全文获取类型
收费全文 | 107篇 |
免费 | 10篇 |
出版年
2021年 | 6篇 |
2020年 | 1篇 |
2019年 | 2篇 |
2018年 | 5篇 |
2017年 | 1篇 |
2016年 | 2篇 |
2015年 | 7篇 |
2014年 | 4篇 |
2013年 | 4篇 |
2012年 | 15篇 |
2011年 | 9篇 |
2010年 | 6篇 |
2009年 | 1篇 |
2008年 | 2篇 |
2007年 | 11篇 |
2006年 | 5篇 |
2005年 | 4篇 |
2004年 | 4篇 |
2003年 | 5篇 |
2002年 | 2篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1988年 | 2篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1977年 | 1篇 |
排序方式: 共有117条查询结果,搜索用时 609 毫秒
71.
Saxena R Elbers CC Guo Y Peter I Gaunt TR Mega JL Lanktree MB Tare A Castillo BA Li YR Johnson T Bruinenberg M Gilbert-Diamond D Rajagopalan R Voight BF Balasubramanyam A Barnard J Bauer F Baumert J Bhangale T Böhm BO Braund PS Burton PR Chandrupatla HR Clarke R Cooper-DeHoff RM Crook ED Davey-Smith G Day IN de Boer A de Groot MC Drenos F Ferguson J Fox CS Furlong CE Gibson Q Gieger C Gilhuijs-Pederson LA Glessner JT Goel A Gong Y Grant SF Grobbee DE Hastie C Humphries SE Kim CE Kivimaki M 《American journal of human genetics》2012,90(3):410-425
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ~50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ~2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups. 相似文献
72.
Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures 总被引:23,自引:0,他引:23
The three-dimensional culture of MCF-10A mammary epithelial cells on a reconstituted basement membrane results in formation of polarized, growth-arrested acini-like spheroids that recapitulate several aspects of glandular architecture in vivo. Oncogenes introduced into MCF-10A cells disrupt this morphogenetic process, and elicit distinct morphological phenotypes. Recent studies analyzing the mechanistic basis for phenotypic heterogeneity observed among different oncogenes (e.g., ErbB2, cyclin D1) have illustrated the utility of this three-dimensional culture system in modeling the biological activities of cancer genes, particularly with regard to their ability to disrupt epithelial architecture during the early aspects of carcinoma formation. Here we provide a collection of protocols to culture MCF-10A cells, to establish stable pools expressing a gene of interest via retroviral infection, as well as to grow and analyze MCF-10A cells in three-dimensional basement membrane culture. 相似文献
73.
ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini
Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumours. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in three-dimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumours, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays. 相似文献
74.
Balasubramanyam K Varier RA Altaf M Swaminathan V Siddappa NB Ranga U Kundu TK 《The Journal of biological chemistry》2004,279(49):51163-51171
75.
Mammary tumors expressing the neu proto-oncogene possess elevated c-Src tyrosine kinase activity. 总被引:14,自引:4,他引:10
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
S K Muthuswamy P M Siegel D L Dankort M A Webster W J Muller 《Molecular and cellular biology》1994,14(1):735-743
Amplification and overexpression of the neu (c-erbB2) proto-oncogene has been implicated in the pathogenesis of 20 to 30% of human breast cancers. Although the activation of Neu receptor tyrosine kinase appears to be a pivotal step during mammary tumorigenesis, the mechanism by which Neu signals cell proliferation is unclear. Molecules bearing a domain shared by the c-Src proto-oncogene (Src homology 2) are thought to be involved in signal transduction from activated receptor tyrosine kinases such as Neu. To test whether c-Src was implicated in Neu-mediated signal transduction, we measured the activity of the c-Src tyrosine kinase in tissue extracts from either mammary tumors or adjacent mammary epithelium derived from transgenic mice expressing a mouse mammary tumor virus promoter/enhancer/unactivated neu fusion gene. The Neu-induced mammary tumors possessed six- to eightfold-higher c-Src kinase activity than the adjacent epithelium. The increase in c-Src tyrosine kinase activity was not due to an increase in the levels of c-Src but rather was a result of the elevation of its specific activity. Moreover, activation of c-Src was correlated with its ability to complex tyrosine-phosphorylated Neu both in vitro and in vivo. Together, these observations suggest that activation of the c-Src tyrosine kinase during mammary tumorigenesis may occur through a direct interaction with activated Neu. 相似文献
76.
77.
The saline pond microalga, Dunaliella salina (Dunal) Teod. maintained in De Walne's (basal) medium under laboratory conditions was confirmed by amplifying the chromosomal DNA of the microalga by PCR with specific primers MA1 and MA2. Seaweed extracts obtained from Sargassum wightii and Ulva lactuca were amended separately at 1.0%, 1.5%, 2.0% and 2.5% levels to the basal medium in order to assess their potential on the growth and concentration of pigments, viz. Chl a, Chl b and beta-carotene of the alga. beta-Carotene was isolated and visible absorption spectrum was taken at 443 and 475 nm confirmed the presence of 9-cis-beta-carotene and all-trans-beta-carotene isomers. Maximum yield, highest division rate (mu) and highest pigment concentrations were observed in the cells grown in 1.5% S. wightii and 2.0% U. lactuca amended medium and these cells were subjected to DAPI staining. The results of epifluorescence microscopy and image analysis revealed a significant enhancement of the cell and nuclear area of the microalgae. 相似文献
78.
Microsystem for transfection of exogenous molecules with spatio-temporal control into adherent cells
Several non-viral techniques involving the use of liposomes, particle bombardment and electroporation have been used for efficient transfection of plasmids and other molecules into cells. Current approaches target whole or bulk regions of tissue, lacking the desired spatial control over the transfection process. In this study, we present a novel approach using microsystems to achieve spatial and temporal control over the transfection process in adherent cells. A 6x6 MEA (microelectrode array) with 100 microm microelectrode dimension was developed on a silicon substrate using standard microfabrication procedures and passivated with a biocompatible layer. Using finite element models, electric field intensities were simulated and locations of optimal electroporation zones in the cell culture on the microelectrode surface were predicted. The MEA was subsequently tested using 3T3 fibroblasts cultured on the MEA surface for 96 h and stimulation voltages in the range of 2-5 V in the presence of propidium iodide (PI), a cell impermeant dye. Maximum electric field intensities in the z-direction were estimated to be in the range of 320-820 V/cm for applied differential voltages in the range of 2-5 V. Cells directly on the top and on the edges of the stimulating microelectrodes in the MEA were preferentially transfected with PI as predicted by the simulations. The results of these experiments demonstrate that spatial and temporal control of desired regions of transfection in vitro can be achieved using MEAs and electroporation. 相似文献
79.
Muthuswamy Balasubramanyam Ramalingham A. Balaji Balakrishnan Subashini Viswanathan Mohan 《Experimental diabetes research》2000,1(4):275-287
Altered cytosolic Ca2+ is implicated in the aetiology
of many diseases including diabetes but there are
few studies on the mechanism(s) of the altered Ca2+
regulation. Using human lymphocytes, we studied
cytosolic calcium (Cai) and various Ca2+ transport
mechanisms in subjects with Type 2 diabetes
mellitus and control subjects. Ca2+-specific fluorescent
probes (Fura-2 and Fluo-3) were used to
monitor the Ca2+ signals. Thapsigargin, a potent and
specific inhibitor of the sarco(endo)plasmic reticulum
Ca2+-ATPase (SERCA), was used to study Ca2+-
store dependent Ca2+ fluxes. Significant (P < 0.05)
elevation of basal Cai levels was observed in
lymphocytes from diabetic subjects. Cai levels were
positively correlated with fasting, plasma glucose
and HbAlc. There was also a significant (P < 0.05)
reduction in plasma membrane calcium (PMCA)
ATPase activity in diabetic subjects compared to
controls. Cells from Type 2 diabetics exhibited an
increased Ca2+ influx (as measured both by Fluo-3
fliorescence and C45a assays) as a consequence of
of thapsigargin-mediated Ca2+ store depletion. Upon
addition of Mn2+ (a surrogate of Ca2+), the fura-2
fluorescence decayed in an exponential fashion and
the rate and extent of this decline was steeper and
greater in cells from type 2 diabetic patients. There
was also a significant (P < 0.05) difference in the
Na+/Ca2+ exchange activity in Type 2 diabetic
patients, both under resting conditions and after challenging the cells with thapsigargin, when the
internal store Ca2+ sequestration was circumvented.
Pharmacological activation of protein kinase C
(PKC) in cells from patients resulted in only partial
inhibition of Ca2+ entry. We conclude that cellular
Ca2+ accumulation in cells from Type 2 diabetes
results from (a) reduction in PMCA ATPase activity,
(b) modulation of Na+/Ca2+ exchange and (3)
increased Ca2+ influx across the plasma membrane. 相似文献