全文获取类型
收费全文 | 15640篇 |
免费 | 1356篇 |
国内免费 | 1932篇 |
专业分类
18928篇 |
出版年
2024年 | 53篇 |
2023年 | 281篇 |
2022年 | 590篇 |
2021年 | 907篇 |
2020年 | 701篇 |
2019年 | 812篇 |
2018年 | 757篇 |
2017年 | 556篇 |
2016年 | 725篇 |
2015年 | 1040篇 |
2014年 | 1252篇 |
2013年 | 1283篇 |
2012年 | 1566篇 |
2011年 | 1446篇 |
2010年 | 909篇 |
2009年 | 736篇 |
2008年 | 811篇 |
2007年 | 753篇 |
2006年 | 613篇 |
2005年 | 534篇 |
2004年 | 388篇 |
2003年 | 306篇 |
2002年 | 283篇 |
2001年 | 191篇 |
2000年 | 182篇 |
1999年 | 177篇 |
1998年 | 123篇 |
1997年 | 115篇 |
1996年 | 117篇 |
1995年 | 96篇 |
1994年 | 89篇 |
1993年 | 67篇 |
1992年 | 85篇 |
1991年 | 55篇 |
1990年 | 57篇 |
1989年 | 50篇 |
1988年 | 35篇 |
1987年 | 27篇 |
1986年 | 28篇 |
1985年 | 29篇 |
1984年 | 15篇 |
1983年 | 15篇 |
1982年 | 13篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 10篇 |
1978年 | 4篇 |
1977年 | 4篇 |
1976年 | 9篇 |
1975年 | 8篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Yubing Yu Yong Li Huixin Peng Qixue Song Xingwen Da Hui Li Zuhan He Xiang Ren Chengqi Xu Yufeng Yao Qing K. Wang 《The Journal of biological chemistry》2022,298(4)
Angiogenic factor AGGF1 (AngioGenic factor with G-patch and FHA (Forkhead-Associated) domain 1) blocks neointimal formation (formation of a new or thickened layer of arterial intima) after vascular injury by regulating phenotypic switching of vascular smooth muscle cells (VSMCs). However, the AGGF1 receptor on VSMCs and the underlying molecular mechanisms of its action are unknown. In this study, we used functional analysis of serial AGGF1 deletions to reveal the critical AGGF1 domain involved in VSMC phenotypic switching. This domain was required for VSMC phenotypic switching, proliferation, cell cycle regulation, and migration, as well as the regulation of cell cycle inhibitors cyclin D, p27, and p21. This domain also contains an RDDAPAS motif via which AGGF1 interacts with integrin α7 (ITGA7), but not α8. In addition, we show that AGGF1 enhanced the expression of contractile markers MYH11, α-SMA, and SM22 and inhibited MEK1/2, ERK1/2, and ELK phosphorylation in VSMCs, and that these effects were inhibited by knockdown of ITGA7, but not by knockdown of ITGA8. In vivo, deletion of the VSMC phenotypic switching domain in mice with vascular injury inhibited the functions of AGGF1 in upregulating α-SMA and SM22, inhibiting MEK1/2, ERK1/2, and ELK phosphorylation, in VSMC proliferation, and in blocking neointimal formation. Finally, we show the inhibitory effect of AGGF1 on neointimal formation was blocked by lentivirus-delivered shRNA targeting ITGA7. Our data demonstrate that AGGF1 interacts with its receptor integrin α7 on VSMCs, and this interaction is required for AGGF1 signaling in VSMCs and for attenuation of neointimal formation after vascular injury. 相似文献
992.
993.
994.
Lin Peng Min Zhao Tianqi Liu Jiangbo Chen Pin Gao Lei Chen Pu Xing Zaozao Wang Jiabo Di Qiang Xu Hong Qu Beihai Jiang Xiangqian Su 《Cell death & disease》2022,13(4)
Genomic instability plays a key role in the initiation and progression of colorectal cancer (CRC). Although cancer driver genes in CRC have been well characterized, identifying novel genes associated with carcinogenesis and treatment remains challenging because of tumor heterogeneity. Here, we analyzed the genomic alterations of 45 samples from CRC patients in northern China by whole-exome sequencing. In addition to the identification of six well-known CRC driver genes (APC, TP53, KRAS, FBXW7, PIK3CA, and PABPC), two tumor-related genes (MTCH2 and HSPA6) were detected, along with RRP7A and GXYLT1, which have not been previously linked to cancer. GXYLT1 was mutated in 40% (18/45) of the samples in our cohort. Functionally, GXYLT1 promoted migration and invasion in vitro and metastasis in vivo, while the GXYLT1S212* mutant induced significantly greater effect. Furthermore, both GXYLT1 and GXYLT1S212* interacted with ERK2. GXYLT1 induced metastasis via a mechanism involving the Notch and MAPK pathways, whereas the GXYLT1S212* mutant mainly promoted metastasis by activating the MAPK pathway. We propose that GXYLT1 acts as a novel metastasis-associated driver gene and GXYLT1S212* might serve as a potential indicator for therapies targeting the MAPK pathway in CRC.Subject terms: Cancer genomics, Colorectal cancer, Metastasis, Oncogenes, Cell signalling 相似文献
995.
对六种灵猫科物种线粒体12 S rRNA基因及其中四种的Cytb基因部分序列进行了测定,并从Gen-Bank获得斑林狸(Prionodon pardicolor)、熊狸(Arctictis binturong)的Cytb基因同源序列。两基因整合序列比对后长755 bp,12 S rRNA基因序列中有70个变异位点,31个简约信息位点,在Cytb基因序列中,共有120个位点呈现变异,60个简约信息位点,Cytb基因的碱基变异百分比高于12 S rRNA基因的碱基变异百分比。使用邻接法(NJ)、最大似然法(ML)重建的分子系统树显示:斑林狸从灵猫亚科中分离出来,支持灵猫亚科的多系起源,而且斑林狸可能是中国起源最早且最特化的灵猫科动物。另外,同属于灵猫亚科的大灵猫(Viverra zibe-tha)、小灵猫(Viverricula indica)聚为一支,同属于棕榈狸亚科的果子狸(Viverricula indica)、熊狸聚为姐妹群,这些与传统形态学分类观点一致。 相似文献
996.
组织通透方法采用高折射率化学试剂对生物组织进行渗透,改变组织的光学均匀性,可以有效地改善光学成像的穿透深度,受到生物医学光学研究领域的重视。利用光学相干层析成像技术,测量通透过程中不同测量深度下组织的散射特征的变化。通过采用系统信号对数的梯度值近似地表征光学散射系数,研究了通透过程中组织的散射特征随渗透时间和测量深度的动态关系。实验证明了组织通透可以有效地增加光子的穿透深度,并改善成像质量。研究发现:不同测量深度处组织的散射系数及其变化幅度、变化过程和变化趋势等均存在一定的差异性,并与组织的微观结构、其通透效果,化学试剂在组织中的渗透行为等有密切关系,有助于组织通透过程的理解,并为组织通透机制提供可能的实验依据。 相似文献
997.
Zixin Peng Alexandre Maciel-Guerra Michelle Baker Xibin Zhang Yue Hu Wei Wang Jia Rong Jing Zhang Ning Xue Paul Barrow David Renney Dov Stekel Paul Williams Longhai Liu Junshi Chen Fengqin Li Tania Dottorini 《PLoS computational biology》2022,18(3)
Anthropogenic environments such as those created by intensive farming of livestock, have been proposed to provide ideal selection pressure for the emergence of antimicrobial-resistant Escherichia coli bacteria and antimicrobial resistance genes (ARGs) and spread to humans. Here, we performed a longitudinal study in a large-scale commercial poultry farm in China, collecting E. coli isolates from both farm and slaughterhouse; targeting animals, carcasses, workers and their households and environment. By using whole-genome phylogenetic analysis and network analysis based on single nucleotide polymorphisms (SNPs), we found highly interrelated non-pathogenic and pathogenic E. coli strains with phylogenetic intermixing, and a high prevalence of shared multidrug resistance profiles amongst livestock, human and environment. Through an original data processing pipeline which combines omics, machine learning, gene sharing network and mobile genetic elements analysis, we investigated the resistance to 26 different antimicrobials and identified 361 genes associated to antimicrobial resistance (AMR) phenotypes; 58 of these were known AMR-associated genes and 35 were associated to multidrug resistance. We uncovered an extensive network of genes, correlated to AMR phenotypes, shared among livestock, humans, farm and slaughterhouse environments. We also found several human, livestock and environmental isolates sharing closely related mobile genetic elements carrying ARGs across host species and environments. In a scenario where no consensus exists on how antibiotic use in the livestock may affect antibiotic resistance in the human population, our findings provide novel insights into the broader epidemiology of antimicrobial resistance in livestock farming. Moreover, our original data analysis method has the potential to uncover AMR transmission pathways when applied to the study of other pathogens active in other anthropogenic environments characterised by complex interconnections between host species. 相似文献
998.
999.
Yue Zhu Xinzhi Peng Qianlei Zhou Langping Tan Cheng Zhang Shaojian Lin Miaoyun Long 《Cell death & disease》2022,13(4)
Papillary thyroid cancer (PTC) is a common endocrine system malignancy all over the world. Aberrant expression of six transmembrane epithelial antigen of the prostate 2 (STEAP2) has been functionally associated with cancer progression in many cancers. Nevertheless, its biological function in PTC is still unclear. Here, we found that PTC tissues had preferentially downregulated STEAP2 as compared with noncancerous tissues. Low STEAP2 expression correlated with aggressive clinicopathological characteristics and dismal prognosis in patients with PTC. We performed gain- and loss-of-function experiments, including cell proliferation assay (Cell Counting Kit-8 assay), EdU (5-ethynyl-2′-deoxyuridine) and colony formation assays, transwell migration, and invasion assays, and constructed a nude mouse xenograft tumor model. The results demonstrated that STEAP2 overexpression inhibited PTC cell proliferation, migration, and invasion in vitro and inhibited lung metastasis and tumorigenicity in vivo. Conversely, silencing STEAP2 yielded the opposite results in vitro. Mechanistically, bioinformatics analysis combined with validation experiments identified STEAP2 as the downstream target of methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification. METTL3 stabilized STEAP2 mRNA and regulated STEAP2 expression positively in an m6A-dependent manner. We also showed that m6A-mediated STEAP2 mRNA translation initiation relied on a pathway dependent on the m6A reader protein YTHDF1. Rescue experiments revealed that silencing STEAP2 partially rescued the tumor-suppressive phenotype induced by METTL3 overexpression. Lastly, we verified that the METTL3–STEAP2 axis functions as an inhibitor in PTC by suppressing epithelial–mesenchymal transition and the Hedgehog signaling pathway. Taken together, these findings strongly suggest that METTL3-mediated STEAP2 m6A modification plays a critical tumor-suppressive role in PTC progression. The METTL3–STEAP2 axis may be a potential therapeutic molecular target against PTC.Subject terms: Metastasis, Prognostic markers 相似文献
1000.
M Kongshaug C Rimington J F Evensen Q Peng J Moan 《The International journal of biochemistry》1990,22(10):1127-1131
1. Binding of added hematoporphyrin (HP) ethers to human plasma proteins and lipoproteins has been investigated by ultracentrifugation. 2. The binding to low density lipoproteins (LDL) has been discussed in terms of photosensitized tumor growth delay of tumors and HPLC-retention time, i.e. degree of polarity. 3. The LDL-binding data show a uniform relationship to sensitizing efficiency and degree of polarity, the only exception being HP-diamyl ether. No such uniform relationship exists for less related dyes, such as HP, tetraphenylporphyrin tetrasulfonate and HP-dimethyl ether. 相似文献