全文获取类型
收费全文 | 2242篇 |
免费 | 225篇 |
国内免费 | 177篇 |
出版年
2023年 | 29篇 |
2022年 | 38篇 |
2021年 | 78篇 |
2020年 | 91篇 |
2019年 | 110篇 |
2018年 | 100篇 |
2017年 | 86篇 |
2016年 | 103篇 |
2015年 | 92篇 |
2014年 | 174篇 |
2013年 | 196篇 |
2012年 | 125篇 |
2011年 | 149篇 |
2010年 | 117篇 |
2009年 | 109篇 |
2008年 | 123篇 |
2007年 | 126篇 |
2006年 | 113篇 |
2005年 | 92篇 |
2004年 | 86篇 |
2003年 | 73篇 |
2002年 | 59篇 |
2001年 | 39篇 |
2000年 | 34篇 |
1999年 | 35篇 |
1998年 | 30篇 |
1997年 | 30篇 |
1996年 | 21篇 |
1995年 | 27篇 |
1994年 | 16篇 |
1993年 | 13篇 |
1992年 | 11篇 |
1991年 | 10篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 5篇 |
1987年 | 8篇 |
1986年 | 3篇 |
1985年 | 23篇 |
1984年 | 10篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 7篇 |
1980年 | 6篇 |
1979年 | 7篇 |
1978年 | 4篇 |
1976年 | 5篇 |
1975年 | 1篇 |
1974年 | 2篇 |
1973年 | 1篇 |
排序方式: 共有2644条查询结果,搜索用时 15 毫秒
71.
Manaswini Jagadeb Surya Narayan Rath 《Journal of biomolecular structure & dynamics》2019,37(13):3388-3398
The emergence of multidrug-resistant Mycobacterium tuberculosis (M.tb) has become one of the major hurdles in the treatment of tuberculosis (TB). Drug-resistant M.tb has evolved with various strategies to avoid killing by the anti-tubercular drugs. Thus, there is a rising need to develop effective anti-TB drugs to improve the treatment of these strains. Traditional drug design approach has earned little success due to time and the cost involved in the process of development of anti-infective drugs. Numerous reports have demonstrated that several mutations in the drug target sites cause emergence of drug-resistant M.tb strains. In this study, we performed computational mutational analysis of M.tb inhA, fabD, and ahpC genes, which are the primary targets for first-line isoniazid (INH) drug. In silico virtual drug screening was performed to identify the potent drugs from a ChEMBL compound library to improve the treatment of INH-resistant M.tb. Further, these compounds were analyzed for their binding efficiency against active drug binding cavity of M.tb wild-type and mutant InhA, FabD and AhpC proteins. The drug efficacy of predicted lead compounds was verified by molecular docking using M.tb wild-type and mutant InhA, FabD and AhpC protein template models. Different in silico and pharmacophore analysis predicted three potent lead compounds with better drug-like properties against both M.tb wild-type and mutant InhA, FabD, and AhpC proteins as compared to INH drug, and thus may be considered as effective drugs for the treatment of INH-resistant M.tb strains. We hypothesize that this work may accelerate drug discovery process for the treatment of drug-resistant TB.
Communicated by Ramaswamy H. Sarma 相似文献
72.
Xue Li Xi Lv Yanping Lin Junfeng Zhen Cao Ruan Wei Duan Yue Li Jianping Xie 《Journal of cellular biochemistry》2019,120(8):12197-12207
The typical two-component regulatory systems (TCSs), consisting of response regulator and histidine kinase, play a central role in survival of pathogenic bacteria under stress conditions such as nutrient starvation, hypoxia, and nitrosative stress. A total of 11 complete paired two-component regulatory systems have been found in Mycobacterium tuberculosis, including a few isolated kinase and regulatory genes. Increasing evidence has shown that TCSs are closely associated with multiple physiological process like intracellular persistence, pathogenicity, and metabolism. This review gives the two-component signal transduction systems in M. tuberculosis and their signal transduction roles in adaption to the environment. 相似文献
73.
The overexpression of P-glycoprotein plays an important role in the process of multidrug resistance (MDR). P-gp inhibitors are one of the effective strategies to reverse tumor MDR. Novel P-gp inhibitors with phthalazinone scaffolds were designed, synthesized and evaluated. Compound 26 was found to be the most promising for further study. Compound 26 possessed high potency (EC50 = 46.2 ± 3.5 nM) and low cytotoxicity.26 possessed high MDR reversal activity towards doxorubicin-resistant K56/A02 cells. Reversal fold (RF) value reach to 44.26. 26 also increased accumulation of doxorubicin (DOX or ADM) or other MDR-related anticancer drugs with different structures. In conclusion, compound 26 deserves more research for its good features as P-gp inhibitor. 相似文献
74.
结核分枝杆菌感染引起的结核病疫情依然严峻。感染的结核菌可分泌一系列效应分子调控、干扰和逃逸宿主免疫。本文综述蛋白酪氨酸磷酸酶PtpA在结核菌感染中发挥的重要作用:经多条途径抑制宿主天然免疫、细胞凋亡及吞噬体-溶酶体融合、调控宿主能量代谢等逃逸免疫杀伤。作为候选药物靶标,靶向PtpA的抑制剂设计、筛选及药物研发较为迟缓,因为PtpA与宿主蛋白酪氨酸磷酸酶hLMW-PTP具有较高一致性。为了进一步探索靶向该分子的更佳途径,分析了ptpA基因转录及PtpA蛋白分泌方面的研究进展及存在问题,为靶向PtpA的其他途径提供参考。 相似文献
75.
Shima Hadifar Abolfazl Fateh Mohammad Hadi Yousefi Seyed Davar Siadat Farzam Vaziri 《Journal of cellular physiology》2019,234(3):2104-2111
Today, diagnosis, vaccination, and treatment of tuberculosis (TB) remain major clinical challenges. Therefore, an introduction of new diagnostic measures and biomarkers is necessary to improve infection control. The ideal biomarker for TB infection can be defined as a host or pathogen-derived biomolecule, which is potent for identifying infection and determining its clinical stage. Exosomes, defined as cell-derived nanovesicles released into biological fluids, are involved in cell–cell communication and immune modulation. These vesicles have emerged as a new platform for improving the clinical diagnosis and prognosis of different infectious diseases and cancers. The role of these nanovehicles, as alternative biomarkers for the improvement of TB diagnosis and treatment, has been demonstrated in a significant body of literature. In this review, we summarized recent progress in the clinical application of exosome-based biomarkers in TB infection. 相似文献
76.
77.
目的 研究抗酸染色结核分枝杆菌(简称结核杆菌)阳性痰涂片标本直接用于耐药性检测的方法。方法 对18株临床分离培养的结核杆菌用利福平进行药敏试验。分别提取菌株DNA和与之对应的痰涂片标本的菌体DNA,用聚合酶链反应(PcR)扩增ropB基因后进行固相杂交和核酸测序检测结核杆菌的耐药性。结果 18株结核杆菌中有12株对利福平耐药。经PCR扩增的ropB片段与探针杂交后,敏感菌株未发现rpoB基因的突变,自耐药菌株提取的DNA中rpoB突变体的检出率为100%(12/12),痰涂片提取DNA的检出率为91.7%(11/12)。所有耐药菌株DNA与痰涂片DNA核酸测序结果相吻合,都有rpoB基因核心区域碱基突变。结论 抗酸染色痰涂片阳性标本可直接用于检测结核杆菌利福平耐药基因rpoB突变体,是一种值得临床实验室推广使用的耐药菌诊断方法。 相似文献
78.
不同抗性品种稻田捕食性节肢动物的群落结构 总被引:4,自引:1,他引:3
对3个类型稻田早、晚稻捕食性节肢动物群落调查,结果表明:共有捕食性节肢动物67种,丰富度以蜘蛛高于捕食性昆虫类;早稻高于晚稻;中抗品种高于抗虫和感虫品种。早稻以皿蛛科Linyphiidae的食虫沟瘤蛛UlmmeliatainsecticepesBoes.etStr.占优势,晚稻则以狼蛛科Lycosidae的相对丰盛度最高。早稻捕食性天敌数量动态以中抗品种峰期最长;感性样田中天敌平均密度与中抗样田差异不显著,与抗虫品种差异显著;捕食性节肢动物多样性随着品种抗性的增强呈降低趋势,优势度随着品种抗性的增强而增强。晚稻3个品种样田中天敌的平均密度差异不显著;各品种样田的多样性明显高于早稻,且波动幅度小于早稻,品种之间多样性差异较小,晚稻群落可能具有较高的稳定性。 相似文献
79.
80.
为探索硫醇乙酰基转移酶(mycothiol acetyltransferase,MshD)在结核分枝杆菌中的生物学特性,本实验利用噬菌体为载体的同源重组技术,构建结核分枝杆菌mshD基因敲除株、mshD基因回补株,用实时定量聚合酶链反应(real time-quantitative polymerase chain reaction, RT-qPCR)对所构建的菌株进行验证。分别收集H37Ra野生株、mshD基因敲除株、mshD基因回补株对数生长期菌液各5 mL, 离心收集菌体并培养,以观察菌落形态、生物膜形成及生长曲线测定;用5 mmol/L H2O2、0.05% SDS,50 ℃热激及低氧条件下分别处理基因敲出菌株和野生菌株,将菌液进行10倍梯度稀释,培养4~6周后检测抗胁迫能力并计算存活率。结果显示, 与野生株H37Ra相比,mshD基因敲除株菌落褶皱减少且菌落偏小,生长趋势较为缓慢;生物膜形成所需时间增长且褶皱明显减少;抗逆能力下降,存活率略低于野生株和回补株。揭示了mshD基因对结核分枝杆菌的生长具有重要作用,为进一步揭示该基因的功能和作用机制奠定了基础。 相似文献