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In vivo selection using a cell-growth switch 总被引:14,自引:0,他引:14
A major obstacle to stem-cell gene therapy rests in the inability to deliver a gene into a therapeutically relevant fraction of stem cells. One way to circumvent this obstacle is to use selection. Vectors containing two linked genes serve as the basis for selection, with one gene encoding a selectable product and the other, a therapeutic protein. Applying selection in vivo has the potential to bring a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically modified cells to be inducibly amplified, thereby averting the risks associated with cytotoxic drugs. This system provides a general platform for conditionally expanding genetically modified cell populations in vivo, and may have widespread applications in gene and cell therapy. 相似文献
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The genome of woodland strawberry (Fragaria vesca) 总被引:3,自引:0,他引:3
Shulaev V Sargent DJ Crowhurst RN Mockler TC Folkerts O Delcher AL Jaiswal P Mockaitis K Liston A Mane SP Burns P Davis TM Slovin JP Bassil N Hellens RP Evans C Harkins T Kodira C Desany B Crasta OR Jensen RV Allan AC Michael TP Setubal JC Celton JM Rees DJ Williams KP Holt SH Ruiz Rojas JJ Chatterjee M Liu B Silva H Meisel L Adato A Filichkin SA Troggio M Viola R Ashman TL Wang H Dharmawardhana P Elser J Raja R Priest HD Bryant DW Fox SE Givan SA Wilhelm LJ Naithani S Christoffels A Salama DY 《Nature genetics》2011,43(2):109-116
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Davis EE Zhang Q Liu Q Diplas BH Davey LM Hartley J Stoetzel C Szymanska K Ramaswami G Logan CV Muzny DM Young AC Wheeler DA Cruz P Morgan M Lewis LR Cherukuri P Maskeri B Hansen NF Mullikin JC Blakesley RW Bouffard GG;NISC Comparative Sequencing Program Gyapay G Rieger S Tönshoff B Kern I Soliman NA Neuhaus TJ Swoboda KJ Kayserili H Gallagher TE Lewis RA Bergmann C Otto EA Saunier S Scambler PJ Beales PL Gleeson JG Maher ER Attié-Bitach T Dollfus H Johnson CA Green ED Gibbs RA Hildebrandt F 《Nature genetics》2011,43(3):189-196
Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ~5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders. 相似文献
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Summary Lycomarasmin is a plasma poison produced byFusarium lycopersici Sacc., the pathogen of tomato wilt. In a dilution of 10–2 and 10–3 mol it causes a pathological wilting of tomato plants and usually disturbs their water balance; in a dilution of 10–4 mol it only disturbs the latter.In the present paper, we develop the theory that in sufficient concentration lycomariasmin damages or destroys thesemipermeability of the plasma boundary layer.In a dilution of 10–2 and 10–3 mol of lycomarasmin the semipermeability of the plasma membranes iscompletely destroyed. Thus on the one hand the conditions for osmotic pressure disappear and irreversible pathological wilting appears, and on the other hand cellular fluid passes into the transpiration current of the cell-membrane and leads to a momentary excess humidity, particularly in the leaf-tissues, and thus also to a momentaryexcess transpiration.The water-deficit regularly observed in wilt-literature is therefore not the cause of pathological wilting but, just as the wilting itself, a consequence of the distruction of the semipermeability of the plasma boundary layer.In a dilution of 10–4 mol lycomarasmin apparently only affects the permeability of the exterior plasma boundary layer forwater, but not for sugars etc. Therefore it only produces an excess of fluid in the leaf tissues and thus an excess transpiration, but no definite inactivation of the plasma membrane and therefore also no pathological wilt. 相似文献
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Becker T Franckenberg S Wickles S Shoemaker CJ Anger AM Armache JP Sieber H Ungewickell C Berninghausen O Daberkow I Karcher A Thomm M Hopfner KP Green R Beckmann R 《Nature》2012,482(7386):501-506
Ribosome-driven protein biosynthesis is comprised of four phases: initiation, elongation, termination and recycling. In bacteria, ribosome recycling requires ribosome recycling factor and elongation factor G, and several structures of bacterial recycling complexes have been determined. In the eukaryotic and archaeal kingdoms, however, recycling involves the ABC-type ATPase ABCE1 and little is known about its structural basis. Here we present cryo-electron microscopy reconstructions of eukaryotic and archaeal ribosome recycling complexes containing ABCE1 and the termination factor paralogue Pelota. These structures reveal the overall binding mode of ABCE1 to be similar to canonical translation factors. Moreover, the iron-sulphur cluster domain of ABCE1 interacts with and stabilizes Pelota in a conformation that reaches towards the peptidyl transferase centre, thus explaining how ABCE1 may stimulate peptide-release activity of canonical termination factors. Using the mechanochemical properties of ABCE1, a conserved mechanism in archaea and eukaryotes is suggested that couples translation termination to recycling, and eventually to re-initiation. 相似文献
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Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. 总被引:21,自引:0,他引:21
R Birkenh?ger E Otto M J Schürmann M Vollmer E M Ruf I Maier-Lutz F Beekmann A Fekete H Omran D Feldmann D V Milford N Jeck M Konrad D Landau N V Knoers C Antignac R Sudbrak A Kispert F Hildebrandt 《Nature genetics》2001,29(3):310-314
Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself. 相似文献
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Summary Homing pigeons show a 5% higher brain weight than fantails and strassers. This difference is statistically significant and independent of body size. There are no allometric differences in the eye weights. 相似文献
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