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排序方式: 共有73条查询结果,搜索用时 16 毫秒
1.
A microRNA component of the p53 tumour suppressor network 总被引:5,自引:0,他引:5
2.
Inactivation of the apoptosis effector Apaf-1 in malignant melanoma 总被引:47,自引:0,他引:47
Soengas MS Capodieci P Polsky D Mora J Esteller M Opitz-Araya X McCombie R Herman JG Gerald WL Lazebnik YA Cordón-Cardó C Lowe SW 《Nature》2001,409(6817):207-211
Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type. 相似文献
3.
Voineagu I Wang X Johnston P Lowe JK Tian Y Horvath S Mill J Cantor RM Blencowe BJ Geschwind DH 《Nature》2011,474(7351):380-384
4.
Zuber J Shi J Wang E Rappaport AR Herrmann H Sison EA Magoon D Qi J Blatt K Wunderlich M Taylor MJ Johns C Chicas A Mulloy JC Kogan SC Brown P Valent P Bradner JE Lowe SW Vakoc CR 《Nature》2011,478(7370):524-528
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. 相似文献
5.
强流脉冲离子束(HIPIB)使材料表面气化产生喷发等离子体从而进行薄膜生长、纳米粉的制备等工作。金属钨的熔点高,热导性好,是耐高热流密度防护层最可能的材料。为了研究金属钨在高热负荷下的响应,建立了HIPIB辐照钨靶的考虑相变的非线性热力学方程,并采用有限元方法数值求解了靶材辐照后的二维温度场演化问题,得到了钨靶温度场的时空演化规律。当离子束流密度为100 A/cm2时,脉冲结束后束流入射中心表层约0.3μm厚的材料熔化,且熔化是从表面开始的,而后因热传导固化;脉冲结束后开始时靶材表面温度急剧下降,而后变得缓慢,温降的梯度在不同时刻均存在峰值,且随时间增加峰值向纵向深度处移动。 相似文献
6.
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas 总被引:1,自引:0,他引:1
Xue W Zender L Miething C Dickins RA Hernando E Krizhanovsky V Cordon-Cardo C Lowe SW 《Nature》2007,445(7128):656-660
Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth. 相似文献
7.
Photosynthetic microbial mats in the 3,416-Myr-old ocean 总被引:2,自引:0,他引:2
Recent re-evaluations of the geological record of the earliest life on Earth have led to the suggestion that some of the oldest putative microfossils and carbonaceous matter were formed through abiotic hydrothermal processes. Similarly, many early Archaean (more than 3,400-Myr-old) cherts have been reinterpreted as hydrothermal deposits rather than products of normal marine sedimentary processes. Here we present the results of a field, petrographic and geochemical study testing these hypotheses for the 3,416-Myr-old Buck Reef Chert, South Africa. From sedimentary structures and distributions of sand and mud, we infer that deposition occurred in normal open shallow to deep marine environments. The siderite enrichment that we observe in deep-water sediments is consistent with a stratified early ocean. We show that most carbonaceous matter was formed by photosynthetic mats within the euphotic zone and distributed as detrital matter by waves and currents to surrounding environments. We find no evidence that hydrothermal processes had any direct role in the deposition of either the carbonaceous matter or the enclosing sediments. Instead, we conclude that photosynthetic organisms had evolved and were living in a stratified ocean supersaturated in dissolved silica 3,416 Myr ago. 相似文献
8.
An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivo 总被引:45,自引:0,他引:45
Hemann MT Fridman JS Zilfou JT Hernando E Paddison PJ Cordon-Cardo C Hannon GJ Lowe SW 《Nature genetics》2003,33(3):396-400
The application of RNA interference (RNAi) to mammalian systems has the potential to revolutionize genetics and produce novel therapies. Here we investigate whether RNAi applied to a well-characterized gene can stably suppress gene expression in hematopoietic stem cells and produce detectable phenotypes in mice. Deletion of the Trp53 tumor suppressor gene greatly accelerates Myc-induced lymphomagenesis, resulting in highly disseminated disease. To determine whether RNAi suppression of Trp53 could produce a similar phenotype, we introduced several Trp53 short hairpin RNAs (shRNAs) into hematopoietic stem cells derived from E(mu)-Myc transgenic mice, and monitored tumor onset and overall pathology in lethally irradiated recipients. Different Trp53 shRNAs produced distinct phenotypes in vivo, ranging from benign lymphoid hyperplasias to highly disseminated lymphomas that paralleled Trp53-/- lymphomagenesis in the E(mu)-Myc mouse. In all cases, the severity and type of disease correlated with the extent to which specific shRNAs inhibited p53 activity. Therefore, RNAi can stably suppress gene expression in stem cells and reconstituted organs derived from those cells. In addition, intrinsic differences between individual shRNA expression vectors targeting the same gene can be used to create an 'epi-allelic series' for dissecting gene function in vivo. 相似文献
9.
Tissue-specific and reversible RNA interference in transgenic mice 总被引:11,自引:0,他引:11
Dickins RA McJunkin K Hernando E Premsrirut PK Krizhanovsky V Burgess DJ Kim SY Cordon-Cardo C Zender L Hannon GJ Lowe SW 《Nature genetics》2007,39(7):914-921
Genetically engineered mice provide powerful tools for understanding mammalian gene function. These models traditionally rely on gene overexpression from transgenes or targeted, irreversible gene mutation. By adapting the tetracycline (tet)-responsive system previously used for gene overexpression, we have developed a simple transgenic system to reversibly control endogenous gene expression using RNA interference (RNAi) in mice. Transgenic mice harboring a tet-responsive RNA polymerase II promoter driving a microRNA-based short hairpin RNA targeting the tumor suppressor Trp53 reversibly express short hairpin RNA when crossed with existing mouse strains expressing general or tissue-specific 'tet-on' or 'tet-off' transactivators. Reversible Trp53 knockdown can be achieved in several tissues, and restoring Trp53 expression in lymphomas whose development is promoted by Trp53 knockdown leads to tumor regression. By leaving the target gene unaltered, this approach permits tissue-specific, reversible regulation of endogenous gene expression in vivo, with potential broad application in basic biology and drug target validation. 相似文献
10.
The effects of exchange-transfusion with a proprietary gelatin-based plasma volume expander, Haemaccel, have been investigated in conscious, chronically-catheterized rats. No adverse changes in basic cardiovascular or respiratory functions occurred during the procedure although an increase in intravascular fluid sodium but not potassium concentration was observed. 相似文献