全文获取类型
收费全文 | 4121篇 |
免费 | 386篇 |
国内免费 | 237篇 |
出版年
2024年 | 3篇 |
2023年 | 37篇 |
2022年 | 116篇 |
2021年 | 208篇 |
2020年 | 123篇 |
2019年 | 160篇 |
2018年 | 176篇 |
2017年 | 130篇 |
2016年 | 172篇 |
2015年 | 283篇 |
2014年 | 287篇 |
2013年 | 341篇 |
2012年 | 358篇 |
2011年 | 346篇 |
2010年 | 208篇 |
2009年 | 176篇 |
2008年 | 236篇 |
2007年 | 195篇 |
2006年 | 153篇 |
2005年 | 160篇 |
2004年 | 114篇 |
2003年 | 118篇 |
2002年 | 89篇 |
2001年 | 84篇 |
2000年 | 69篇 |
1999年 | 72篇 |
1998年 | 42篇 |
1997年 | 39篇 |
1996年 | 40篇 |
1995年 | 38篇 |
1994年 | 27篇 |
1993年 | 20篇 |
1992年 | 24篇 |
1991年 | 24篇 |
1990年 | 17篇 |
1989年 | 9篇 |
1988年 | 11篇 |
1987年 | 12篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 5篇 |
1983年 | 3篇 |
1982年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有4744条查询结果,搜索用时 640 毫秒
91.
The Frequency and Clinical Significance of IDH1 Mutations in Chinese Acute Myeloid Leukemia Patients
Objective
Mutations in the gene encoding isocitrate dehydrogenease 1 (IDH1) occur in various hematopoietic tumors including acute myeloid leukemia (AML), myeloproliferative neoplasms and myelodysplastic syndromes. IDH1 mutations are significant in both diagnosis and prognosis of these conditions. In the present study we determined the prevalence and clinical significance of IDH1 mutations in 349 samples from newly diagnosed AML patients.Results
Of the 349 AML patient specimens analyzed, 35 (10.03%) were found to have IDH1 mutations including 4 IDH1 R132 mutations and 31 non-R132 mutations. IDH1 non-R132 mutations were largely concentrated within AML-M1 (35.72%, p<0.01). We identified five IDH1 mutations that were novel to AML: (1) c.299 G>A, p.R100Q; (2) c.311G>T, p.G104V; (3) c.322T>C, p.F108L; (4) c.356G>A, p.R119Q; and (5) c.388A>G, p.I130V. In addition, we identified three IDH1 mutations that were previously described in AML. The frequency of IDH1 mutations in AML patients with normal karyotype was 9.9%. IDH1 non-R132 mutations were concurrent with mutations in FLT3-ITD (p<0.01), CEBPA (p<0.01), and NRAS (p<0.01), as well as the overexpression of MN1 (p<0.01) and WT1(p<0.01). The overall survival (OS) in the patients with IDH1 non-R132 mutations compared to patients without IDH1 mutations don''t reach statistically significance (median 521 days vs median: not reached; n.s.).Conclusion
IDH1 non-R132 mutations occurred frequently in newly diagnosed adult Chinese AML patients, and these mutations were associated with genetic alterations. The OS was not influenced by IDH1 non-R132 mutations in the present study. 相似文献92.
Yuanyuan Jiang Guorong Lu Laura R. Trescott Yuning Hou Xiaoqing Guan Shuo Wang Angelique Stamenkovich Joseph Brunzelle Nualpun Sirinupong Chunying Li Zhe Yang 《PloS one》2013,8(12)
NHERF1 is a PDZ adaptor protein that scaffolds the assembly of diverse signaling complexes and has been implicated in many cancers. However, little is known about the mechanism responsible for its scaffolding promiscuity or its ability to bind to multiple targets. Computational studies have indicated that PDZ promiscuity may be attributed to its conformational dynamics, but experimental evidence for this relationship remains very limited. Here we examine the conformational flexibility of the NHERF1 PDZ1 domain using crystal lattice trapping via solving PDZ1 structure of a new crystal form. The structure, together with prior PDZ1 structures of a different space group, reveals that 4 of 11 ligand-interacting residues undergo significant crystal packing-induced structural changes. Most of these residues correspond to the residues involved in allosteric transition when a peptide ligand binds. In addition, a subtle difference in ligand conformations causes the same peptide to bind in slightly different modes in different crystal forms. These findings indicate that substantial structural flexibility is present in the PDZ1 peptide-binding pocket, and the structural substate trapped in the present crystal form can be utilized to represent the conformational space accessible to the protein. Such knowledge will be critical for drug design against the NHERF1 PDZ1 domain, highlighting the continued need for experimentally determined PDZ1-ligand complexes. 相似文献
93.
Qiumei Guan 《Journal of molecular modeling》2013,19(12):5129-5133
When ligands are coordinated to quantum dots (QDs), the ring current of the ligand strongly influences the applications of the QDs, for example in solar cell technology. The Raman spectrum of the ligand can be used to probe and identify ions or measure ion concentrations. Here, we investigated, using a theoretical method, the aromaticities and Raman spectra of CdTe, CdSe, and CdS QDs coordinated with thiosalicylic acid ligands. We found that the aromaticity of the benzene ring in free thiosalicylic acid increased when it was used as a QD ligand. The ring currents of the benzene rings in the CdTe–ligand, CdSe–ligand, and CdS–ligand systems were stronger than the ring current of the benzene ring in free thiosalicylic acid; in other words, the QDs influence the ring current—they enhance the electron transfer rate of the benzene ring. We also discovered that the CdTe–ligand and CdSe–ligand systems have stronger ring currents than the CdS–ligand system. The high electronegativity and vacant d orbital of the sulfur atom influence the ring current of the ligand in the CdS–ligand system. Further, the Raman spectrum of free thiosalicylic acid was different from the spectra of the ligands in the QD–ligand systems: the Raman spectra of COO? in each QD–ligand system was enhanced compared with that of the COO? in free thiosalicylic acid. Figure
Structures and NMR and Raman spectra of QDs coordinated to thiosalicylic acid ligands 相似文献
94.
Yehui Zhou Jing Lan Wei Wang Qin Shi Yang Lan Zhiyi Cheng Honggeng Guan 《Journal of molecular histology》2013,44(5):555-563
E3 ubiquitin ligases regulate a variety of biological processes through the ubiquitin–proteasome system, together with ubiquitin activating enzyme E1 and ubiquitin-conjugating enzyme E2. Previous studies have demonstrated that zinc and ring finger 3 (ZNRF3), which belongs to the E3 ubiquitin ligases family is involved in the Wnt signalling pathway, which plays an important role in causing cancer. However, the expression and function of ZNRF3 in human gastric adenocarcinoma still remains unclear. Immunohistochemical and western blot analysis showed a significant down-regulation of ZNRF3 protein in gastric adenocarcinoma tissues compared with adjacent normal gastric tissues. In addition, there was a correlation between the down-regulation of ZNRF3 and poor tissue differentiation in gastric adenocarcinoma. To investigate the potential function of ZNRF3 in cell proliferation and apoptosis, a gastric cell line SGC7901 was employed. The over-expression of wild-type ZNRF3, which was accomplished by the transient transfection of recombinant pEGFP-ZNRF3 (or empty plasmids as control) into the cell line SGC7901, was confirmed by western blot analysis. Flow-cytometry-based and Cell Counting Kit-8 assays showed that over-expression of wt ZNRF3 induced apoptosis and suppressed proliferation. ZNRF3-overexpressing gastric cells displayed partly attenuated protein levels of beta-catenin and TCF-4 compared with those transfected with the empty plasmid. Our study demonstrates a novel gastric adenocarcinoma suppressor and reveals that ZNRF3 inhibits gastric cancer cell growth and promotes the cell apoptosis by affecting the Wnt/beta-catenin/TCF signalling pathway. 相似文献
95.
Jun-Lin Guan Anna Katharina Simon Mark Prescott Javier A. Menendez Fei Liu Fen Wang Chenran Wang Ernst Wolvetang Alejandro Vazquez-Martin Jue Zhang 《Autophagy》2013,9(6):830-849
Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future. 相似文献
96.
Juanjuan Zhang Fuxin Zhao Qun Fu Min Liang Yi Tong Xiaoling Liu Bei Lin Hui Mi Minglian Zhang Qi-Ping Wei Ling Xue Pingping Jiang Xiangtian Zhou Jun Qin Mo Taosheng Huang Jia Qu Min-Xin Guan 《Mitochondrion》2013,13(6):772-781
Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation. 相似文献
97.
98.
99.
Jiangchao Li Xiaodong Li Yan Li Hong Yang Lijing Wang Yanru Qin Haibo Liu Li Fu Xin-Yuan Guan 《PloS one》2013,8(1)
MicroRNAs (miRNAs) play important roles in the regulation of genes associated with cancer development and progression. By the more deeply characterization of miRNAs’ effect in cancer development, it requires a useful tool to investigate expression and distribution of a miRNA in cancer cells and tissues. To fulfill this application demand, we developed a miRNA in situ hybridization (MISH) approach using the 2′-Fluoro modified miRNA probe in combination with enzyme-labeled fluorescence (ELF) signal amplification approach. MISH was used to study expression of miR-375 in esophageal squamous cell carcinoma (ESCC) cell lines and tissues using a tissue microarray (TMA) containing 300 cases. The results showed that our MISH approach is a practical way to detect expression and distribution of a tested miRNA in both cultured cells and archive tissue sections. MISH results also showed that miR-375 was frequently downregulated in ESCCs, which was significantly associated with advanced clinical stage (p = 0.003) tumor metastasis (p = 0.04) and poor outcome (p = 0.04) of ESCC. Moreover, the accuracy of MISH results could be confirmed by QRT-PCR. Our results demonstrated that MISH is a useful and reliable tool to study miRNA expression in solid tumors. Downregulation of miR-375 can be used as a biomarker to predict the outcome of ESCC. 相似文献
100.