全文获取类型
收费全文 | 331篇 |
免费 | 30篇 |
出版年
2020年 | 3篇 |
2019年 | 7篇 |
2017年 | 4篇 |
2016年 | 11篇 |
2015年 | 6篇 |
2014年 | 12篇 |
2013年 | 20篇 |
2012年 | 20篇 |
2011年 | 22篇 |
2010年 | 11篇 |
2009年 | 8篇 |
2008年 | 8篇 |
2007年 | 13篇 |
2006年 | 8篇 |
2005年 | 12篇 |
2004年 | 11篇 |
2003年 | 20篇 |
2002年 | 8篇 |
2001年 | 6篇 |
2000年 | 7篇 |
1999年 | 12篇 |
1998年 | 6篇 |
1995年 | 4篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 3篇 |
1983年 | 3篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 6篇 |
1967年 | 4篇 |
1965年 | 2篇 |
1960年 | 2篇 |
1913年 | 2篇 |
1875年 | 2篇 |
排序方式: 共有361条查询结果,搜索用时 15 毫秒
61.
62.
Kirk D. Robarge Shirley A. Brunton Georgette M. Castanedo Yong Cui Michael S. Dina Richard Goldsmith Stephen E. Gould Oivin Guichert Janet L. Gunzner Jason Halladay Wei Jia Cyrus Khojasteh Michael F.T. Koehler Karen Kotkow Hank La Rebecca L. LaLonde Kevin Lau Leslie Lee Derek Marshall James C. Marsters Minli Xie 《Bioorganic & medicinal chemistry letters》2009,19(19):5576-5581
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC. 相似文献
63.
A novel series of analogs of 2-amino-dihydrotetrabenazine derivatives, 4–6, targeting the vesicular monoamine transporter have been prepared. In vitro binding was carried out in tissue homogenates prepared from rat striatal tissue homogenates with both [125I]-iodovinyl-TBZ and [3H]DTBZ. There was a good correlation (r2 = 0.925) between the affinities of the different compounds for [125I]-iodovinyl-TBZ and [3H]-DTBZ binding. Compound 5 exhibited a better affinity for the vesicular monoamine transporter (Ki = 8.68 ± 1.26 nM and 7.01 ± 0.07 nM, respectively), which may be a good lead compound for further structural modification to develop useful probes for VMAT2. 相似文献
64.
Wu C So J Davis-Dusenbery BN Qi HH Bloch DB Shi Y Lagna G Hata A 《Molecular and cellular biology》2011,31(23):4760-4774
Hypoxia contributes to the pathogenesis of various human diseases, including pulmonary artery hypertension (PAH), stroke, myocardial or cerebral infarction, and cancer. For example, acute hypoxia causes selective pulmonary artery (PA) constriction and elevation of pulmonary artery pressure. Chronic hypoxia induces structural and functional changes to the pulmonary vasculature, which resembles the phenotype of human PAH and is commonly used as an animal model of this disease. The mechanisms that lead to hypoxia-induced phenotypic changes have not been fully elucidated. Here, we show that hypoxia increases type I collagen prolyl-4-hydroxylase [C-P4H(I)], which leads to prolyl-hydroxylation and accumulation of Argonaute2 (Ago2), a critical component of the RNA-induced silencing complex (RISC). Hydroxylation of Ago2 is required for the association of Ago2 with heat shock protein 90 (Hsp90), which is necessary for the loading of microRNAs (miRNAs) into the RISC, and translocation to stress granules (SGs). We demonstrate that hydroxylation of Ago2 increases the level of miRNAs and increases the endonuclease activity of Ago2. In summary, this study identifies hypoxia as a mediator of the miRNA-dependent gene silencing pathway through posttranslational modification of Ago2, which might be responsible for cell survival or pathological responses under low oxygen stress. 相似文献
65.
66.
67.
68.
Pei-Chien Tsai Szu-Wei Huang Hsiang-Lin Tsai Cheng-Jen Ma Ming-Feng Hou I-Ping Yang Yung-Song Wang Suh-Hang Hank Juo Jaw-Yuan Wang 《PloS one》2014,9(9)
Background
Gastric cancer is common cancer. Discovering novel genetic biomarkers might help to identify high-risk individuals. Copy number variation (CNV) has recently been shown to influence risk for several cancers. The aim of the present study was sought to test the association between copy number at a variant region and GC.Methods
A total of 110 gastric cancer patients and 325 healthy volunteers were enrolled in this study. We searched for a CNV and found a CNV (Variation 7468) containing part of the APC gene, the SRP19 gene and the REEP5 gene. We chose four probes targeting at APC-intron8, APC-exon9, SRP19 and REEP5 to interrogate this CNV. Specific Taqman probes labeled by different reporter fluorophores were used in a real-time PCR platform to obtain copy number. Both the original non-integer data and transformed integer data on copy number were used for analyses.Results
Gastric caner patients had a lower non-integer copy number than controls for the APC-exon9 probe (Adjusted p = 0.026) and SRP19 probe (Adjusted p = 0.002). The analysis of integer copy number yielded a similar pattern although less significant (Adjusted p = 0.07 for APC-exon9 probe and Adjusted p = 0.02 for SRP19 probe).Conclusions
Losses of a CNV at 5q22, especially in the DNA region surrounding APC-exon 9, may be associated with a higher risk of gastric cancer. 相似文献69.
Rebecca Oester Ryan Greenway Marvin Moosmann Ruben Sommaruga Barbara Tartarotti Jakob Brodersen Blake Matthews 《Ecology and evolution》2022,12(4)
Trait expression of natural populations often jointly depends on prevailing abiotic environmental conditions and predation risk. Copepods, for example, can vary their expression of compounds that confer protection against ultraviolet radiation (UVR), such as astaxanthin and mycosporine‐like amino acids (MAAs), in relation to predation risk. Despite ample evidence that copepods accumulate less astaxanthin in the presence of predators, little is known about how the community composition of planktivorous fish can affect the overall expression of photoprotective compounds. Here, we investigate how the (co‐)occurrence of Arctic charr (Salvelinus alpinus) and threespine stickleback (Gasterosteus aculeatus) affects the photoprotective phenotype of the copepod Leptodiaptomus minutus in lake ecosystems in southern Greenland. We found that average astaxanthin and MAA contents were lowest in lakes with stickleback, but we found no evidence that these photoprotective compounds were affected by the presence of charr. Furthermore, variance in astaxanthin among individual copepods was greatest in the presence of stickleback and the astaxanthin content of copepods was negatively correlated with increasing stickleback density. Overall, we show that the presence and density of stickleback jointly affect the content of photoprotective compounds by copepods, illustrating how the community composition of predators in an ecosystem can determine the expression of prey traits that are also influenced by abiotic stressors. 相似文献
70.
A real-time PCR assay for the detection of Campylobacter jejuni in foods after enrichment culture 总被引:3,自引:0,他引:3
Sails AD Fox AJ Bolton FJ Wareing DR Greenway DL 《Applied and environmental microbiology》2003,69(3):1383-1390
A real-time PCR assay was developed for the quantitative detection of Campylobacter jejuni in foods after enrichment culture. The specificity of the assay for C. jejuni was demonstrated with a diverse range of Campylobacter species, related organisms, and unrelated genera. The assay had a linear range of quantification over six orders of magnitude, and the limit of detection was approximately 12 genome equivalents. The assay was used to detect C. jejuni in both naturally and artificially contaminated food samples. Ninety-seven foods, including raw poultry meat, offal, raw shellfish, and milk samples, were enriched in blood-free Campylobacter enrichment broth at 37 degrees C for 24 h, followed by 42 degrees C for 24 h. Enrichment cultures were subcultured to Campylobacter charcoal-cefoperazone-deoxycholate blood-free selective agar, and presumptive Campylobacter isolates were identified with phenotypic methods. DNA was extracted from enrichment cultures with a rapid lysis method and used as the template in the real-time PCR assay. A total of 66 samples were positive for C. jejuni by either method, with 57 samples positive for C. jejuni by subculture to selective agar medium and 63 samples positive in the real-time PCR assay. The results of both methods were concordant for 84 of the samples. The total time taken for detection from enrichment broth samples was approximately 3 h for the real-time PCR assay, with the results being available immediately at the end of PCR cycling, compared to 48 h for subculture to selective agar. This assay significantly reduces the total time taken for the detection of C. jejuni in foods and is an important model for other food-borne pathogens. 相似文献