排序方式: 共有37条查询结果,搜索用时 31 毫秒
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Yusa K Rashid ST Strick-Marchand H Varela I Liu PQ Paschon DE Miranda E Ordóñez A Hannan NR Rouhani FJ Darche S Alexander G Marciniak SJ Fusaki N Hasegawa M Holmes MC Di Santo JP Lomas DA Bradley A Vallier L 《Nature》2011,478(7369):391-394
Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies. 相似文献
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Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues. 相似文献
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Mungall AJ Palmer SA Sims SK Edwards CA Ashurst JL Wilming L Jones MC Horton R Hunt SE Scott CE Gilbert JG Clamp ME Bethel G Milne S Ainscough R Almeida JP Ambrose KD Andrews TD Ashwell RI Babbage AK Bagguley CL Bailey J Banerjee R Barker DJ Barlow KF Bates K Beare DM Beasley H Beasley O Bird CP Blakey S Bray-Allen S Brook J Brown AJ Brown JY Burford DC Burrill W Burton J Carder C Carter NP Chapman JC Clark SY Clark G Clee CM Clegg S Cobley V Collier RE Collins JE Colman LK Corby NR Coville GJ 《Nature》2003,425(6960):805-811
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Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility 总被引:14,自引:0,他引:14
Parkes M Barrett JC Prescott NJ Tremelling M Anderson CA Fisher SA Roberts RG Nimmo ER Cummings FR Soars D Drummond H Lees CW Khawaja SA Bagnall R Burke DA Todhunter CE Ahmad T Onnie CM McArdle W Strachan D Bethel G Bryan C Lewis CM Deloukas P Forbes A Sanderson J Jewell DP Satsangi J Mansfield JC;Wellcome Trust Case Control Consortium Cardon L Mathew CG 《Nature genetics》2007,39(7):830-832
A genome-wide association scan in individuals with Crohn's disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13. 相似文献
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Gregory SG Barlow KF McLay KE Kaul R Swarbreck D Dunham A Scott CE Howe KL Woodfine K Spencer CC Jones MC Gillson C Searle S Zhou Y Kokocinski F McDonald L Evans R Phillips K Atkinson A Cooper R Jones C Hall RE Andrews TD Lloyd C Ainscough R Almeida JP Ambrose KD Anderson F Andrew RW Ashwell RI Aubin K Babbage AK Bagguley CL Bailey J Beasley H Bethel G Bird CP Bray-Allen S Brown JY Brown AJ Buckley D Burton J Bye J Carder C Chapman JC Clark SY Clarke G Clee C Cobley V Collier RE Corby N 《Nature》2006,441(7091):315-321
The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome. 相似文献
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McPherson JD Marra M Hillier L Waterston RH Chinwalla A Wallis J Sekhon M Wylie K Mardis ER Wilson RK Fulton R Kucaba TA Wagner-McPherson C Barbazuk WB Gregory SG Humphray SJ French L Evans RS Bethel G Whittaker A Holden JL McCann OT Dunham A Soderlund C Scott CE Bentley DR Schuler G Chen HC Jang W Green ED Idol JR Maduro VV Montgomery KT Lee E Miller A Emerling S Kucherlapati Gibbs R Scherer S Gorrell JH Sodergren E Clerc-Blankenburg K Tabor P Naylor S Garcia D de Jong PJ Catanese JJ Nowak N 《Nature》2001,409(6822):934-941
The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map. 相似文献
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Briggs TA Rice GI Daly S Urquhart J Gornall H Bader-Meunier B Baskar K Baskar S Baudouin V Beresford MW Black GC Dearman RJ de Zegher F Foster ES Francès C Hayman AR Hilton E Job-Deslandre C Kulkarni ML Le Merrer M Linglart A Lovell SC Maurer K Musset L Navarro V Picard C Puel A Rieux-Laucat F Roifman CM Scholl-Bürgi S Smith N Szynkiewicz M Wiedeman A Wouters C Zeef LA Casanova JL Elkon KB Janckila A Lebon P Crow YJ 《Nature genetics》2011,43(2):127-131
We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sj?gren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity. 相似文献