全文获取类型
收费全文 | 296篇 |
免费 | 37篇 |
国内免费 | 7篇 |
专业分类
儿科学 | 6篇 |
基础医学 | 70篇 |
口腔科学 | 3篇 |
临床医学 | 12篇 |
内科学 | 55篇 |
皮肤病学 | 6篇 |
神经病学 | 65篇 |
特种医学 | 3篇 |
外科学 | 13篇 |
综合类 | 38篇 |
预防医学 | 6篇 |
眼科学 | 9篇 |
药学 | 31篇 |
中国医学 | 8篇 |
肿瘤学 | 15篇 |
出版年
2023年 | 5篇 |
2022年 | 5篇 |
2021年 | 21篇 |
2020年 | 10篇 |
2019年 | 10篇 |
2018年 | 8篇 |
2017年 | 10篇 |
2016年 | 9篇 |
2015年 | 15篇 |
2014年 | 11篇 |
2013年 | 25篇 |
2012年 | 19篇 |
2011年 | 14篇 |
2010年 | 13篇 |
2009年 | 9篇 |
2008年 | 12篇 |
2007年 | 15篇 |
2006年 | 7篇 |
2005年 | 12篇 |
2004年 | 8篇 |
2003年 | 8篇 |
2002年 | 6篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 6篇 |
1998年 | 3篇 |
1997年 | 9篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1973年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有340条查询结果,搜索用时 203 毫秒
21.
Lysosomal protease inhibitors induce signs of human brain aging in rat hippocampal slices. The present studies tested if they (1) also cause neurofibrillary tangles and (2) reproduce regional patterns of pathology found in Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or generalized (chloroquine) inhibitors of lysosomal proteases generated meganeurites of the type found in aged human cortex. Surveys and quantitative analyses established that the meganeurites developed almost exclusively in AD vulnerable regions. Antibodies against the phosphorylated tau protein in neurofibrillary tangles labeled thick filaments running through neurons in the superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general appearance of the stained structures resembled that of early stage tangles. More mature tangle-like profiles were found at a number of sites after longer incubations; these were threefold more frequent in the superficial (AD vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots indicated that essentially all phosphorylated tau labeling in the slices involved approximately 29-kDa fragments of the native isoforms. These findings establish that lysosomal dysfunction triggers the parallel formation of meganeurites and tangles with the regional distribution of both effects reflecting that for AD vulnerability. 相似文献
22.
人体乳腺单纯癌癌细胞超微结构的定量研究 总被引:1,自引:1,他引:0
应用体视学方法对10例晚期女性乳腺单纯癌癌细胞线粒体、溶酶体、粗面内质网、核糖体的28个形态结构参数进行体视学测定和分析。结果发现,癌细胞与正常细胞比较,4种细胞器的有关体积、表面积、面数密度及数密度等17种形态参数有高度显著和显著差异;线粒体、粗面内质网形态结构均发生了显著变化,核糖体的数目明显增多。上述研究为今后研究不同期乳腺癌癌细胞超微结构的定量变化打下基础,并力求对乳腺癌的分期及病因提供较准确的定量依据。 相似文献
23.
Richard B. Sewell John D. Horowitz Susan A. Grinpukel Glenn Martin 《Clinical and experimental pharmacology & physiology》1989,16(1):25-32
1. Perhexilene, a long-acting anti-anginal drug, can induce adverse effects on the liver which may be dose-dependent. At high concentrations, perhexilene causes marked morphological changes in hepatocyte lysosomes. The current study examined the effect of 'therapeutic' doses of perhexilene on hepatic lysosomal function, particularly the biliary release of lysosomal enzymes, using an isolated perfused rat liver (IPRL) model. 2. Pharmacokinetic studies demonstrated that clearance of single doses of perhexilene by the perfused rat liver was dose-dependent and established a 'therapeutic' dose of 0.6 mg using the IPRL. A 5 day pretreatment regimen of 20 mg/kg per day was shown to produce 'therapeutic' perhexilene concentrations of 150-210 ng/ml. 3. At perhexilene concentrations equating the 'therapeutic' range in man, the major effect of perhexilene was at the biliary pole of the hepatocyte. In 5 day pretreatment dose studies, lysosomal enzyme excretion into bile was markedly increased. In single dose studies, the increase in biliary lysosomal enzyme output partially reflected an increase in bile water production which was not seen with the 5 day pretreatment regimen. Hepatic and perfusate lysosomal enzyme activities were not affected. 4. This selective effect of perhexilene on hepatocyte-to-bile lysosomal excretion may reflect intracellular lysosomal drug localization. 相似文献
24.
Garcinone E Blocks Autophagy Through Lysosomal Functional Destruction in Ovarian Cancer Cells 下载免费PDF全文
Xiao-Huang Xu Yu-Chi Chen Yu-Lian Xu Zhe-Ling Feng Qian-Yu Liu Xia Guo Li-Gen Lin Jin-Jian Lu 《World Journal of Traditional Chinese Medicine》2021,(2)
Background: High proliferative rate of cancer cells requires autophagy to maintain nutrient supply and intracellular homeostasis. As a result, impairing autophagic flux could be a novel strategy of cancer therapy. Aims and Objectives: In this study, the mechanism of a xanthone derivative isolated from Garcinia mangostana, garcinone E(GE), was investigated. Materials and Methods: Fluorescence assay was used to observe the accumulation and location of autophagosome and lysosome. Flow cytometry with Lyso-tracker red, MDC, and AO staining were applied to evaluate the lysosome accumulation and cellular acidity. Western blot and RT-qPCR were performed to evaluate the protein and mRNA levels, respectively. Results: GE could cause enhancement of LC3 II and p62 and the accumulation of autophagosome and lysosome. Meanwhile, it limited the protein level of Rab7, increased lysosomal pH, and inhibited the maturation of lysosomal hydrolases such as Cathepsin L, therefore blockaded the fusion of autophagosome and lysosome. Moreover, GE acted as a TFEB modulator by downregulating its protein level, which might contribute to autophagy dysfunction in ovarian cancer cells. Conclusions: GE interfered autophagosome–lysosome fusion in cancer cells, which demonstrated its application as an autophagy regulator and a potential therapeutic agent. 相似文献
25.
《Molecular therapy》2020,28(4):1078-1091
26.
27.
Jürgen Zschocke Nicole Zimmermann Barbara Berning Vanessa Ganal Florian Holsboer Theo Rein 《Neuropsychopharmacology》2011,36(8):1754-1768
In the search for antidepressants'' (ADs'') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI- and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis. 相似文献
28.
Wei P Smeyne RJ Bao D Parris J Morgan JI 《The European journal of neuroscience》2007,26(10):2962-2978
Cbln1 is a secreted glycoprotein essential for synapse structure and function in cerebellum that is also expressed in extracerebellar structures where its function is unknown. Furthermore, Cbln1 assembles into homomeric complexes and heteromeric complexes with three family members (Cbln2-Cbln4), thereby influencing each other's degradation and secretion. Therefore, to understand its function, it is essential to establish the location of Cbln1 relative to other family members. The localization of Cbln1 in brain was determined using immunohistochemistry and cbln1-lacZ transgenic mice. Cbln1-like immunoreactivity (CLI) was always punctate and localized to the cytoplasm of neurons. The punctate CLI colocalized with cathepsin D, a lysosomal marker, but not with markers of endoplasmic reticulum or Golgi, indicating that Cbln1 is present in neuronal endosomes/lysosomes. This may represent the cellular mechanism underlying the regulated degradation of Cbln1 observed in vivo. Outside the cerebellum, CLI mapped to multiple brain regions that were frequently synaptically interconnected, warranting their analysis in cbln1-null mice. Furthermore, whereas CLI increased dramatically in the cerebellum of cbln3-null mice it was unchanged in extracerebellar neurons. This opens the possibility that other family members that are coexpressed in these areas control Cbln1 levels, potentially by modulating processing in the endolysosomal pathway. During development of cbln1-lacZ mice, beta-galactosidase staining was first observed in proliferating granule cell precursors prior to synaptogenesis and thereafter in maturing and adult granule cells. As cbln3 is only expressed in post-mitotic, post-migratory granule cells, Cbln1 homomeric complexes in precursors and Cbln1-Cbln3 heteromeric complexes in mature granule cells may have distinct functions and turnover. 相似文献
29.
Marie Abitbol Jean-Laurent Thibaud Natasha J. Olby Christophe Hitte Jean-Philippe Puech Marie Maurer Fanny Pilot-Storck Benoit Hédan Stéphane Dréano Sandra Brahimi Delphine Delattre Catherine André Fran?oise Gray Fran?oise Delisle Catherine Caillaud Florence Bernex Jean-Jacques Panthier Geneviève Aubin-Houzelstein Stéphane Blot Laurent Tiret 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(33):14775-14780
Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs’ disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs'' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis. 相似文献
30.
Joanna M. Rybicka Dale R. Balce Morgan F. Khan Regina M. Krohn Robin M. Yates 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(23):10496-10501
The phagosomal lumen in macrophages is the site of numerous interacting chemistries that mediate microbial killing, macromolecular degradation, and antigen processing. Using a non-hypothesis-based screen to explore the interconnectivity of phagosomal functions, we found that NADPH oxidase (NOX2) negatively regulates levels of proteolysis within the maturing phagosome of macrophages. Unlike the NOX2 mechanism of proteolytic control reported in dendritic cells, this phenomenon in macrophages is independent of changes to lumenal pH and is also independent of hydrolase delivery to the phagosome. We found that NOX2 mediates the inhibition of phagosomal proteolysis in macrophages through reversible oxidative inactivation of local cysteine cathepsins. We also show that NOX2 activity significantly compromises the phagosome''s ability to reduce disulfides. These findings indicate that NOX2 oxidatively inactivates cysteine cathepsins through sustained ablation of the reductive capacity of the phagosomal lumen. This constitutes a unique mechanism of spatiotemporal control of phagosomal chemistries through the modulation of the local redox environment. In addition, this work further implicates the microbicidal effector NOX2 as a global modulator of phagosomal physiologies, particularly of those pertinent to antigen processing. 相似文献