全文获取类型
收费全文 | 1677篇 |
免费 | 132篇 |
国内免费 | 60篇 |
出版年
2023年 | 7篇 |
2022年 | 35篇 |
2021年 | 67篇 |
2020年 | 37篇 |
2019年 | 57篇 |
2018年 | 53篇 |
2017年 | 41篇 |
2016年 | 73篇 |
2015年 | 107篇 |
2014年 | 116篇 |
2013年 | 122篇 |
2012年 | 151篇 |
2011年 | 123篇 |
2010年 | 84篇 |
2009年 | 70篇 |
2008年 | 70篇 |
2007年 | 84篇 |
2006年 | 66篇 |
2005年 | 75篇 |
2004年 | 56篇 |
2003年 | 57篇 |
2002年 | 49篇 |
2001年 | 40篇 |
2000年 | 20篇 |
1999年 | 35篇 |
1998年 | 19篇 |
1997年 | 9篇 |
1996年 | 14篇 |
1995年 | 13篇 |
1994年 | 16篇 |
1993年 | 11篇 |
1992年 | 11篇 |
1991年 | 13篇 |
1990年 | 6篇 |
1989年 | 9篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 11篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1981年 | 3篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1975年 | 3篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1970年 | 2篇 |
排序方式: 共有1869条查询结果,搜索用时 15 毫秒
961.
Jie Li Peng Xu Di Wu Minjie Guan Xuanwen Weng Yongzhen Lu Yuwei Zeng Rongchang Chen 《Cell death & disease》2021,12(8)
Hypoxia promotes inflammation in the tumor microenvironment. Although hypoxia-inducible factor 1α (HIF1α) is a master modulator of the response to hypoxia, the exact mechanisms through which HIF1α regulates the induction of inflammation remain largely unclear. Using The Cancer Genome Atlas Lung Squamous Cell Carcinoma (TCGA-LUSC) database, we divided patients with LUSC into two groups based on low or high HIF1α expression. After analyzing the differentially expressed genes in these two groups, we found that HIF1α was positively correlated with interleukin 1A (IL1A) and IL6 expression. Our in vitro study showed that hypoxic stress did not induce IL1A or IL6 expression in tumor cells or macrophages but dramatically enhanced their expression when co-cultured with tumor cells. We then investigated the effect of tumor-derived exosomes on macrophages. Our data suggested that the changes in miR101 in the tumor-derived exosomes played an important role in IL1A and IL6 expression in macrophages, although the hypoxic stress did not change the total amount of exosome secretion. The expression of miR101 in exosomes was suppressed by hypoxic stress, since depletion of HIF1α in tumor cells recovered the miR101 expression in both tumor cells and exosomes. In vitro, miRNA101 overexpression or uptake enriched exosomes by macrophages suppressed their reprogramming into a pro-inflammatory state by targeting CDK8. Injection of miR101 into xenografted tumors resulted in the suppression of tumor growth and macrophage tumor infiltration in vivo. Collectively, this study suggests that the HIF1α-dependent suppression of exosome miR101 from hypoxic tumor cells activates macrophages to induce inflammation in the tumor microenvironment.Subject terms: Small-cell lung cancer, Small-cell lung cancer 相似文献
962.
T-cell receptors (TCRs) are proteins that recognize peptides from foreign proteins bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This interaction enables the T cells to initiate a cell-mediated immune response to terminate cells displaying the foreign peptide on their MHC. Naturally occurring TCRs have high specificity but low affinity toward the peptide-MHC (pepMHC) complex. This prevents the usage of solubilized TCRs for diagnosis and treatment of viral infections or cancers. Efforts to enhance the binding affinity of several TCRs have been reported in recent years, through randomized libraries and in vitro selection. However, there have been no reported efforts to enhance the affinity via structure-based design, which allows more control and understanding of the mechanism of improvement. Here, we have applied structure-based design to a human TCR to improve its pepMHC binding. Our design method evolved based on iterative steps of prediction, testing, and generating more predictions based on the new data. The final design function, named ZAFFI, has a correlation of 0.77 and average error of 0.35 kcal/mol with the binding free energies of 26 point mutations for this system that we measured by surface plasmon resonance (SPR). Applying the filter that we developed to remove nonbinding predictions, this correlation increases to 0.85, and the average error decreases to 0.3 kcal/mol. Using this algorithm, we predicted and tested several point mutations that improved binding, with one giving over sixfold binding improvement. Four of the point mutations that improved binding were then combined to give a mutant TCR that binds the pepMHC 99 times more strongly than the wild-type TCR. 相似文献
963.
Jian Wei Sun Min De Jin Chun Jiang Zhou Qing Kai Yang Man Li Weng Lin De Duan Pu Xu Jia Hai Ma Bin Wang 《Plant Molecular Biology Reporter》2005,23(3):251-262
Twenty-sevenPorphyra lines from 5 classes, including lines widely used in China, wild lines, and lines introduced to China from abroad in recent
years, were screened by means of amplified fragment length polymorphism (AFLP) with 24 primer pairs. From the generated AFLP
products, 13 bands that showed stable and repeatable AFLP patterns amplified by primer pairs M-CGA/E-AA and M-CGA/E-TA were
scored and used to develop the DNA fingerprints of the 27Porphyra lines. Moreover, the DNA fingerprinting patterns were converted into computer language expressed with digitals 1 and 0, which
represented the presence (numbered as 1) or absence (numbered as 0) of the corresponding band. On the basis of these results,
computerized AFLP DNA fingerprints were constructed in which each of the 27Porphyra lines has its unique AFLP fingerprinting pattern and can be easily distinguished from others. Software called PGI-AFLP (Porphyra germ-plasm identification-AFLP) was designed for identification of the 27Porphyra lines. In addition, 21 specific AFLP markers from 15Porphyra lines were identified; 6 AFLP markers from 4Porphyra lines were sequenced, and 2 of them were successfully converted into SCAR (sequence characterized amplification region) markers.
The developed AFLP DNA fingerprinting and specific molecular markers provide useful ways for the identification, classification,
and resource protection of thePorphyra lines. 相似文献
964.
965.
Wen Xu Yiming Mu Jiajun Zhao Dalong Zhu Qiuhe Ji Zhiguang Zhou Bin Yao Anhua Mao Samuel S. Engel Bin Zhao Yan Bi Longyi Zeng Xingwu Ran Juming Lu Linong Ji Wenying Yang Weiping Jia Jianping Weng 《中国科学:生命科学英文版》2017,60(3):225-238
Despite the current guideline’s recommendation of a timely stepwise intensification therapy, the “clinical inertia”, termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia. 相似文献
966.
967.
ATLAS: A database linking binding affinities with structures for wild‐type and mutant TCR‐pMHC complexes
下载免费PDF全文
![点击此处可从《Proteins》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Tyler Borrman Jennifer Cimons Michael Cosiano Michael Purcaro Brian G. Pierce Brian M. Baker Zhiping Weng 《Proteins》2017,85(5):908-916
The ATLAS (Altered TCR Ligand Affinities and Structures) database ( https://zlab.umassmed.edu/atlas/web /) is a manually curated repository containing the binding affinities for wild‐type and mutant T cell receptors (TCRs) and their antigens, peptides presented by the major histocompatibility complex (pMHC). The database links experimentally measured binding affinities with the corresponding three dimensional (3D) structures for TCR‐pMHC complexes. The user can browse and search affinities, structures, and experimental details for TCRs, peptides, and MHCs of interest. We expect this database to facilitate the development of next‐generation protein design algorithms targeting TCR‐pMHC interactions. ATLAS can be easily parsed using modeling software that builds protein structures for training and testing. As an example, we provide structural models for all mutant TCRs in ATLAS, built using the Rosetta program. Utilizing these structures, we report a correlation of 0.63 between experimentally measured changes in binding energies and our predicted changes. Proteins 2017; 85:908–916. © 2016 Wiley Periodicals, Inc. 相似文献
968.
Xueting Zou Mengwei Weng Xu Ji Rong Guo Weijiang Zheng Wen Yao 《Journal of microbiology (Seoul, Korea)》2017,55(9):703-710
In China, antimicrobials and copper are used extensively as growth-promoting agents for piglets. This study aimed to characterize the role of in-feed copper in the emergence of copper-tolerant and antibiotic-resistant Enterococcus and Lactobacillus isolates in Chinese pig farms. Feces of the same eight piglets from four litters at 7 and 55 days old and their mothers were traced in order to isolate Enterococcus spp. and Lactobacillus spp.. The minimum inhibitory concentrations of 10 antimicrobials and copper sulfate were determined using an agar dilution method. The feed levels of Cu2+ for lactating sows, suckling piglets, and weaned piglets were 6, 177, and 18 mg/kg, respectively. All the 136 Enterococcus isolates were sensitive to vancomycin; and the resistance rates to penicillin, enrofloxacin, and high level streptomycin resistance increased significantly after weaning. For the 155 Lactobacillus isolates, the resistance rates to ampicillin, chloramphenicol, tetracycline, and enrofloxacin were significantly higher in weaned piglets. The ratios of copper tolerant Enterococcus and Lactobacillus isolates both increased significantly after weaning (P < 0.05). A phenotypic correlation was observed after classifying the isolates into two groups (CuSO4 MIC50 < 16 or ≧16 for enterococci; CuSO4 MIC50 < 12 or ≧12 for lactobacilli) and comparing the antimicrobial-resistant percentage of two groups. On species level, a significant increase of E. faecalis to enrofloxacin was observed in line with the increase of copper MIC (P < 0.05). The findings revealed the changes of the antibiotic resistance and copper tolerance level of enterococci and lactobacilli between suckling and weaned piglets and demonstrated that there might be a strong association between in-feed copper and increased antibiotic resistance in enterococci and lactobacilli in Chinese intensive swine farms. 相似文献
969.
Lien-Chen Wu Yi-Jie Kuo Fu-Wen Sun Chia-Hsien Chen Chang-Jung Chiang Pei-Wei Weng Yang-Hwei Tsuang Yi-You Huang 《Cell and tissue banking》2017,18(3):383-396
Recent advances in tissue engineering have led to potential new strategies, especially decellularization protocols from natural tissues, for the repair, replacement, and regeneration of intervertebral discs. This study aimed to validate our previously reported method for the decellularization of annulus fibrosus (AF) tissue and to quantify potentially antigenic α-Gal epitopes in the decellularized tissue. Porcine AF tissue was decellularized using different freeze–thaw temperatures, chemical detergents, and incubation times in order to determine the optimal method for cell removal. The integrity of the decellularized material was determined using biochemical and mechanical tests. The α-Gal epitope was quantified before and after decellularization. Decellularization with freeze–thaw in liquid nitrogen, an ionic detergent (0.1% SDS), and a 24 h incubation period yielded the greatest retention of GAG and collagen relative to DNA reduction when tested as single variables. Combined, these optimal decellularization conditions preserved more GAG while removing the same amount of DNA as the conditions used in our previous study. Components and biomechanical properties of the AF matrix were retained. The decellularized AF scaffold exhibited suitable immune-compatibility, as evidenced by successful in vivo remodeling and a decrease in the α-Gal epitope. Our study defined the optimal conditions for decellularization of porcine AF tissues while preserving the biological composition and mechanical properties of the scaffold. Under these conditions, immunocompatibility was evidenced by successful in vivo remodeling and reduction of the α-Gal epitope in the decellularized material. Decellularized AF scaffolds are potential candidates for clinical applications in spinal surgery. 相似文献
970.
Yupeng Pan Xinjing Liang Meiling Gao Hanqiang Liu Huanwen Meng Yiqun Weng Zhihui Cheng 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2017,130(3):573-586