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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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Trefoil factors 总被引:6,自引:0,他引:6
Trefoil factor family (TFF) peptides have many in vivo and in vitro effects on restitution, wound healing, apoptosis, cell motility, adhesion and vectorial ion pumping, amongst others. (125)I-TFF peptides bind to cell membranes with classical saturable ability. It would be surprising if there were not TFF-protein interactions that would explain these actions, but to date no convincing TFF-binding partner has been shown which unambiguously takes part in any of these functions. Nevertheless, several TFF-binding proteins exist, including the small intestinal CRP-ductin (muclin), which binds TFF2, and the recently described gastric foveolar proteins TFIZ1 (TFF1-binding) and blottin (TFF2-binding), any of which may yet interact in novel ways to elicit TFF-mediated events. This review describes the expression and, where known, the functions of such proteins. 相似文献
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Jones DH Nakashima T Sanchez OH Kozieradzki I Komarova SV Sarosi I Morony S Rubin E Sarao R Hojilla CV Komnenovic V Kong YY Schreiber M Dixon SJ Sims SM Khokha R Wada T Penninger JM 《Nature》2006,440(7084):692-696
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells. 相似文献
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Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion. 总被引:4,自引:0,他引:4
R Estévez T Boettger V Stein R Birkenh?ger E Otto F Hildebrandt T J Jentsch 《Nature》2001,414(6863):558-561
Renal salt loss in Bartter's syndrome is caused by impaired transepithelial transport in the loop of Henle. Sodium chloride is taken up apically by the combined activity of NKCC2 (Na+-K--2Cl- cotransporters) and ROMK potassium channels. Chloride ions exit from the cell through basolateral ClC-Kb chloride channels. Mutations in the three corresponding genes have been identified that correspond to Bartter's syndrome types 1-3. The gene encoding the integral membrane protein barttin is mutated in a form of Bartter's syndrome that is associated with congenital deafness and renal failure. Here we show that barttin acts as an essential beta-subunit for ClC-Ka and ClC-Kb chloride channels, with which it colocalizes in basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Disease-causing mutations in either ClC-Kb or barttin compromise currents through heteromeric channels. Currents can be stimulated further by mutating a proline-tyrosine (PY) motif on barttin. This work describes the first known beta-subunit for CLC chloride channels and reveals that heteromers formed by ClC-K and barttin are crucial for renal salt reabsorption and potassium recycling in the inner ear. 相似文献
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简要介绍水平排列硅光二极管色传感器的制作工艺,该器件波长在500nm到650nm范围内有一个单调的近于线性的光谱响应。入射光波长为600nm时,入射光强度化五个数量级,测出的波长基本不变,器件波长分辨率、最低入射光强、长时间测量的波长漂移以及波长温漂系数等特性的测量结果表明:该类色传感器已达高性能实用要求。 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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Horizontal gene transfer (HGT), the acquisition of genetic material from non-parental lineages, is known to be important in bacterial evolution. In particular, HGT provides rapid access to genetic innovations, allowing traits such as virulence, antibiotic resistance and xenobiotic metabolism to spread through the human microbiome. Recent anecdotal studies providing snapshots of active gene flow on the human body have highlighted the need to determine the frequency of such recent transfers and the forces that govern these events. Here we report the discovery and characterization of a vast, human-associated network of gene exchange, large enough to directly compare the principal forces shaping HGT. We show that this network of 10,770 unique, recently transferred (more than 99% nucleotide identity) genes found in 2,235 full bacterial genomes, is shaped principally by ecology rather than geography or phylogeny, with most gene exchange occurring between isolates from ecologically similar, but geographically separated, environments. For example, we observe 25-fold more HGT between human-associated bacteria than among ecologically diverse non-human isolates (P = 3.0 × 10(-270)). We show that within the human microbiome this ecological architecture continues across multiple spatial scales, functional classes and ecological niches with transfer further enriched among bacteria that inhabit the same body site, have the same oxygen tolerance or have the same ability to cause disease. This structure offers a window into the molecular traits that define ecological niches, insight that we use to uncover sources of antibiotic resistance and identify genes associated with the pathology of meningitis and other diseases. 相似文献