全文获取类型
收费全文 | 317篇 |
免费 | 25篇 |
出版年
2023年 | 1篇 |
2022年 | 10篇 |
2021年 | 16篇 |
2020年 | 14篇 |
2019年 | 28篇 |
2018年 | 21篇 |
2017年 | 16篇 |
2016年 | 19篇 |
2015年 | 14篇 |
2014年 | 25篇 |
2013年 | 41篇 |
2012年 | 27篇 |
2011年 | 25篇 |
2010年 | 11篇 |
2009年 | 9篇 |
2008年 | 18篇 |
2007年 | 12篇 |
2006年 | 7篇 |
2005年 | 3篇 |
2004年 | 3篇 |
2003年 | 4篇 |
2002年 | 6篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
排序方式: 共有342条查询结果,搜索用时 31 毫秒
71.
Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53-dependent apoptosis in human cancer cells. Notably, HAUSP can also target the N-Myc oncoprotein in a p53-independent manner. Moreover, newly synthesized HAUSP inhibitors are more potent than the commercially available inhibitors to suppress N-Myc activities in p53 mutant cells for growth suppression. Taken together, our study demonstrates the utility of HAUSP inhibitors to target cancers in both a p53-depdentent and -independent manner. 相似文献
72.
Omid Tavassoly Dorin Sade Santu Bera Shira Shaham-Niv David J. Vocadlo Ehud Gazit 《Journal of molecular biology》2018,430(20):3847-3862
Quinolinic acid (QA), a downstream neurometabolite in the kynurenine pathway, the biosynthetic pathway of tryptophan, is associated with neurodegenerative diseases pathology. Mutations in genes encoding kynurenine pathway enzymes, which control the level of QA production, are linked with elevated risk of developing Parkinson's disease. Recent findings have revealed the accumulation and deposition of QA in post-mortem samples, as well as in cellular models of Alzheimer's disease and related disorders. Furthermore, intrastriatal inoculation of mice with QA results in increased levels of phosphorylated α-synuclein and neurodegenerative pathological and behavioral characteristics. However, the cellular and molecular mechanisms underlying the involvement of QA accumulation in protein aggregation and neurodegeneration remain elusive. We recently established that self-assembled ordered structures are formed by various metabolites and hypothesized that these “metabolite amyloids” may seed amyloidogenic proteins. Here we demonstrate the formation of QA amyloid-like fibrillar assemblies and seeding of α-synuclein aggregation by these nanostructures both in vitro and in cell culture. Notably, α-synuclein aggregation kinetics was accelerated by an order of magnitude. Additional amyloid-like properties of QA assemblies were demonstrated using thioflavin T assay, powder X-ray diffraction and cell apoptosis analysis. Moreover, fluorescently labeled QA assemblies were internalized by neuronal cells and co-localized with α-synuclein aggregates. In addition, we observed cell-to-cell propagation of fluorescently labeled QA assemblies in a co-culture of treated and untreated cells. Our findings suggest that excess QA levels, due to mutations in the kynurenine pathway, for example, may lead to the formation of metabolite assemblies that seed α-synuclein aggregation, resulting in neuronal toxicity and induction of Parkinson's disease. 相似文献
73.
Hedieh Keshavarz-Bahaghighat Mohammad Reza Sepand Mohammad Hossein Ghahremani Mehdi Aghsami Nima Sanadgol Ameneh Omidi Vida Bodaghi-Namileh Omid Sabzevari 《Biological trace element research》2018,184(2):422-435
Augmentation of mitochondrial oxidative stress through activating a series of deadly events has implicated as the main culprit of arsenic toxicity and therapeutic approaches based on improving mitochondrial function hold a great promise for attenuating the arsenic-induced toxicity. Acetyl-l-carnitine (ALC) through balancing the coenzyme A (CoA)/acyl-CoA ratio plays an important role in mitochondrial metabolism and thereby can help protect hippocampal neurons from oxidative damage. In the present study, we aimed to explore the effect of arsenic interactions on the mitochondrial function in the hippocampus of rats. Rats were randomly divided into five groups of control (distilled water), sodium arsenite (NaAsO2, 20 mg/kg), and co-treatment of NaAsO2 with various doses of ALC in three groups (100, 200, 300 mg/kg) and were treated orally for 21 consecutive days. Our results point out that arsenic exposure caused oxidative stress in rats’ hippocampus, which led to the reactive oxygen species (ROS) generation, mitochondrial swelling, the collapse of the mitochondrial membrane potential, and release of cytochrome c. It also altered Bcl-2/Bax expression ratio and increased caspase-3 and caspase-9 activities. Furthermore, arsenic exposure via activation of NF-κB and microglia increased inflammation. ALC could concentration-dependently counteract the arsenic-induced oxidative stress, modulate the antioxidant defense capacity, and improve mitochondrial functions. In addition, ALC decreased the expression of both death-associated proteins and of inflammatory markers. These findings indicate that ALC improved the arsenic-induced hippocampal mitochondrial dysfunction which underlines the importance of ALC in providing a possible therapeutic strategy for the prevention of arsenic-induced neurodegeneration. 相似文献
74.
75.
76.
77.
A new species of mite is described from Iran, Laelaspisella
elsae
sp. n. (Acari: Laelapidae). The new species was collected from bark of elm trees in Isfahan province. A revised diagnosis for Laelaspisella, as well as a key to the world species of the genus, are presented. Two species groups of Laelaspisella are proposed: those with seta pd3 on genu I and those without pd3 on genu I. Pseudoparasitus (Gymnolaelaps) tonsilis Karg, 1989a is transferred to Laelaspisella, based on its hypertrichous holodorsal shield, metasternal setae st4 absent and genu IV with ten setae. The problems with Laelaspisella
canestrinii are explained and Laelaspisella
canestrinii
sensu
Berlese (1903), (1904) and Costa (1962) is provided with a new name, Laelaspisella
berlesei Joharchi, nom. n. 相似文献
78.
79.
Nersi?Jafary Omid Hoda?Morovati Mohsen?Amini Ahmad-Reza?Dehpour Alireza?Partoazar Morteza?Rafiee-Tehrani Farid?DorkooshEmail author 《AAPS PharmSciTech》2016,17(6):1457-1467
Molecularly imprinted nano-particles (MINPs) selective for olanzapine were prepared using methacrylic acid (MA) as monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker, and 2,2-azobis (2-isobutyronitrile) (AIBN) as the initiator in 36 different ratios. The reaction runs with considerable fine powder formation were selected for further binding and selectivity studies. The MINP with the best selectivity (MINP-32) was chosen for further structural characterization by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), adsorption-desorption isotherm for specific surface area, volume and average pore diameter determination. All characterization methods confirmed the successful formation of MINP. The optimum conditions for maximum template loading on the MINP-32 were found by experimental design using response surface methodology (RSM) and choosing absorbent amount, pH, and time as the main factors. MINPs with maximum template loading also indicated significant selectivity between template and its analog (clozapine). The release profile demonstrated a maximum release of about 95% after 288 h for MINP-32 in comparison with about 94% after 120 h for non-MINP-32. The same slow release of drug from MINP-32 was also observed during animal study of the plasma level of template, 20–28 μg/ml versus 5–10 μg/ml. The MINP-32 of this study represents a desirable ability to keep the memory of the template with significant selectivity and good capability to control the release of template in vitro and in vivo and hence could be a promising drug delivery system. 相似文献
80.
Cell competition where ‘loser’ cells are eliminated by neighbors with higher fitness is a widespread phenomenon in development. However, a growing body of evidence argues cells with somatic mutations compete with their wild type counterparts in the earliest stages of cancer development. Recent studies have begun to shed light on the molecular and cellular mechanisms that alter the competitiveness of cells carrying somatic mutations in adult tissues. Cells with a ‘winner’ phenotype create clones which may expand into extensive fields of mutant cells within normal appearing epithelium, favoring the accumulation of further genetic alterations and the evolution of cancer. Here we focus on how mutations which disrupt the Notch signaling pathway confer a ‘super competitor’ status on cells in squamous epithelia and consider the broader implications for cancer evolution. 相似文献