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991.
Xiaodong Ma Lei Xu Jiayi Cao Yubo Zhou Jia Li Tao Liu Yongzhou Hu 《Chemical biology & drug design》2014,84(5):497-504
A series of novel di‐ and tripeptidyl epoxyketone derivatives composed of β‐amino acids were designed, synthesized and evaluated for their proteasome inhibitory activities and anti‐proliferation activities against two multiple myeloma cell lines RPMI 8226 and NCI‐H929 and normal cells (peripheral blood mononucleated cells). Among these tested compounds, tripeptidyl analogues showed much more potent activities than dipeptides, and four tripeptidyl compounds exhibited proteasome inhibitory activities with IC50 values ranging from 0.97 ± 0.05 to 1.85 ± 0.11 μm . In addition, all the four compounds showed anti‐proliferation activities with IC50 values at low micromolar levels against two multiple myeloma cell lines and weak activities against normal cells. Furthermore, Western blot analysis was performed to verify the proteasome inhibition induced by compounds 21d and 21e . All the experimental results validated that the β‐amino acid building block has the potential for the development of proteasome inhibitors. 相似文献
992.
Yangling Li Peihua LuoJincheng Wang Jiabin DaiXiaochun Yang Honghai WuBo Yang Qiaojun He 《Toxicology and applied pharmacology》2014
Combretastatin A-4 (CA-4) has already entered clinical trials of solid tumors over ten years. However, the limited anticancer activity and dose-dependent toxicity restrict its clinical application. Here, we offered convincing evidence that CA-4 induced autophagy in various cancer cells, which was demonstrated by acridine orange staining of intracellular acidic vesicles, the degradation of p62, the conversion of LC3-I to LC3-II and GFP-LC3 punctate fluorescence. Interestingly, CA-4-mediated apoptotic cell death was further potentiated by pretreatment with autophagy inhibitors (3-methyladenine and bafilomycin A1) or small interfering RNAs against the autophagic genes (Atg5 and Beclin 1). The enhanced anticancer activity of CA-4 and 3-MA was further confirmed in the SGC-7901 xenograft tumor model. These findings suggested that CA-4-elicited autophagic response played a protective role that impeded the eventual cell death while autophagy inhibition was expected to improve chemotherapeutic efficacy of CA-4. Meanwhile, CA-4 treatment led to phosphorylation/activation of JNK and JNK-dependent phosphorylation of Bcl-2. Importantly, JNK inhibitor or JNK siRNA inhibited autophagy but promoted CA-4-induced apoptosis, indicating a key requirement of JNK-Bcl-2 pathway in the activation of autophagy by CA-4. We also identified that pretreatment of Bcl-2 inhibitor (ABT-737) could significantly enhance anticancer activity of CA-4 due to inhibition of autophagy. Taken together, our data suggested that the JNK-Bcl-2 pathway was considered as the critical regulator of CA-4-induced protective autophagy and a potential drug target for chemotherapeutic combination. 相似文献
993.
Lack of association between lysyl oxidase-like 1 polymorphisms and primary open angle glaucoma:a meta-analysis 下载免费PDF全文
Wen Sun Yan Sheng Yu Weng Chun-Xiao Xu Susan E.I. Williams Yu-Tao Liu Michael A. Hauser R. Rand Allingham Ming-Juan Jin Guang-Di Chen 《国际眼科》2014,7(3):550-556
AIM: To study the associations between lysyl oxidase-like 1 (LOXL1) polymorphisms and primary open angle glaucoma (POAG) remain inconsistent. In this study, we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG risk.METHODS: Published literature from PubMed and other databases were retrieved. All studies evaluating the association between LOXL1 polymorphisms (rs2165241, rs1048661, rs3825942) and POAG risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model.RESULTS: Twelve studies were identified as eligible articles, with thirteen (2098 cases and 16 473 controls), thirteen (1795 cases and 2916 controls) and sixteen population cohorts (2456 cases and 2846 controls) for the association of rs2165241, rs1048661 and rs3825942 with POAG risk respectively. Overall analyses showed no association between each LOXL1 polymorphism and POAG risk, and the negative associations were remained when the subjects were stratified as Caucasian and Asian. The heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations (TC vs CC:OR, 0.79, 95%CI:0.63-0.99), and rs1048661 was associated with increased POAG risk in hospital-based populations in a dominant model (TT vs CC+CT:OR, 1.23, 95%CI:1.01-1.50); however, these associations were not found in population-based subjects.CONCLUSION: This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG risk. Given the limited sample size, the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation. 相似文献
994.
工业自动化控制技术的广泛运用和海量制造过程数据的收集和分析,为现代中药制药工艺品质的大幅提升提供了宝贵的数据和信息资源。因此在中药制药企业建立数据集成与管理系统变得非常重要,它将使得工厂生产数据的收集、保存、分析、展示和交流变得简单、高效。通过数据集成、数据挖掘、数据可视化等技术的综合运用,可以打破数据孤岛,整合所有数据,提取出有用信息,并发现和沉淀生产知识,最终提高生产过程质量。该文分析了中药制药过程有关工业大数据分析的若干关键技术,重点就数据集成、数据挖掘与数据可视化技术进行了具体探讨。该文结合了生脉注射液生产历史数据,进行了数据挖掘与可视化实例分析,并展望了数据可视化技术在中药数字制药中的前景。 相似文献
995.
目的探究蛋白激酶抑制剂对木犀草素与葡萄糖醛酸结合的影响。方法分别将不同浓度的蛋白激酶抑制剂(姜黄素和钙感光蛋白C)与LS174T细胞共孵育1 h后裂解细胞,获得的细胞S9成分与木犀草素进行体外孵育,用高效液相色谱法测定孵育液中葡萄糖醛酸结合产物。通过Real-time PCR和Western blot分别测定处理后的LS174T细胞中UGT1A在mRNA水平和蛋白水平的表达变化。结果木犀草素与经蛋白激酶抑制剂处理后的细胞共孵育,其葡萄糖醛酸结合受到抑制。而Real-time PCR和Western blot均表明,蛋白激酶抑制剂对UGT1A的表达无影响。结论蛋白激酶抑制剂可抑制木犀草素与葡萄糖醛酸的结合,而这种抑制作用是间接的。蛋白激酶抑制剂很可能通过调控UGTs磷酸化修饰而改变UGTs活性进而导致木犀草素与葡萄糖醛酸结合减少。 相似文献
996.
该文研究生脉注射液中主要成分人参皂苷Rg1和Rb1在心肌缺血大鼠体内的药动学过程及其诱导体内NO释放效应的药动学-药效学(PK-PD)结合模型。以大鼠皮下注射异丙肾上腺素(ISO)制备心肌缺血模型。模型大鼠静脉给予生脉注射液(10.8 mL·kg-1),于给药后不同时间点采集大鼠血清,测定血清中人参皂苷Rg1和Rb1的浓度,绘制药-时曲线,拟合药动学模型,计算药动学参数;同时测定血清中NO代谢产物NO2-和NO3-水平,绘制时-效曲线,采用Sheiner等提出的效应室理论建立PK-PD结合模型,计算药效学参数。研究结果显示人参皂苷Rg1和Rb1在大鼠体内的药动学过程均符合二房室开放模型,人参皂苷Rg1在体内表现出快消除的特点,人参皂苷Rb1表现出慢消除的特点。生脉注射液诱导大鼠体内NO释放效应与人参皂苷Rg1和Rb1的血药浓度不直接相关,效应滞后于血药浓度,效应与人参皂苷Rg1和Rb1的效应室浓度成良好的相关性,符合Sigmoid-Emax模型。该研究成功建立了生脉注射液在心肌缺血大鼠体内的PK-PD结合模型,可较有效地用于预测生脉注射液的血药浓度和效应。 相似文献
997.
一种基于近红外光谱技术的熊胆粉粗提物洗涤工艺优化方法 总被引:1,自引:1,他引:0
在熊胆粉粗提物的乙酸乙酯洗涤工艺中,需要根据原料的性质对所用洗涤溶剂的倍数进行调整,才能提高产品的纯度和产率。该文采用近红外光谱反映熊胆粉粗提物原料的整体性质,对这一工艺进行了优化。按照不同的熊胆粉粗提物和乙酸乙酯用量设计试验,采集熊胆粉粗提物的近红外光谱,提取出光谱数据的前8个主成分,同乙酸乙酯用量一起作为输入变量,对熊胆粉提取物成品的纯度和收率进行回归。试验共计40组,其中30组校正集,用于建立模型;10组验证集,用于对所建模型进行评估。所建模型的校正、内部交叉验证和外部验证结果满意,纯度模型的相关系数分别为0.902,0.896,0.883,校正误差均方根(RMSEC),交互验证均方根误差(RMSECV),预测误差均方差(RMSEP)分别为1.22%,1.48%,1.59%。收率模型的相关系数分别为0.921,0.859,0.916;RMSEC,RMSECV,RMSEP分别为1.39%,1.65%,1.53%。结果表明,熊胆粉粗提物的近红外光谱结合乙酸乙酯用量可准确预测所得成品的纯度和收率,利用所建模型可以根据熊胆粉粗提物的性质优选出最为合适的乙酸乙酯用量,提高熊胆粉提取物的纯度和收率。 相似文献
998.
目的:利用近红外光谱技术,建立红参提取过程中关键组分的定量模型,实现快速检测功能;以近红外光谱为基础,结合动力学方程,建立提取过程动态趋势模型,实现全过程预测功能。方法:在线采集红参提取液近红外光谱,以HPLC获取关键成分数据,使用最小二乘法(PLSR)建立红参总皂苷的定量模型;通过定量模型以及近红外光谱,结合传质动力学方程,拟合建立提取过程随时间的动态关系模型,实现提取过程预测。结果:红参总皂苷定量模型的校正集相关系数r、校正均方根误差RMSEC、预测均方根误差RMSEP分别为0.996 09,0.018 9,0.016 8;以红参提取一阶动力学方程结合NIR定量模型建立提取过程趋势预测模型,模型显示趋势预测性能良好,具有较高的精度。结论:近红外法获得的定量模型拥有较好的检测精度,能实现快速在线检测功能;所建立的全过程提取动力学方程与实际提取过程趋势较为契合,满足预测需求。 相似文献
999.
目的:观察全脑缺血后海马神经元损伤中5-脂氧酶(5-LOX)的表达变化,并探讨5-LOX选择性抑制剂zileuton对全脑缺血海马神经元损伤的保护作用。方法:在双侧颈总动脉阻断结合降压药诱导大鼠全脑缺血模型,Western blot方法检测脑缺血损伤中5-LOX的表达改变;免疫组织化学及免疫荧光双标染色方法观察5-LOX的分布特征。应用5-LOX选择性抑制剂zileuton(10、30、50 mg/kg,缺血前后2 h灌胃给药,以后每日2次,共3 d)观察脑缺血后海马神经元的损伤变化。结果:大鼠全脑缺血后3~14 d,海马CA1神经元产生迟发性神经元死亡;海马5-LOX表达在全脑缺血后1~7 d增高,并于3 d达高峰;在海马CA1区,5-LOX主要表达在神经元胞浆,脑缺血后5-LOX发生核移位现象。5-LOX抑制剂zileuton(30和50 mg/kg)能减少全脑缺血后海马CA1神经元的死亡。结论:5-LOX参与大鼠全脑缺血诱导的海马神经元损伤,5-LOX抑制剂zileuton对全脑缺血海马神经元损伤有保护作用。 相似文献
1000.