全文获取类型
收费全文 | 467篇 |
免费 | 6篇 |
国内免费 | 5篇 |
专业分类
478篇 |
出版年
2023年 | 1篇 |
2022年 | 2篇 |
2021年 | 7篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 5篇 |
2017年 | 4篇 |
2015年 | 20篇 |
2014年 | 54篇 |
2013年 | 43篇 |
2012年 | 41篇 |
2011年 | 57篇 |
2010年 | 52篇 |
2009年 | 24篇 |
2008年 | 22篇 |
2007年 | 28篇 |
2006年 | 17篇 |
2005年 | 15篇 |
2004年 | 15篇 |
2003年 | 11篇 |
2002年 | 12篇 |
2001年 | 4篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1998年 | 3篇 |
1997年 | 7篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 6篇 |
1993年 | 2篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
排序方式: 共有478条查询结果,搜索用时 0 毫秒
1.
原位缺口平移标记断裂DNA技术及其在检测流行性出血热尸检和实验动物组织中细胞凋亡和早期死亡的应用 总被引:1,自引:0,他引:1
原位缺口平移技术(ISNT)已被用于检测细胞核中DNA断裂鉴别尸检组织中细胞的凋亡和坏死断裂、流行性出血热(EHF)组织中存在散在单个细胞变性死亡和灶性梗死样坏死,前者带有细胞凋亡的特征。本文以EHF肝脏和实验性病毒感染鼠脑组织为例,应用缺口平移法,在DNA聚合酶或Klenow酶的作用下,将地高辛标记的dUTP掺入合成到DNA的断裂部位,通过碱性磷酸酶标抗地高辛抗体免疫组化法显示细胞DNA的断裂,检测和鉴别细胞的凋亡和坏死。为分析死后解剖时间间隔及组织固定时间对该方法的影响,本文选用死后2~140h尸检、经常规固定石蜡包埋后存放10~35年的标本和在10%福尔马林固定了10~35年之后再进行常规处理的标本。实验时用蛋白酶K(PK)消化前后对比并分别在标记反应液中略去DNA聚合酶作为阴性对照,用DNA酶消化组织人为制造DNA缺日作为阳性对照。结果发现,未经PK消化的组织,仅灶性肝细胞核ISNT标记阳性,经PK消化后,散在的带有凋亡特征的肝细胞胞核也出现阳性,灶性肝细胞胞核标记染色增强,但无论是蛋白酶消化与否,明确梗死样坏死的肝细胞均不被标记。结果还发现,死后2~24h内尸检组织和长时间(10~34年)存放的石 相似文献
2.
Yamanaka K Saito Y Yamamori T Urano Y Noguchi N 《The Journal of biological chemistry》2011,286(28):24666-24673
24(S)-Hydroxycholesterol (24S-OHC) produced by cholesterol 24-hydroxylase expressed mainly in neurons plays an important physiological role in the brain. Conversely, it has been reported that 24S-OHC possesses potent cytotoxicity. The molecular mechanisms of 24S-OHC-induced cell death have not yet been fully elucidated. In this study, using human neuroblastoma SH-SY5Y cells and primary cortical neuronal cells derived from rat embryo, we characterized the form of cell death induced by 24S-OHC. SH-SY5Y cells treated with 24S-OHC exhibited neither fragmentation of the nucleus nor caspase activation, which are the typical characteristics of apoptosis. 24S-OHC-treated cells showed necrosis-like morphological changes but did not induce ATP depletion, one of the features of necrosis. When cells were treated with necrostatin-1, an inhibitor of receptor-interacting serine/threonine kinase 1 (RIPK1) required for necroptosis, 24S-OHC-induced cell death was significantly suppressed. The knockdown of RIPK1 by transfection of small interfering RNA of RIPK1 effectively attenuated 24S-OHC-induced cell death. It was found that neither SH-SY5Y cells nor primary cortical neuronal cells expressed caspase-8, which was regulated for RIPK1-dependent apoptosis. Collectively, these results suggest that 24S-OHC induces neuronal cell death by necroptosis, a form of programmed necrosis. 相似文献
3.
最近的报道指出,某些病毒有诱导体外细胞凋亡的作用,借以限制病毒的扩散。为探讨HSV-2在体内诱导细胞凋亡的效果及其形态学特点,用 HSV-2 333株感染小鼠阴道,于感染后不同天数处死动物,取其阴道,固定于10%中性福尔马林,TUNEL末端标记染色显示凋亡的细胞,光镜下进行原位观察。结果显示:感染后的第1天粘膜上皮内即出现大量的凋亡细胞,第2天至11天凋亡细胞的数量及在上皮内的分布范围达最高水平。早期的凋亡细胞见于感染后所有标本,其核染色质形态及分布似正常细胞,但它被TUNEL标记染成棕黄色;晚期的凋亡细胞亦见于所有标本,其胞核缩小,染色质浓缩并在核周边集聚,核中心空化。载有凋亡细胞的上皮在阴道粘膜上分布很广,最广的可占全阴道上皮的2/3。同时可见HSV.2引起的上皮细胞坏死及疱疹形成,二者均由凋亡细胞包围。凋亡细胞不断地由上皮表面脱落至阴道,未见凋亡小体及吞噬现象。结果提示,HSV-2 333株阴道感染可同时诱导细胞坏死及凋亡,细胞凋亡可能在限制病毒产生子代及限制感染区域扩展起重要作用。 相似文献
4.
László Virág Agnieszka Robaszkiewicz Jose Manuel Rodriguez-Vargas Francisco Javier Oliver 《Molecular aspects of medicine》2013
Poly(ADP-ribosyl)ation (PARylation) is a reversible protein modification carried out by the concerted actions of poly(ADP-ribose) polymerase (PARP) enzymes and poly(ADP-ribose) (PAR) decomposing enzymes such as PAR glycohydrolase (PARG) and ADP-ribosyl hydrolase 3 (ARH3). Reversible PARylation is a pleiotropic regulator of various cellular functions but uncontrolled PARP activation may also lead to cell death. The cellular demise pathway mediated by PARylation in oxidatively stressed cells has been described almost thirty years ago. However, the underlying molecular mechanisms have only begun to emerge relatively recently. PARylation has been implicated in necroptosis, autophagic cell death but its role in extrinsic and intrinsic apoptosis appears to be less predominant and depends largely on the cellular model used. Currently, three major pathways have been made responsible for PARP-mediated necroptotic cell death: (1) compromised cellular energetics mainly due to depletion of NAD, the substrate of PARPs; (2) PAR mediated translocation of apoptosis inducing factor (AIF) from mitochondria to nucleus (parthanatos) and (3) a mostly elusive crosstalk between PARylation and cell death/survival kinases and phosphatases. Here we review how these PARP-mediated necroptotic pathways are intertwined, how PARylation may contribute to extrinsic and intrinsic apoptosis and discuss recent developments on the role of PARylation in autophagy and autophagic cell death. 相似文献
5.
Francisco J. Padillo Adolfo Cruz Carmen Navarrete Inmaculada Bujalance Javier Briceño José I. Gallardo 《Free radical research》2013,47(7):697-704
The induction of oxidative stress precedes liver injury during experimental obstructive jaundice (OJ). In this sense, different evidences suggest that melatonin (MEL), as antioxidant, may be useful in the protection against apoptosis and necrosis during experimental cholestasis. In addition, we will also assess if MEL-dependent protection is related to a recovery of antioxidant status disturbances induced by OJ. Cholestasis was achieved by double ligature and sectioning of the principal bile duct. MEL was injected intraperitoneally (500?μg/kg/day). Lipid peroxidation was evaluated by the measurement of malondialdehyde (MDA) content in liver. Different parameters related to antioxidant status, such as reduced glutathione (GSH), glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD) were determined in liver. Liver injury was assessed by alanine aminotransferase (ALT) in serum, histological examination, DNA fragmentation and TUNEL assay. The activation of perisinusoidal stellate cells was evaluated by immunohistochemical measurement of α-smooth muscle actin in liver sections. The induction of OJ increased all the parameters related to apoptosis and necrosis in liver. The induction of liver injury was associated with stellate cell activation, as well as an increase in MDA (p<0.0001) and a reduction in GSH, GPx, catalase and SOD content (p<0.0001) in liver. MEL reduced hepatic apoptosis and necrosis (p<0.004) with a significant improvement in all oxidative stress markers. In conclusion, our results showed that MEL recovered the antioxidant status and reduced apoptosis and necrosis induced by experimental cholestasis. 相似文献
6.
Manousos Makridakis Maria G. Roubelakis Antonia Vlahou 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(11):2380-2384
Stem cells have been considered as possible therapeutic vehicles for different health related problems such as cardiovascular and neurodegenerative diseases and cancer. Secreted molecules are key mediators in cell–cell interactions and influence the cross talk with the surrounding tissues. There is strong evidence supporting that crucial cellular functions such as proliferation, differentiation, communication and migration are strictly regulated from the cell secretome. The investigation of stem cell secretome is accumulating continuously increasing interest given the potential use of these cells in regenerative medicine. The scope of the review is to report the main findings from the investigation of stem cell secretome by the use of contemporary proteomics methods and discuss the current status of research in the field. This article is part of a Special Issue entitled: An Updated Secretome. 相似文献
7.
Jingjing Ben Yan Zhang Rongmei Zhou Haiyang Zhang Xudong Zhu Xiaoyu Li Hanwen Zhang Nan Li Xiaodan Zhou Hui Bai Qing Yang Donghai Li Yong Xu Qi Chen 《The Journal of biological chemistry》2013,288(27):20076-20084
Atherosclerosis is considered a disease of chronic inflammation largely initiated and perpetuated by macrophage-dependent synthesis and release of pro-inflammatory mediators. Class A scavenger receptor (SR-A) expressed on macrophages plays a key role in this process. However, how SR-A-mediated pro-inflammatory response is modulated in macrophages remains ill defined. Here through immunoprecipitation coupled with mass spectrometry, we reported major vault protein (MVP) as a novel binding partner for SR-A. The interaction between SR-A and MVP was confirmed by immunofluorescence staining and chemical cross-linking assay. Treatment of macrophages with fucoidan, a SR-A ligand, led to a marked increase in TNF-α production, which was attenuated by MVP depletion. Further analysis revealed that SR-A stimulated TNF-α synthesis in macrophages via the caveolin- instead of clathrin-mediated endocytic pathway linked to p38 and JNK, but not ERK, signaling pathways. Importantly, fucoidan invoked an enrichment of MVP in lipid raft, a caveolin-reliant membrane structure, and enhanced the interaction among SR-A, caveolin, and MVP. Finally, we demonstrated that MVP elimination ameliorated SR-A-mediated apoptosis in macrophages. As such, MVP may fine-tune SR-A activity in macrophages which contributes to the development of atherosclerosis. 相似文献
8.
9.
Vimal A. Patel Daniel J. Lee Lanfei Feng Angelika Antoni Wilfred Lieberthal John H. Schwartz Joyce Rauch David S. Ucker Jerrold S. Levine 《The Journal of biological chemistry》2010,285(3):1829-1840
During apoptosis, cells acquire new activities that enable them to modulate the fate and function of interacting phagocytes, particularly macrophages (mϕ). Although the best known of these activities is anti-inflammatory, apoptotic targets also influence mϕ survival and proliferation by modulating proximal signaling events, such as MAPK modules and Akt. We asked whether modulation of these same signaling events extends to epithelial cells, a minimally phagocytic cell type. We used BU.MPT cells, a mouse kidney epithelial cell line, as our primary model, but we also evaluated several epithelial cell lines of distinct tissue origins. Like mϕ, mouse kidney epithelial cells recognized apoptotic and necrotic targets through distinct non-competing receptors, albeit with lower binding capacity and markedly reduced phagocytosis. Also, modulation of inflammatory activity and MAPK-dependent signaling by apoptotic and necrotic targets was indistinguishable in kidney epithelial cells and mϕ. In contrast, modulation of Akt-dependent signaling differed dramatically between kidney epithelial cells and mϕ. In kidney epithelial cells, modulation of Akt was linked to target cell recognition, independently of phagocytosis, whereas in mϕ, modulation was linked to phagocytosis. Moreover, recognition of apoptotic and necrotic targets by kidney epithelial cells elicited opposite responses; apoptotic targets inhibited whereas necrotic targets stimulated Akt activity. These data confirm that nonprofessional phagocytes recognize and respond to dying cells, albeit in a manner partially distinct from mϕ. By acting as sentinels of environmental change, apoptotic and necrotic targets may permit neighboring viable cells, especially non-migratory epithelial cells, to monitor and adapt to local stresses. 相似文献