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1.
Matthew A. Wheeler Alice Warley Roland G. Roberts Elisabeth Ehler Juliet A. Ellis 《Cellular and molecular life sciences : CMLS》2010,67(5):781-796
How mutations in the protein emerin lead to the cardiomyopathy associated with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is unclear. We identified emerin at the adherens junction of the intercalated disc, where it co-localised with the catenin family of proteins. Emerin bound to wild type β-catenin both in vivo and in vitro. Mutating the GSK3β phosphorylation sites on β-catenin abolished this binding. Wild type but not mutant forms of emerin associated with X-EDMD were able to reduce β-catenin protein levels. Cardiomyocytes from emerin-null mice hearts exhibited erroneous β-catenin distribution and intercalated disc architecture. Treatment of wild type cardiomyocytes with phenylephrine, which inactivates GSK3β, redistributed emerin and β-catenin. Emerin was identified as a direct target of GSK3β activity since exogenous expression of GSK3β reduced emerin levels at the nuclear envelope. We propose that perturbation to or total loss of the emerin–β-catenin complex compromises both intercalated disc function and β-catenin signalling in cardiomyocytes. 相似文献
2.
Injection of a purified serotonin (and tryptophan)-degrading enzyme into mice produced a pronounced hypothermia when the mice were maintained at 22 degrees C, but not at 30 degrees C. Brain levels of serotonin and tryptophan were strikingly depleted, but concentrations of norepinephrine and dopamine remained unchanged. 相似文献
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Young DA Wright AP Roberts JL Warner RC Young NW Greenbaum JS Schroeder DM Holt JW Sugden DE Blankenship DD van Ommen TD Siegert MJ 《Nature》2011,474(7349):72-75
The first Cenozoic ice sheets initiated in Antarctica from the Gamburtsev Subglacial Mountains and other highlands as a result of rapid global cooling ~34 million years ago. In the subsequent 20 million years, at a time of declining atmospheric carbon dioxide concentrations and an evolving Antarctic circumpolar current, sedimentary sequence interpretation and numerical modelling suggest that cyclical periods of ice-sheet expansion to the continental margin, followed by retreat to the subglacial highlands, occurred up to thirty times. These fluctuations were paced by orbital changes and were a major influence on global sea levels. Ice-sheet models show that the nature of such oscillations is critically dependent on the pattern and extent of Antarctic topographic lowlands. Here we show that the basal topography of the Aurora Subglacial Basin of East Antarctica, at present overlain by 2-4.5?km of ice, is characterized by a series of well-defined topographic channels within a mountain block landscape. The identification of this fjord landscape, based on new data from ice-penetrating radar, provides an improved understanding of the topography of the Aurora Subglacial Basin and its surroundings, and reveals a complex surface sculpted by a succession of ice-sheet configurations substantially different from today's. At different stages during its fluctuations, the edge of the East Antarctic Ice Sheet lay pinned along the margins of the Aurora Subglacial Basin, the upland boundaries of which are currently above sea level and the deepest parts of which are more than 1?km below sea level. Although the timing of the channel incision remains uncertain, our results suggest that the fjord landscape was carved by at least two iceflow regimes of different scales and directions, each of which would have over-deepened existing topographic depressions, reversing valley floor slopes. 相似文献
5.
Dawson MA Prinjha RK Dittmann A Giotopoulos G Bantscheff M Chan WI Robson SC Chung CW Hopf C Savitski MM Huthmacher C Gudgin E Lugo D Beinke S Chapman TD Roberts EJ Soden PE Auger KR Mirguet O Doehner K Delwel R Burnett AK Jeffrey P Drewes G Lee K Huntly BJ Kouzarides T 《Nature》2011,478(7370):529-533
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Roberts AE Araki T Swanson KD Montgomery KT Schiripo TA Joshi VA Li L Yassin Y Tamburino AM Neel BG Kucherlapati RS 《Nature genetics》2007,39(1):70-74
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation. 相似文献
8.
E A Donley N R Claussen S L Cornish J L Roberts E A Cornell C E Wieman 《Nature》2001,412(6844):295-299
When atoms in a gas are cooled to extremely low temperatures, they will-under the appropriate conditions-condense into a single quantum-mechanical state known as a Bose-Einstein condensate. In such systems, quantum-mechanical behaviour is evident on a macroscopic scale. Here we explore the dynamics of how a Bose-Einstein condensate collapses and subsequently explodes when the balance of forces governing its size and shape is suddenly altered. A condensate's equilibrium size and shape is strongly affected by the interatomic interactions. Our ability to induce a collapse by switching the interactions from repulsive to attractive by tuning an externally applied magnetic field yields detailed information on the violent collapse process. We observe anisotropic atom bursts that explode from the condensate, atoms leaving the condensate in undetected forms, spikes appearing in the condensate wavefunction and oscillating remnant condensates that survive the collapse. All these processes have curious dependences on time, on the strength of the interaction and on the number of condensate atoms. Although the system would seem to be simple and well characterized, our measurements reveal many phenomena that challenge theoretical models. 相似文献
9.
Clustering of organisms can be a consequence of social behaviour, or of the response of individuals to chemical and physical cues. Environmental variability can also cause clustering: for example, marine turbulence transports plankton and produces chlorophyll concentration patterns in the upper ocean. Even in a homogeneous environment, nonlinear interactions between species can result in spontaneous pattern formation. Here we show that a population of independent, random-walking organisms ('brownian bugs'), reproducing by binary division and dying at constant rates, spontaneously aggregates. Using an individual-based model, we show that clusters form out of spatially homogeneous initial conditions without environmental variability, predator-prey interactions, kinesis or taxis. The clustering mechanism is reproductively driven-birth must always be adjacent to a living organism. This clustering can overwhelm diffusion and create non-poissonian correlations between pairs (parent and offspring) or organisms, leading to the emergence of patterns. 相似文献
10.
D J Roberts A G Craig A R Berendt R Pinches G Nash K Marsh C I Newbold 《Nature》1992,357(6380):689-692
Adhesion of parasitized erythrocytes to post-capillary venular endothelium or uninfected red cells is strongly implicated in the pathogenesis of severe Plasmodium falciparum malaria. Neoantigens at the infected red-cell surface adhere to a variety of host receptors, demonstrate serological diversity in field isolates and may also be a target of the host-protective immune response. Here we use sequential cloning of P. falciparum by micromanipulation to investigate the ability of a parasite to switch antigenic and cytoadherence phenotypes. Our data show that antigens at the parasitized cell surface undergo clonal variation in vitro in the absence of immune pressure at the rate of 2% per generation with concomitant modulations of the adhesive phenotype. A clone has the potential to switch at high frequency to a variety of antigenic and adhesive phenotypes, including a new type of cytoadherence behaviour, 'auto-agglutination' of infected erythrocytes. This rapid appearance of antigenic and functional heterogeneity has important implications for pathogenesis and acquired immunity. 相似文献