全文获取类型
收费全文 | 3043篇 |
免费 | 255篇 |
国内免费 | 97篇 |
专业分类
耳鼻咽喉 | 11篇 |
儿科学 | 29篇 |
妇产科学 | 27篇 |
基础医学 | 607篇 |
口腔科学 | 136篇 |
临床医学 | 258篇 |
内科学 | 678篇 |
皮肤病学 | 56篇 |
神经病学 | 245篇 |
特种医学 | 16篇 |
外国民族医学 | 1篇 |
外科学 | 148篇 |
综合类 | 193篇 |
预防医学 | 54篇 |
眼科学 | 13篇 |
药学 | 665篇 |
中国医学 | 88篇 |
肿瘤学 | 170篇 |
出版年
2024年 | 8篇 |
2023年 | 36篇 |
2022年 | 40篇 |
2021年 | 108篇 |
2020年 | 72篇 |
2019年 | 80篇 |
2018年 | 84篇 |
2017年 | 90篇 |
2016年 | 91篇 |
2015年 | 117篇 |
2014年 | 156篇 |
2013年 | 350篇 |
2012年 | 160篇 |
2011年 | 179篇 |
2010年 | 156篇 |
2009年 | 143篇 |
2008年 | 151篇 |
2007年 | 123篇 |
2006年 | 130篇 |
2005年 | 130篇 |
2004年 | 125篇 |
2003年 | 109篇 |
2002年 | 84篇 |
2001年 | 85篇 |
2000年 | 40篇 |
1999年 | 54篇 |
1998年 | 72篇 |
1997年 | 59篇 |
1996年 | 45篇 |
1995年 | 45篇 |
1994年 | 41篇 |
1993年 | 28篇 |
1992年 | 23篇 |
1991年 | 18篇 |
1990年 | 30篇 |
1989年 | 7篇 |
1988年 | 6篇 |
1987年 | 14篇 |
1986年 | 9篇 |
1985年 | 23篇 |
1984年 | 8篇 |
1983年 | 14篇 |
1982年 | 10篇 |
1981年 | 9篇 |
1980年 | 8篇 |
1979年 | 9篇 |
1978年 | 6篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1968年 | 2篇 |
排序方式: 共有3395条查询结果,搜索用时 28 毫秒
71.
【目的】研究microRNA-30a-5p(miR-30a-5p)对人宫颈癌Hela细胞上皮-间质转化功能的影响及其相关机制。【方法】宫颈癌Hela细胞株分别转染目的mir的模拟物和阴性对照模拟物,分别以30a-5p组、NC组命名并标记细胞。同时,以未经过处理的Hela细胞作为对照(Control组)。分别用逆转录-聚合酶链反应法检测各组宫颈癌细胞的miR-30a-5p含量。Transwell实验检测3组细胞迁移能力和侵袭能力。Western-blot法检测3组细胞神经-钙粘素(N-cadherin)、α-连环蛋白(α-Catenin)和泛素水解酶22(USP22)表达水平。运用生物信息学方法预测miR-30a-5p的靶基因。采用Western blot法检测USP22过表达对miR-30a-5p抑制EMT的拮抗作用。双荧光素酶实验检测miR-30a-5p与USP22的关系。建立皮下移植瘤模型观察miR-30a-5p的体内作用。【结果】30a-5p组宫颈癌细胞miR-30a-5p的表达水平明显上调,表达水平为Control组的853.82(862.26~843.11)倍(P<0.01)。30a-5p组侵袭细胞数量8.17(8.32~8.03)明显低于Control组(P<0.01)。30a-5p组细胞N-cadherin蛋白的细胞内含量明显下降,α-Catenin蛋白的细胞内含量明显上升,USP22蛋白表达量明显降低。合并USP22过表达处理的30a-5p组宫颈癌细胞中N-cadherin蛋白表达量明显升高,α-Catenin蛋白表达量明显降低。双荧光素酶检验结果显示USP22为miR-30a-5p的下游靶基因(P<0.01)。30a-5p组皮下移植瘤明显小于Control组(P<0.01)。与Control组肿瘤组织相比,30a-5p组肿瘤组织miR-30a-5p的相对含量升高,USP22蛋白含量降低,N-cadherin蛋白的含量降低,α-Catenin蛋白含量升高。【结论】miR-30a-5p在宫颈癌Hela细胞中,可能通过靶向识别下游靶基因USP22,进而抑制其翻译。最终实现对宫颈癌细胞EMT过程的抑制。 相似文献
72.
《HIV clinical trials》2013,14(1):13-19
AbstractPurpose: The purpose of our study was to evaluate the efficacy of indinavir (IDV) in a twice daily dosing regimen with coadministration of 100 mg ritonavir (RTV) and to explore the influence of plasma drug levels in the rate of virologic response. Method: We performed a prospective study of 59 patients who switched to a salvage regimen with two nucleoside analogs plus the combination of 100 mg RTV plus 800 mg IDV twice daily. Pharmacokinetics of IDV and RTV were assessed in 11 patients. Results: Previous antiretroviral exposure was 44 months, and 78% and 39% of patients had previously failed regimens with either IDV or RTV. Median CD4 count was 248 × 106/L and HIV load was 3.9 log10 copies/mL. The median number of mutations in the protease gene was 9 (3–14), predominantly at residues 82 (53%), 90 (42%), and 46 (32%). After 24 weeks, 61% of patients had a viral load decrease greater than 1 log10, and 38% had a viral load below 50 copies/mL. Nephrolitiasis, hematuria, or flank pain was observed in 13 patients (22%), leading to withdrawal in six cases (10%). IDV trough levels were well above the IC95 (median 1.75 mg/L, interquartile range 1.07-2.57), but RTV trough levels were below the IC95 in 88% of patients. There was a close correlation between higher peak levels of IDV, virological response, and renal toxicity. Conclusion: RTV/IDV 100/800 mg in a twice daily dosing regimen is associated with a significant virological response in patients with antiretroviral treatment failure. The correlation between plasma drug levels, toxicity, and response suggests the usefulness of individualized drug monitoring. 相似文献
73.
A serine protease homologue Bombyx mori scarface induces a short and fat body shape in silkworm 下载免费PDF全文
R.‐X. Wang X.‐L. Tong T.‐T. Gai C.‐L. Li L. Qiao H. Hu M.‐J. Han Z.‐H. Xiang C. Lu F.‐Y. Dai 《Insect molecular biology》2018,27(3):319-332
Body shape is one of the most prominent and basic characteristics of any organism. In insects, abundant variations in body shape can be observed both within and amongst species. However, the molecular mechanism underlying body shape fine‐tuning is very complex and has been largely unknown until now. In the silkworm Bombyx mori, the tubby (tub) mutant has an abnormal short fat body shape and the abdomen of tub larvae expands to form a fusiform body shape. Morphological investigation revealed that the body length was shorter and the body width was wider than that of the Dazao strain. Thus, this mutant is a good model for studying the molecular mechanisms of body shape fine‐tuning. Using positional cloning, we identified a gene encoding the serine protease homologue, B. mori scarface (Bmscarface), which is associated with the tub phenotype. Sequence analysis revealed a specific 312‐bp deletion from an exon of Bmscarface in the tub strain. In addition, recombination was not observed between the tub and Bmscarface loci. Moreover, RNA interference of Bmscarface resulted in the tub‐like phenotype. These results indicate that Bmscarface is responsible for the tub mutant phenotype. This is the first study to report that mutation of a serine protease homologue can induce an abnormal body shape in insects. 相似文献
74.
《Journal of investigative surgery》2013,26(4):285-296
Tolmetin sodium in a hyaluronic acid carrier (tolmetin-HA) was previously shown to reduce adhesion formation and alter the kinetics and levels of cellular influx into the peritoneal cavity after surgery. In this study, the effect of tolmetin-HA on the level of protease activity in macrophage-conditioned media was determined. The level of collagenase activity in macrophage-conditioned media was supressed at 12 and 24 h after administration of tolmetin-HA. Alternatively, the peak level of elastase activity measured in macrophage-conditioned media was unchanged after tolmetin-HA treatment, but the kinetics of expression of maximal protease activity was delayed from 12 h in the control surgical rabbits to 24 h in tolmetin-HA-treated rabbits. Elevated plasminogen activator activity was detected in acid-treated conditioned media from the tolmetin-HA-treated rabbits when compared to control levels. However, no alteration in the level of plasminogen activator inhibitor activity was present in conditioned media of macrophages harvested from tolmetin-HA-treated rabbits compared to controls. These data suggest that tolmetin-HA treatment altered the levels of neutral protease activity secreted by postsurgical macrophages and may therefore elevate the fibrinolytic potential of the peritoneal cavity after surgery. 相似文献
75.
Leila Akkari Vasilena Gocheva Jemila C. Kester Karen E. Hunter Marsha L. Quick Lisa Sevenich Hao-Wei Wang Christoph Peters Laura H. Tang David S. Klimstra Thomas Reinheckel Johanna A. Joyce 《Genes & development》2014,28(19):2134-2150
During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function. 相似文献
76.
77.
Duchenne muscular dystrophy (DMD) is caused by the production of a non‐functional dystrophin gene product and a failure to accumulate functional dystrophin protein in muscle cells. This leads to membrane instability, loss of Ca2+ homoeostasis and widespread cellular injury. Associated with these changes are increased protease activities in a variety of proteolytic systems. As such, there have been numerous investigations directed towards determining the therapeutic potential of protease inhibition. In this review, evidence from genetic and/or pharmacological inhibition of proteases as a treatment strategy for DMD is systematically evaluated. Specifically, we review the potential roles of calpain, proteasome, caspase, matrix metalloproteinase and serine protease inhibition as therapeutic approaches for DMD. We conclude that despite early results to the contrary, inhibition of calpain proteases is unlikely to be successful. Conversely, evidence suggests that inhibition of proteasome, matrix metalloproteinases and serine proteases does appear to decrease disease severity. An important caveat to these conclusions, however, is that the fundamental cause of DMD, dystrophin deficiency, is not corrected by this strategy. Hence, this should not be viewed as a cure, but rather, protease inhibitors should be considered for inclusion in a therapeutic cocktail. Physiological Relevance. Selective modulation of protease activity has the potential to profoundly change intracellular physiology resulting in a possible treatment for DMD. However, alteration of protease activities could also lead to worsening of disease progression by promoting the accumulation of substrates in the cell. The balance of benefit and potential damage caused by protease inhibition in human DMD patients is largely unexplored. 相似文献
78.
《Expert opinion on therapeutic patents》2013,23(3):311-337
Introduction: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. Areas covered: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. Expert opinion: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 – 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials. 相似文献
79.
Wing Chow Prina Donga Aurélie Côté-Sergent Carmine Rossi Patrick Lefebvre Marie-Hélène Lafeuille 《Current medical research and opinion》2020,36(8):1313-1323
Abstract
Objective
Evidence suggests that integrase strand transfer inhibitors (INSTIs) are associated with greater weight gain than other antiretrovirals. This real-world study compares weight/body mass index (BMI) change between insured US patients with human immunodeficiency virus (HIV-1) initiating a protease inhibitor (PI) or INSTI. 相似文献80.
Erik W. Martin Marguerite S. Buzza Kathryn H. Driesbaugh Shihui Liu Yolanda M. Fortenberry Stephen H. Leppla Toni M. Antalis 《Oncotarget》2015,6(32):33534-33553
The membrane-anchored serine proteases are a unique group of trypsin-like serine proteases that are tethered to the cell surface via transmembrane domains or glycosyl-phosphatidylinositol-anchors. Overexpressed in tumors, with pro-tumorigenic properties, they are attractive targets for protease-activated prodrug-like anti-tumor therapies. Here, we sought to engineer anthrax toxin protective antigen (PrAg), which is proteolytically activated on the cell surface by the proprotein convertase furin to instead be activated by tumor cell-expressed membrane-anchored serine proteases to function as a tumoricidal agent. PrAg''s native activation sequence was mutated to a sequence derived from protein C inhibitor (PCI) that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS. PrAg-PCIS was resistant to furin cleavage in vitro, yet cytotoxic to multiple human tumor cell lines when combined with FP59, a chimeric anthrax toxin lethal factor-Pseudomonas exotoxin fusion protein. Molecular analyses showed that PrAg-PCIS can be cleaved in vitro by several serine proteases including the membrane-anchored serine protease testisin, and mediates increased killing of testisin-expressing tumor cells. Treatment with PrAg-PCIS also potently attenuated the growth of testisin-expressing xenograft tumors in mice. The data indicates PrAg can be engineered to target tumor cell-expressed membrane-anchored serine proteases to function as a potent tumoricidal agent. 相似文献