly diverse group of organisms, making up a significant part of eukaryotic diversity. Little is currently known about the drivers of fungal population differentiation and subsequent divergence of species, particularly in symbiotic, mycorrhizal fungi. Here, we investigate the population structure and environmental adaptation in Suillus brevipes (Peck) Kuntze, a wind‐dispersed soil fungus that is symbiotic with pine trees. We assembled and annotated the reference genome for Su. brevipes and resequenced the whole genomes of 28 individuals from coastal and montane sites in California. We detected two clearly delineated coast and mountain populations with very low divergence. Genomic divergence was restricted to few regions, including a region of extreme divergence containing a gene encoding for a membrane Na+/H+ exchanger known for enhancing salt tolerance in plants and yeast. Our results are consistent with a very recent split between the montane and coastal Su. brevipes populations, with few small genomic regions under positive selection and a pattern of dispersal and/or establishment limitation. Furthermore, we identify a putatively adaptive gene that motivates further functional analyses to link genotypes and phenotypes and shed light on the genetic basis of adaptive traits. 相似文献
97.
98.
Madeleine Zetterberg Annica Sjölander Malin von Otter Mona Seibt Palmér Sara Landgren Lennart Minthon Anders Wallin Niels Andreasen Kaj Blennow Henrik Zetterberg 《Molecular neurodegeneration》2010,5(1):1-5
Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE ε4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD. 相似文献
99.
Eman Saad Elzanfaly Enas Abdel Hakim Amer Sara Abdel Basset Galal Hala Elsayed Zaazaa 《Luminescence》2019,34(1):64-69
A spectrofluorimetric method for the determination of eptifibatide is presented based on its native fluorescence. The type of solvent and the wavelength of maximum excitation and emission were carefully selected to optimize the experimental conditions. Under the specified experimental conditions, the linearities obtained between the emission intensity and the corresponding concentrations of eptifibatide were in the range 0.1–2.5 μg/ml for the calibration curve constructed for direct determination of eptifibatide in dosage form and 0.05–2.2 μg/ml for the calibration curve constructed in spiked human plasma with a good correlation coefficient (r > 0.99). The lower limit of quantification for the calibration curve constructed in human plasma was 0.05 μg/ml. Recovery results for eptifibatide in spiked plasma samples and in dosage form, represented as mean ± % RSD, were 95.17 ± 1.94 and 100.29 ± 1.33 respectively. The suggested procedures were validated according to the International Conference on Harmonization (ICH) guidelines for the direct determination of eptifibatide in its pure form and dosage form and United States Food and Drug Administration (US FDA) Guidance for Industry, Bioanalytical Method Validation for the assay of eptifibatide in human plasma. 相似文献
100.
Giovanni Corso Joana Figueiredo Simone Pietro De Angelis Federica Corso Antonia Girardi Joana Pereira Raquel Seruca Bernardo Bonanni Patricia Carneiro Gabriella Pravettoni Elena Guerini Rocco Paolo Veronesi Giacomo Montagna Virgilio Sacchini Sara Gandini 《Journal of cellular and molecular medicine》2020,24(11):5930-5936
E-cadherin protein (CDH1 gene) integrity is fundamental to the process of epithelial polarization and differentiation. Deregulation of the E-cadherin function plays a crucial role in breast cancer metastases, with worse prognosis and shorter overall survival. In this narrative review, we describe the inactivating mechanisms underlying CDH1 gene activity and its possible translation to clinical practice as a prognostic biomarker and as a potential targeted therapy. 相似文献