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排序方式: 共有197条查询结果,搜索用时 15 毫秒
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Parton LE Ye CP Coppari R Enriori PJ Choi B Zhang CY Xu C Vianna CR Balthasar N Lee CE Elmquist JK Cowley MA Lowell BB 《Nature》2007,449(7159):228-232
A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes. 相似文献
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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
5.
Biasing reaction pathways with mechanical force 总被引:1,自引:0,他引:1
During the course of chemical reactions, reactant molecules need to surmount an energy barrier to allow their transformation into products. The energy needed for this process is usually provided by heat, light, pressure or electrical potential, which act either by changing the distribution of the reactants on their ground-state potential energy surface or by moving them onto an excited-state potential energy surface and thereby facilitate movement over the energy barrier. A fundamentally different way of initiating or accelerating a reaction is the use of force to deform reacting molecules along a specific direction of the reaction coordinate. Mechanical force has indeed been shown to activate covalent bonds in polymers, but the usual result is chain scission. Here we show that mechanically sensitive chemical groups make it possible to harness the mechanical forces generated when exposing polymer solutions to ultrasound, and that this allows us to accelerate rearrangement reactions and bias reaction pathways to yield products not obtainable from purely thermal or light-induced reactions. We find that when placed within long polymer strands, the trans and cis isomers of a 1,2-disubstituted benzocyclobutene undergo an ultrasound-induced electrocyclic ring opening in a formally conrotatory and formally disrotatory process, respectively, that yield identical products. This contrasts with reaction initiation by light or heat alone, in which case the isomers follow mutually exclusive pathways to different products. Mechanical forces associated with ultrasound can thus clearly alter the shape of potential energy surfaces so that otherwise forbidden or slow processes proceed under mild conditions, with the directionally specific nature of mechanical forces providing a reaction control that is fundamentally different from that achieved by adjusting chemical or physical parameters. Because rearrangement in our system occurs before chain scission, the effect we describe might allow the development of materials that are activated by mechanical stress fields. 相似文献
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Zuber J Shi J Wang E Rappaport AR Herrmann H Sison EA Magoon D Qi J Blatt K Wunderlich M Taylor MJ Johns C Chicas A Mulloy JC Kogan SC Brown P Valent P Bradner JE Lowe SW Vakoc CR 《Nature》2011,478(7370):524-528
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. 相似文献
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The developmental dynamics of the maize leaf transcriptome 总被引:5,自引:0,他引:5
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Bis JC DeCarli C Smith AV van der Lijn F Crivello F Fornage M Debette S Shulman JM Schmidt H Srikanth V Schuur M Yu L Choi SH Sigurdsson S Verhaaren BF DeStefano AL Lambert JC Jack CR Struchalin M Stankovich J Ibrahim-Verbaas CA Fleischman D Zijdenbos A den Heijer T Mazoyer B Coker LH Enzinger C Danoy P Amin N Arfanakis K van Buchem MA de Bruijn RF Beiser A Dufouil C Huang J Cavalieri M Thomson R Niessen WJ Chibnik LB Gislason GK Hofman A Pikula A Amouyel P Freeman KB Phan TG Oostra BA Stein JL 《Nature genetics》2012,44(5):545-551
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. 相似文献
9.
Sequence and analysis of chromosome 2 of the plant Arabidopsis thaliana 总被引:21,自引:0,他引:21
Lin X Kaul S Rounsley S Shea TP Benito MI Town CD Fujii CY Mason T Bowman CL Barnstead M Feldblyum TV Buell CR Ketchum KA Lee J Ronning CM Koo HL Moffat KS Cronin LA Shen M Pai G Van Aken S Umayam L Tallon LJ Gill JE Adams MD Carrera AJ Creasy TH Goodman HM Somerville CR Copenhaver GP Preuss D Nierman WC White O Eisen JA Salzberg SL Fraser CM Venter JC 《Nature》1999,402(6763):761-768
Arabidopsis thaliana (Arabidopsis) is unique among plant model organisms in having a small genome (130-140 Mb), excellent physical and genetic maps, and little repetitive DNA. Here we report the sequence of chromosome 2 from the Columbia ecotype in two gap-free assemblies (contigs) of 3.6 and 16 megabases (Mb). The latter represents the longest published stretch of uninterrupted DNA sequence assembled from any organism to date. Chromosome 2 represents 15% of the genome and encodes 4,037 genes, 49% of which have no predicted function. Roughly 250 tandem gene duplications were found in addition to large-scale duplications of about 0.5 and 4.5 Mb between chromosomes 2 and 1 and between chromosomes 2 and 4, respectively. Sequencing of nearly 2 Mb within the genetically defined centromere revealed a low density of recognizable genes, and a high density and diverse range of vestigial and presumably inactive mobile elements. More unexpected is what appears to be a recent insertion of a continuous stretch of 75% of the mitochondrial genome into chromosome 2. 相似文献
10.
Nitrification is a key stage in the nitrogen cycle; it enables the transformation of nitrogen into an oxidized, inorganic state. The availability of nitrates produced by this process often limits primary productivity and is an important determinant in plant community ecology and biodiversity. Chemoautotrophic prokaryotes are recognized as the main facilitators of this process, although heterotrophic nitrification by fungi may be significant under certain conditions. However, there has been neither biochemical nor ecological evidence to support nitrification by photoautotrophic plants. Here we show how certain legumes that accumulate the toxin, 3-nitropropionic acid, generate oxidized inorganic nitrogen in their shoots, which is returned to the soil in their litter. In nitrogen-fixing populations this 'new' nitrate and nitrite can be derived from the assimilation of nitrogen gas. Normally, the transformation of elemental nitrogen from the atmosphere into a fixed oxidized form (as nitrate) is represented in the nitrogen cycle as a multiphasic process involving several different organisms. We show how this can occur in a single photoautotrophic organism, representing a previously undescribed feature of this biogeochemical cycle. 相似文献