全文获取类型
收费全文 | 34958篇 |
免费 | 2855篇 |
国内免费 | 1876篇 |
专业分类
39689篇 |
出版年
2024年 | 68篇 |
2023年 | 389篇 |
2022年 | 932篇 |
2021年 | 1633篇 |
2020年 | 1033篇 |
2019年 | 1249篇 |
2018年 | 1224篇 |
2017年 | 864篇 |
2016年 | 1324篇 |
2015年 | 2022篇 |
2014年 | 2363篇 |
2013年 | 2547篇 |
2012年 | 3082篇 |
2011年 | 2762篇 |
2010年 | 1718篇 |
2009年 | 1428篇 |
2008年 | 1661篇 |
2007年 | 1513篇 |
2006年 | 1350篇 |
2005年 | 1141篇 |
2004年 | 1019篇 |
2003年 | 864篇 |
2002年 | 743篇 |
2001年 | 677篇 |
2000年 | 681篇 |
1999年 | 655篇 |
1998年 | 386篇 |
1997年 | 335篇 |
1996年 | 359篇 |
1995年 | 333篇 |
1994年 | 325篇 |
1993年 | 216篇 |
1992年 | 351篇 |
1991年 | 270篇 |
1990年 | 306篇 |
1989年 | 257篇 |
1988年 | 189篇 |
1987年 | 171篇 |
1986年 | 152篇 |
1985年 | 134篇 |
1984年 | 121篇 |
1983年 | 95篇 |
1982年 | 77篇 |
1981年 | 61篇 |
1979年 | 75篇 |
1978年 | 55篇 |
1977年 | 53篇 |
1975年 | 59篇 |
1974年 | 47篇 |
1973年 | 50篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Chen YJ Huang WC Wei YL Hsu SC Yuan P Lin HY Wistuba II Lee JJ Yen CJ Su WC Chang KY Chang WC Chou TC Chou CK Tsai CH Hung MC 《PloS one》2011,6(6):e21428
Background
The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive.Methodology/Principal Findings
Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib.Conclusions/Significance
Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR. 相似文献952.
Liao WL Heo GY Dodder NG Reem RE Mast N Huang S Dipatre PL Turko IV Pikuleva IA 《Journal of proteome research》2011,10(1):241-248
Cytochrome P450 enzymes (CYP or P450) 46A1 and 27A1 play important roles in cholesterol elimination from the brain and retina, respectively, yet they have not been quantified in human organs because of their low abundance and association with membrane. On the basis of our previous development of a multiple reaction monitoring (MRM) workflow for measurements of low-abundance membrane proteins, we quantified CYP46A1 and CYP27A1 in human brain and retina samples from four donors. These enzymes were quantified in the total membrane pellet, a fraction of the whole tissue homogenate, using 1?N-labled recombinant P450s as internal standards. The average P450 concentrations/mg of total tissue protein were 345 fmol of CYP46A1 and 110 fmol of CYP27A1 in the temporal lobe, and 60 fmol of CYP46A1 and 490 fmol of CYP27A1 in the retina. The corresponding P450 metabolites were then measured in the same tissue samples and compared to the P450 enzyme concentrations. Investigation of the enzyme-product relationships and analysis of the P450 measurements based on different signature peptides revealed a possibility of retina-specific post-translational modification of CYP27A1. The data obtained provide important insights into the mechanisms of cholesterol elimination from different neural tissues. 相似文献
953.
Qingmei Han Haiyan Zhao Lili Huang Heinrich Buchenauer Yuhu Zuo Zhensheng Kang 《Journal of Phytopathology》2011,159(5):368-376
Resistance of soybean cultivars, depending on single dominant genes to Phytophthora sojae, may easily be overcome by emerging new virulent races. Light microscopy (LM) and electron microscopy (EM) were used to study the infection process of the wild‐type isolate Ps411 and metalaxyl‐resistant mutant Ps411‐M of P. sojae in hypocotyls of soybean seedlings grown from untreated and metalaxyl‐treated seeds. The isolate Ps411‐M of P. sojae exhibited a high degree of resistance to metalaxyl compared to Ps411. The pathogenic fitness of Ps411‐M in hypocotyls of soybean seedlings was lower compared to Ps411. LM observations showed distinct differences in the infection process of both isolates in hypocotyls of treated soybean seedlings. EM studies revealed differences in the prepenetration stage between Ps411 and Ps411‐M on hypocotyls grown from seeds treated with 0.02% metalaxyl until the whole seed surface coated. The number of infection sites was markedly reduced and few hyphae continued to spread. Numerous ultrastructural alterations in hyphae were observed in treated hypocotyls infected with Ps411, including pronounced thickening of hyphal cell walls and encasement of haustorium‐like bodies; electron‐dense material was deposited in host cell walls in contact with hyphal cells. Neither the prepenetration process nor penetration or spread of hyphae in the hypocotyls of the resistant isolate was affected in treated compared to non‐treated tissue. While in treated hypocotyls infected with the wild‐type isolate, host defence reactions were induced, no such reactions were detected in treated hypocotyls infected with the resistant isolate. Hypocotyls from metalaxyl‐treated seeds infected with the wild‐type isolate resembled an incompatible interaction, whereas during infection with the metalaxyl‐resistant mutant, the compatible interaction was not changed. 相似文献
954.
Genming Luo Yongbiao Wang Hao Yang Thomas J. Algeo Lee R. Kump Junhua Huang Shucheng Xie 《Palaeogeography, Palaeoclimatology, Palaeoecology》2011,299(1-2):70-82
Large perturbations to the global carbon cycle occurred during the Permian–Triassic boundary mass extinction, the largest extinction event of the Phanerozoic Eon (542 Ma to present). Controversy concerning the pattern and mechanism of variations in the marine carbonate carbon isotope record of the Permian–Triassic crisis interval (PTCI) and their relationship to the marine mass extinction has not been resolved to date. Herein, high-resolution carbonate carbon isotope profiles (δ13Ccarb), accompanied by lithofacies, were generated for four sections with microbialite (Taiping, Zuodeng, Cili, and Chongyang) in South China to better constrain patterns and controls on δ13Ccarb variation in the PTCI and to test hypotheses about the temporal relationship between perturbations to the global carbon cycle and the marine mass extinction event. All four study sections exhibit a stepwise negative shift in δ13Ccarb during the Late Permian–Early Triassic, with the shift preceding the end-Permian crisis being larger (> 3‰) than that following it (1–2‰). The pre-crisis shifts in δ13Ccarb are widely correlatable and, hence, represent perturbations to the global carbon cycle. The comparatively smaller shifts following the crisis demonstrate that the marine mass extinction event itself had at most limited influence on the global carbon cycle, and that both Late Permian δ13Ccarb shifts and the mass extinction must be attributed to some other cause. Their origin cannot be uniquely determined from C-isotopic data alone but appears to be most compatible with a mechanism based on episodic volcanism in combination with collapse of terrestrial ecosystems and soil erosion. 相似文献
955.
956.
957.
【目的】克隆伯克霍尔德菌ZYB002菌株中的新型脂肪酶lip C24基因,测定其基本酶学性质,为后续深入研究该基因在菌株中的生理功能奠定基础。【方法】根据洋葱伯克霍尔德菌JK321菌株的全基因组DNA信息,直接设计引物从伯克霍尔德菌ZYB002菌株基因组中扩增出lip C24基因,并对之进行原核表达、重组蛋白的纯化及酶学性质分析。【结果】lip C24基因全长1317 bp,编码438个氨基酸残基;多肽链中具有保守五肽-G-X1-S-X2-G-序列;重组蛋白Lip C24的分子量为45 k Da;能有效水解各种对硝基苯酯,对中链脂肪酸的对硝基苯酯表现出偏爱性;其催化水解反应的最适温度为40℃,最适p H7.5;40℃下的半衰期为15.72 min,在p H 7.0-8.0的条件下,具有较好的稳定性。【结论】lip C24的编码产物为一个45 k Da蛋白,具有明显的脂肪酶活性,为中温中性脂肪酶。 相似文献
958.
959.
960.
Attention‐deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and adolescents with high heritability. Evidence is accumulating that SLC1A3 may play a role in ADHD etiology. Therefore, a two‐stage case‐control study was conducted on 752 cases and 774 controls to explore the role of SLC1A3 in ADHD. Bioinformatic annotations and functional experiments were applied to reveal the potential biological mechanisms. Finally, SLC1A3 rs1049522 showed significant association with ADHD risk in two stages with CA genotype vs AA genotype, odds ratio (OR) = 0.694 (95% confidence interval, CI = 0.570‐0.844) and dominant model, OR = 0.749 (95% CI = 0.621‐0.904) in the combined stage. Besides, rs1049522 was found to be related to ADHD hyperactive/impulsive symptom, and rs1049522‐C showed increased SLC1A3 mRNA expression in the cerebellar cortex. Dual‐luciferase reporter assay further indicated that rs1049522‐C allele enhanced SLC1A3 expression by disrupting the hsa‐miR‐3171 binding site. In conclusion, SLC1A3 variant rs1049522 was implicated in ADHD susceptibility in a Chinese Han population probably by enhancing the SLC1A3 expression in a miRNA‐mediated manner. 相似文献