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排序方式: 共有60条查询结果,搜索用时 46 毫秒
1.
Li H Haurigot V Doyon Y Li T Wong SY Bhagwat AS Malani N Anguela XM Sharma R Ivanciu L Murphy SL Finn JD Khazi FR Zhou S Paschon DE Rebar EJ Bushman FD Gregory PD Holmes MC High KA 《Nature》2011,475(7355):217-221
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease. 相似文献
2.
Crossan GP van der Weyden L Rosado IV Langevin F Gaillard PH McIntyre RE;Sanger Mouse Genetics Project Gallagher F Kettunen MI Lewis DY Brindle K Arends MJ Adams DJ Patel KJ 《Nature genetics》2011,43(2):147-152
The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. 相似文献
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Engert JC Bérubé P Mercier J Doré C Lepage P Ge B Bouchard JP Mathieu J Melançon SB Schalling M Lander ES Morgan K Hudson TJ Richter A 《Nature genetics》2000,24(2):120-125
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis. 相似文献
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Summary One of the products of the chromic acid oxidation of the animal triterpene ambreine (V) has been identified with the lactone C16H26O2 (III) whichRuzicka and coll. had isolated by oxidation of the plant diterpene sclareol (II). This identification confirms recent findings of the authors and ofRuzicka, Dürst andJeger and shows that the hydroxyle of ambreine (V) is at the same place as the hydroxyle of sclareol which is attached to the perhydronaphtalene ring.
4me communication sur les constituants de l'ambre gris 相似文献
4me communication sur les constituants de l'ambre gris 相似文献
8.
B. Thébaud J.-F. Arnal J. C. Mercier A.-T. Dinh-Xuan 《Cellular and molecular life sciences : CMLS》1999,55(8-9):1103-1112
Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The
rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated
lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood
flow is increased. Inhaled NO has been succesfully applied to treat persistent pulmonary hypertension of the newborn, reducing
the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound
hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to
be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary
vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient
improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established.
NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory
tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased
in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased
in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation
of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous
NO. 相似文献
9.
Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. 总被引:14,自引:0,他引:14
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