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排序方式: 共有82条查询结果,搜索用时 31 毫秒
1.
PTC124 targets genetic disorders caused by nonsense mutations 总被引:1,自引:0,他引:1
Welch EM Barton ER Zhuo J Tomizawa Y Friesen WJ Trifillis P Paushkin S Patel M Trotta CR Hwang S Wilde RG Karp G Takasugi J Chen G Jones S Ren H Moon YC Corson D Turpoff AA Campbell JA Conn MM Khan A Almstead NG Hedrick J Mollin A Risher N Weetall M Yeh S Branstrom AA Colacino JM Babiak J Ju WD Hirawat S Northcutt VJ Miller LL Spatrick P He F Kawana M Feng H Jacobson A Peltz SW Sweeney HL 《Nature》2007,447(7140):87-91
Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options. 相似文献
2.
The study of bosonic modes that couple to the charge carriers is a key element in understanding superconductivity. Using atomic-resolution scanning-tunnelling microscopy (STM) to extract the spectrum of these modes in the high-temperature superconductor Bi2Sr2CaCu2O(8+delta), Lee et al. find a mode whose frequency does not depend on doping but that changes on isotopic substitution of 16O with 18O. From this, they infer a role for lattice modes (phonons). However, examination of their data reveals a weaker, but distinct, feature that has all the characteristics of the magnetic excitation identified as the bosonic mode in other competing experiments. We therefore suggest that the lattice mode seen by Lee et al. is not relevant to superconductivity and is due to inelastic tunnelling through the insulating oxide layer. 相似文献
3.
International Consortium for Blood Pressure Genome-Wide Association Studies Ehret GB Munroe PB Rice KM Bochud M Johnson AD Chasman DI Smith AV Tobin MD Verwoert GC Hwang SJ Pihur V Vollenweider P O'Reilly PF Amin N Bragg-Gresham JL Teumer A Glazer NL Launer L Zhao JH Aulchenko Y Heath S Sõber S Parsa A Luan J Arora P Dehghan A Zhang F Lucas G Hicks AA Jackson AU Peden JF Tanaka T Wild SH Rudan I Igl W Milaneschi Y Parker AN Fava C Chambers JC Fox ER Kumari M Go MJ van der Harst P Kao WH 《Nature》2011,478(7367):103-109
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. 相似文献
4.
Bing Joe Hwang Ching Hsiang Chen Loka Subramanyam Sarma Din-gao Liu Jyh Fu Lee 《复旦学报(自然科学版)》2007,46(5)
1 Results Bimetallic particles in the nanometer size range are of substantial interest due to their vast applications in catalysis[1].The synthesis of bimetallic nanoparticles with definite size with a well-control over their nanostructure remains a challenging problem.Thus there exists a great demand for both synthesis and atomic level characterization of nanostructure of bimetallic nanoparticles (NPs).With the recent advent of high-intensity tunable sources of X-rays,now available at synchrotron radia... 相似文献
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6.
本文报道了新的含铜的氧化物的物相 Pr_(1.3)Bi_(0.1)Sr_(0.3)Ca_(0.2)Cu_2O_6的制奋、单晶结构和电磁性能.由单晶 X 射线衍射数据分析,该氧化物属四方晶系,空间群 D_(4λ)~(17)—l4/mmm.测得晶胞常数为α=3.831×10~(-10)m,c=19.642×10~(-10)m,Z=2,V=288.3×10~(-20)m~3。在4.5—300K 温度范围内,该物相不显超导性能。经高压纯氧气氛焙烧或经纯160 Pa 氧焙烧后再经氩气氛处理的 Pr_(2-x)(Sr,Ca)_(l+2)Cu_2O_(?)(x≈0至0.4)样品也不显超导性能. 相似文献
7.
Neurons in most regions of the mammalian nervous system are generated over an extended period of time during development. Maintaining sufficient numbers of progenitors over the course of neurogenesis is essential to ensure that neural cells are produced in correct numbers and diverse types. The underlying molecular mechanisms, like those governing stem-cell self-renewal in general, remain poorly understood. We report here that mouse numb and numblike (Nbl), two highly conserved homologues of Drosophila numb, play redundant but critical roles in maintaining neural progenitor cells during embryogenesis, by allowing their progenies to choose progenitor over neuronal fates. In Nbl mutant embryos also conditionally mutant for mouse numb in the nervous system, early neurons emerge in the expected spatial and temporal pattern, but at the expense of progenitor cells, leading to a nearly complete depletion of dividing cells shortly after the onset of neurogenesis. Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities. 相似文献
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9.
The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin 总被引:20,自引:0,他引:20
Insulin stimulates glucose transport by promoting exocytosis of the glucose transporter Glut4 (refs 1, 2). The dynamic processes involved in the trafficking of Glut4-containing vesicles, and in their targeting, docking and fusion at the plasma membrane, as well as the signalling processes that govern these events, are not well understood. We recently described tyrosine-phosphorylation events restricted to subdomains of the plasma membrane that result in activation of the G protein TC10 (refs 3, 4). Here we show that TC10 interacts with one of the components of the exocyst complex, Exo70. Exo70 translocates to the plasma membrane in response to insulin through the activation of TC10, where it assembles a multiprotein complex that includes Sec6 and Sec8. Overexpression of an Exo70 mutant blocked insulin-stimulated glucose uptake, but not the trafficking of Glut4 to the plasma membrane. However, this mutant did block the extracellular exposure of the Glut4 protein. So, the exocyst might have a crucial role in the targeting of the Glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion. 相似文献
10.
Genetic engineering is a powerful tool for exploring correlations between structure and function in proteins, but as yet we are unable to use it for effective protein design. One of the most interesting examples, which would seem to be obvious, is reversing the polarity of an ion pair. Changing a positively charged protein group, that provides a strong binding for negative substrates, to a negative group is expected to provide an effective binding site for a positively charged substrate. But several recent experiments on aspartate aminotransferase, trypsin and aspartate transcarbamoylase (Schachman, H. K. personal communication) have indicated that polarity reversal is not so successful. Here we argue that the same factors that make the enzyme an effective system for the (-+) pair will make it a much less effective system for the (+-) pair. We also point out that the unusually low effective dielectric constant (epsilon approximately equal to 13) for the (-+) interaction is due to its microenvironment and this will destabilize a (+-) arrangement having an entirely different dielectric constant (epsilon approximately equal to 80). The calculations presented here evaluate the energetics of ion pairs in protein active sites on a semiquantitative level. This is particularly important when dealing with strong, functionally important interactions that are difficult to evaluate with macroscopic models. 相似文献