全文获取类型
收费全文 | 1818篇 |
免费 | 351篇 |
国内免费 | 138篇 |
专业分类
耳鼻咽喉 | 10篇 |
儿科学 | 14篇 |
妇产科学 | 52篇 |
基础医学 | 450篇 |
口腔科学 | 30篇 |
临床医学 | 102篇 |
内科学 | 307篇 |
皮肤病学 | 49篇 |
神经病学 | 94篇 |
特种医学 | 32篇 |
外科学 | 194篇 |
综合类 | 218篇 |
预防医学 | 59篇 |
眼科学 | 19篇 |
药学 | 293篇 |
中国医学 | 81篇 |
肿瘤学 | 303篇 |
出版年
2024年 | 14篇 |
2023年 | 65篇 |
2022年 | 164篇 |
2021年 | 226篇 |
2020年 | 166篇 |
2019年 | 118篇 |
2018年 | 154篇 |
2017年 | 170篇 |
2016年 | 174篇 |
2015年 | 148篇 |
2014年 | 235篇 |
2013年 | 202篇 |
2012年 | 143篇 |
2011年 | 133篇 |
2010年 | 64篇 |
2009年 | 54篇 |
2008年 | 28篇 |
2007年 | 24篇 |
2006年 | 11篇 |
2005年 | 1篇 |
2004年 | 1篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1995年 | 2篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有2307条查询结果,搜索用时 15 毫秒
1.
It has been suggested that the cytoplasmic amino-terminal tail of invariant chain (Ii) contains a sorting signal that directs trafficking of the major histocompatibility complex (MHC) class II: Ii oligomeric complex to endocytic compartments. This model is based, in part, on the observation that in the absence of MHC class II molecules, Ii is detectable in lysosomal structures, a phenotype that is dependent on an intact NH2 terminus. However, the route by which Ii gains access to endosomal compartments in the absence of class II molecules remains uncertain. Here we report a mechanism that localizes Ii in lysosomal compartments independently of class II. We show that murine Ii can be detected by immunofluorescence within late endocytic compartments of stably transfected Ltk? mouse fibroblasts. Immunochemical studies indicate that degradation of Ii in these cells is sensitive to the lysosomotropic agent ammonium chloride, yet the majority of Ii that undergoes this apparent lysosomal degradation is sensitive to the enzyme endoglycosidase H. This finding suggests that Ii may reach the lysosomal compartment by a route that bypasses the Golgi complex. Consistent with this possibility, we found that in contrast to Ii which is complexed to class II molecules, transport of free Ii to lysosomes is prevented by 3-methyladenine, an inhibitor of the autophagic pathway of protein degradation, a process which involves direct transport from the endoplasmic reticulum to lysosomes. These data suggest the route of transport that leads to endosomal localization of Ii in the absence of class II is distinct from that taken when expressed with class II. This forces a re-evaluation of the concept that the cytosolic tail of Ii contains a dominant Golgi-to-endosomal sorting signal. 相似文献
2.
Summary The ultrastructure of the physiological cell death was studied in distal ventral bulbar cushions of 15 chick embryo hearts on the 4th and 5th day of incubation. Microperfusion fixation was performed. The ultracytochemistry of a lysosomal hydrolytic enzyme acid phosphatase was also investigated in another 15 embryonic hearts.In the course of the cell degeneration an increase in cellulr autophagy was observed without previous cytoplasmic or nuclear changes or phagocyte ingestion. A cytoplasmic diffusion of acid phosphatase outside of lysosomes was observed.Besides the cell death with the marked participation of the lysosomal system, another kind of dying cells was found, characterized by their nuclear pycnosis and cytoplasmic condensation. Starting from the 5th day of incubation the dying and dead cells were found phagocytized by some of their neighbouring viable mesenchymal cells. A formation of ribosomal crystals was not observed.The formation and fate of cytolysomes as well as the fate of phagocytes are discussed. The presence of pre-necrotic cells with important autophagy and of necrotic cells with nuclear changes was related to the possibility of a dual cause of the cell death. In the case of pre-necrotic cells the epigenetic factors like the biomechanic action of hemodynamics were considered, while the necrotic cells seem to be programmed to death by their genome.Finally the uniformity of cell death ultrastructure in different organs and species was noticed. 相似文献
3.
目的 研究Homer1b/c蛋白在谷氨酸诱发的细胞自噬中的作用及机制。方法 选用小鼠海马细胞系HT22细胞,通过500 ?mol/L谷氨酸处理建立细胞损伤模型。用siRNA慢病毒转染方式下调Homer1b/c表达和10 ?mol/LBAPTA-AM(1,2-双(2-氨基苯氧基)乙烷-N,N,N`,N`-四乙酸四乙酸甲酯,钙离子螯合剂)、10 mmol/L4-PBA(4-苯基丁酸,内质网应激抑制剂)分别抑制细胞内钙离子释放和内质网应激后,使用蛋白质印迹法检测Homer1b/c,自噬蛋白Beclin-1、微管相关蛋白轻链3(LC3),以及内质网应激标志蛋白CHOP(人内质网应激相关蛋白)、GRP-78(葡萄糖调节蛋白78)的表达水平。每组实验均进行3次,采用独立样本t检验和单因素方差分析进行统计学分析。结果 谷氨酸处理HT22细胞12 h后,Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值均升高(P<0.05),下调Homer1b/c表达可降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。抑制细胞内钙离子释放和抑制内质网应激均能降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。然而在下调Homer1b/c表达后,抑制细胞内钙离子释放和抑制内质网应激未能进一步降低Beclin-1表达和LC3-Ⅱ/LC3-Ⅰ比值的升高程度(P<0.05)。结论 Homer1b/c能够调节谷氨酸诱导的自噬,其调节作用可能与内质网功能有关。 相似文献
4.
目的探讨抑制蛋白酶体活性是否可以诱导人乳腺癌细胞MCF-7的自我吞噬,1,6二磷酸果糖对自我吞噬的影响及自我吞噬对细胞增殖的作用。方法采用MTT法检测细胞增殖,蛋白质印迹检测自我吞噬相关蛋白LC3的表达。结果蛋白酶体抑制剂硼替佐米以剂量依赖方式抑制MCF-7细胞的增殖并诱导细胞的自我吞噬,但是,当1,6二磷酸果糖与硼替佐米联合应用后,可逆转硼替佐米诱导的自我吞噬并增强硼替佐米对MCF-7细胞的增殖抑制。结论蛋白酶体活性的抑制可诱导人乳腺癌细胞MCF-7的自我吞噬代偿性激活,1,6二磷酸果糖可抑制激活的自我吞噬,其与硼替佐米的联合应用可增强其抑瘤效应。 相似文献
5.
目的探讨抗肿瘤药物羟喜树碱(HCPT)对宫颈癌HeLa细胞作用的机制。方法 CCK8检测Hela细胞增殖,Western blot检测自噬和凋亡相关蛋白的表达,GFP-LC3 shRNA转染和Hoechst染色后,荧光显微镜下观察细胞自噬特异小体量的改变以及凋亡形态学的变化。结果 HCPT抑制Hela细胞生长呈浓度依赖性(P<0.05),IC503μmol/L HCPT作用Hela细胞后,自噬相关蛋白Beclin1、p62的表达以及LC3-Ⅱ/LC3-Ⅰ比值发生改变,差异有显著性意义(P均<0.05);凋亡相关蛋白Bax、cleaved caspase-3、Bcl-2表达也发生明显改变(P均<0.05);荧光显微镜下观察Hela细胞带有GFP-LC3的自噬体增加,凋亡细胞也增多(P均<0.05)。结论 HCPT能够诱导HeLa细胞中自噬相关基因Beclin1、p62以及LC3的表达增强,从而激活细胞自噬发生;且HCPT能够激活宫颈癌HeLa细胞发生自噬,进而诱导细胞凋亡来达到抗肿瘤目的。 相似文献
6.
Boyong Jang Shibing Guo Rui Bai Wanlin Liu Yulin Gong Zhenqun Zhao 《Orthopaedic Surgery》2022,14(10):2669
ObjectiveTo study the relationship between vascular endothelial cells (VEC) and autophagy, and its regulatory mechanism in steroid‐induced avascular necrosis of the femoral head (SANFH).MethodsIn cell experiment, VEC were isolated and cultured from the femoral head of Sprague–Dawley rats and divided into three groups: blank control group (Ctrl), methylprednisolone group (MP), and methylprednisolone+mTOR‐shRNA group (MP + shmTOR). The autophagy formation was observed by transmission electron microscope. The mRNA expression of PI3K, Akt, mTOR, Beclin1 and MAP1LC3 was detected by RT‐PCR and the protein expression was detected by Western blot and immunofluorescence. Expression of the damage marker 6‐keto‐PGF1α was detected by the ELISA method. In vivo experiment, after establishing the model, the grouping method was the same as cell experiment. Autophagosomes were observed by same method, and the expression of related factors was detected by the same method in cell experiment.ResultsIn the cell experiment, autophagosomes in the MP group were significantly lower than in the Ctrl group, and the autophagosomes in the MP + shmTOR group were intermediate between two groups (P < 0.05). The mRNA expression levels of PI3K, Akt and mTOR in the MP group were significantly higher than in the Ctrl group, while the MP+ shmTOR group presented intermediate levels between these groups (average gray value were 3837.90, 2996.30, 3005.60, F = 428.64, P < 0.05). MRNA expression levels of Beclin1 and MAP1LC3 in the MP group were significantly lower than that in Ctrl group (P < 0.05). The content of 6‐keto‐PGF1α in the MP + shmTOR group was higher than in the Ctrl group and lower than in the MP group at the evaluated time intervals (average absorbance value were 104.98, 206.83, 145.91, F = 352.83, P < 0.01). In vivo experiment, the content of 6‐Keto‐PGF1α in the hormone group increased as time went on; the mTOR‐si group was higher than that in control group, but lower than that in the hormone group (P < 0.01). The mRNA expressions of Beclin1 and MAP1LC3 in the control group were higher than those in the hormone group, while the mRNA expressions of PI3K, Akt and mTOR were lower than those in the mTOR‐si group (P < 0.05).ConclusionThe steroid inhibited the physiological protective effect of autophagy on SANFH by increasing the expression of PI3K/Akt/mTOR signaling pathway related factors and decreasing the expression of Beclin1 and MAP1LC3 in the femoral head VEC. 相似文献
7.
Seong Bin Jo So Jung Sung Hong Seok Choi Jae-Sung Park Yong-Kil Hong Young Ae Joe 《Biomolecules & therapeutics.》2022,30(6):616
Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has been suggested as a repositioning candidate for the treatment of brain tumors. However, the efficacy of MBZ needs further study to improve the beneficial effect on the survival of those patients. In this study, we explored a novel strategy to improve MBZ efficacy using a drug combination. When glioblastoma cells were treated with MBZ, cell proliferation was dose-dependently inhibited with an IC50 of less than 1 µM. MBZ treatment also inhibited glioblastoma cell migration with an IC50 of less than 3 µM in the Boyden chamber migration assay. MBZ induced G2-M cell cycle arrest in U87 and U373 cells within 24 h. Then, at 72 h of treatment, it mainly caused cell death in U87 cells with an increased sub-G1 fraction, whereas polyploidy was seen in U373 cells. However, MBZ treatment did not affect ERK1/2 activation stimulated by growth factors. The marked induction of autophagy by MBZ was observed, without any increased expression of autophagy-related genes ATG5/7 and Beclin 1. Co-treatment with MBZ and the autophagy inhibitor chloroquine (CQ) markedly enhanced the anti-proliferative effects of MBZ in the cells. Triple combination treatment with temozolomide (TMZ) (another autophagy inducer) further enhanced the anti-proliferative effect of MBZ and CQ. The combination of MBZ and CQ also showed an enhanced effect in TMZ-resistant glioblastoma cells. Therefore, we suggest that the modulation of protective autophagy could be an efficient strategy for enhancing the anti-tumor efficacy of MBZ in glioblastoma cells. 相似文献
8.
<正>急性肺损伤(acute lung injury,ALI)是急危重症患者常见的一种器官损伤,肺实质细胞死亡是ALI的基础,明确细胞死亡的发生机制将为防治ALI提供重要的理论支撑[1]。细胞自噬(autophagy)是细胞代谢过程中的衰老细胞器和异常蛋白质等成分降解的过程,受多条信号通路与多种信号分子的调节,有利于维持细胞稳态;病理状态下,自噬被激活或抑 相似文献
9.
<正>衰老是在细胞、组织和器官水平上发生的生理性内稳态的渐进性损害过程。就代谢角度而言,该过程主要表现为体成分、胰岛素抵抗、自噬功能障碍、线粒体和炎症反应的变化,其中涉及生长激素、胰岛素/胰岛素样生长因子1及各种能量感应系统如AMP活化蛋白激酶(AMP-activated protein kinase,AMPK)、沉默信息调节因子(silent information regula‐tors,SIRTs)等多条信号通路的变化[1]。而从临床角 相似文献
10.