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11.
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
12.
Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications 总被引:2,自引:0,他引:2
Solá RJ Rodríguez-Martínez JA Griebenow K 《Cellular and molecular life sciences : CMLS》2007,64(16):2133-2152
Glycosylation constitutes one of the most important posttranslational modifications employed by biological systems to modulate
protein biophysical properties. Due to the direct biochemical and biomedical implications of achieving control over protein
stability and function by chemical means, there has been great interest in recent years towards the development of chemical
strategies for protein glycosylation. Since current knowledge about glycoprotein biophysics has been mainly derived from the
study of naturally glycosylated proteins, chemical glycosylation provides novel insights into its mechanistic understanding
by affording control over glycosylation parameters. This review presents a survey of the effects that natural and chemical
glycosylation have on the fundamental biophysical properties of proteins (structure, dynamics, stability, and function). This
is complemented by a mechanistic discussion of how glycans achieve such effects and discussion of the implications of employing
chemical glycosylation as a tool to exert control over protein biophysical properties within biochemical and biomedical applications.
Received 15 December 2006; received after revision 28 March 2007; accepted 25 April 2007 相似文献
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14.
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 总被引:14,自引:0,他引:14
van Heel DA Franke L Hunt KA Gwilliam R Zhernakova A Inouye M Wapenaar MC Barnardo MC Bethel G Holmes GK Feighery C Jewell D Kelleher D Kumar P Travis S Walters JR Sanders DS Howdle P Swift J Playford RJ McLaren WM Mearin ML Mulder CJ McManus R McGinnis R Cardon LR Deloukas P Wijmenga C 《Nature genetics》2007,39(7):827-829
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. 相似文献
15.
Lindahl E Nyman U Melles E Sigmundsson K Ståhlberg M Wahren J Obrink B Shafqat J Joseph B Jörnvall H 《Cellular and molecular life sciences : CMLS》2007,64(4):479-486
Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is
internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide,
we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport
into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at
4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive
mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated
binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components
to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence
of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that
of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action.
Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006 相似文献
16.
V.A.帕瑟根 《国外科技新书评介》2007,(2):7-7
分子间的范德华力是十分微弱的,但可以说普遍的存在着,在很多体系中起着巨大的作用,在物理学、化学、生物学等学科中得到了广泛的研究。但怎样计算范德华力?如何考虑各种条件对范德华力的影响? 相似文献
17.
Strell C Lang K Niggemann B Zaenker KS Entschladen F 《Cellular and molecular life sciences : CMLS》2007,64(24):3306-3316
The extravasation of leukocytes and tumor cells is a multi-step process with the involvement of various adhesion molecules
depending on the three steps rolling, adhesion, and diapedesis. We have developed an in vitro model, by which we investigated the rolling and adhesion of neutrophil granulocytes and MDA-MB-468 human breast carcinoma
cells to lung endothelial cells under physiological flow-conditions. We found that norepinephrine had an inhibitory function
on the fMLP-promoted adhesion of neutrophil granulocytes due to a down-regulation of β2-integrin. Furthermore, neutrophil
granulocytes serve as linking cells for the interaction of the MDA-MB-468 cells with the endothelium, which are both β2-integrin
negative, but express the β2-integrin ligand ICAM-1. In addition, we show here that N-cadherin is up-regulated on the endothelial
cells and on neutrophil granulocytes in response to fMLP. This up-regulation resulted in a significant increase of adherent
MDA-MB-468 cells, which are also N-cadherin positive.
Received 3 September 2007; received after revision 17 October 2007; accepted 22 October 2007 相似文献
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20.
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants 总被引:2,自引:0,他引:2
Wellcome Trust Case Control Consortium;Australo-Anglo-American Spondylitis Consortium 《Nature genetics》2007,39(11):1329-1337
We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases. 相似文献