K-ATP channel gene expression is induced by urocortin and mediates its cardioprotective effect

Background-Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.Methods and Results-We have analyzed global changes in gone expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K-ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.Conclusions-This is, to our knowledge, the first report of the altered expression of a K-ATP. channel subunit induced by a cardioprotective agent and demonstrates that K-ATP, channel opening is essential for the effect of this novel cardioprotective agent

Boundary Conditions for Interacting Membranes

We investigate supersymmetric boundary conditions in both the Bagger-Lambert and the ABJM theories of interacting membranes. We find boundary conditions associated to the fivebrane, the ninebrane and the M-theory wave. For the ABJM theory we are able to understand the enhancement of supersymmetry to produce the (4,4) supersymmetry of the self-dual string. We also include supersymmetric boundary conditions on the gauge fields that cancel the classical gauge anomaly of the Chern-Simons terms.Comment: 36 pages, latex, v2 minor typos correcte

Area-level deprivation and adiposity in children: is the relationship linear?

OBJECTIVE: It has been suggested that childhood obesity is inversely associated with deprivation, such that the prevalence is higher in more deprived groups. However, comparatively few studies actually use an area-level measure of deprivation, limiting the scope to assess trends in the association with obesity for this indicator. Furthermore, most assume a linear relationship. Therefore, the aim of this study was to investigate associations between area-level deprivation and three measures of adiposity in children: body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). DESIGN: This is a cross-sectional study in which data were collected on three occasions a year apart (2005-2007). SUBJECTS: Data were available for 13,333 children, typically aged 11-12 years, from 37 schools and 542 lower super-output areas (LSOAs). MEASURES: Stature, mass and WC. Obesity was defined as a BMI and WC exceeding the 95th centile according to British reference data. WHtR exceeding 0.5 defined obesity. The Index of Multiple Deprivation affecting children (IDACI) was used to determine area-level deprivation. RESULTS: Considerable differences in the prevalence of obesity exist between the three different measures. However, for all measures of adiposity the highest probability of being classified as obese is in the middle of the IDACI range. This relationship is more marked in girls, such that the probability of being obese for girls living in areas at the two extremes of deprivation is around half that at the peak, occurring in the middle. CONCLUSION: These data confirm the high prevalence of obesity in children and suggest that the relationship between obesity and residential area-level deprivation is not linear. This is contrary to the 'deprivation theory' and questions the current understanding and interpretation of the relationship between obesity and deprivation in children. These results could help make informed decisions at the local level

The molecular characterisation of Escherichia coli K1 isolated from neonatal nasogastric feeding tubes

Background: The most common cause of Gram-negative bacterial neonatal meningitis is E. coli K1. It has a mortality rate of 10–15%, and neurological sequelae in 30– 50% of cases. Infections can be attributable to nosocomial sources, however the pre-colonisation of enteral feeding tubes has not been considered as a specific risk factor. Methods: Thirty E. coli strains, which had been isolated in an earlier study, from the residual lumen liquid and biofilms of neonatal nasogastric feeding tubes were genotyped using pulsed-field gel electrophoresis, and 7-loci multilocus sequence typing. Potential pathogenicity and biofilm associated traits were determined using specific PCR probes, genome analysis, and in vitro tissue culture assays. Results: The E. coli strains clustered into five pulsotypes, which were genotyped as sequence types (ST) 95, 73, 127, 394 and 2076 (Achman scheme). The extra-intestinal pathogenic E. coli (ExPEC) phylogenetic group B2 ST95 serotype O1:K1:NM strains had been isolated over a 2 week period from 11 neonates who were on different feeding regimes. The E. coli K1 ST95 strains encoded for various virulence traits associated with neonatal meningitis and extracellular matrix formation. These strains attached and invaded intestinal, and both human and rat brain cell lines, and persisted for 48 h in U937 macrophages. E. coli STs 73, 394 and 2076 also persisted in macrophages and invaded Caco-2 and human brain cells, but only ST394 invaded rat brain cells. E. coli ST127 was notable as it did not invade any cell lines. Conclusions: Routes by which E. coli K1 can be disseminated within a neonatal intensive care unit are uncertain, however the colonisation of neonatal enteral feeding tubes may be one reservoir source which could constitute a serious health risk to neonates following ingestion

Phase transition and hyperscaling violation for scalar Black Branes

We investigate the thermodynamical behavior and the scaling symmetries of the scalar dressed black brane (BB) solutions of a recently proposed, exactly integrable Einstein-scalar gravity model [1], which also arises as compactification of (p-1)-branes with a smeared charge. The extremal, zero temperature, solution is a scalar soliton interpolating between a conformal invariant AdS vacuum in the near-horizon region and a scale covariant metric (generating hyperscaling violation on the boundary field theory) asymptotically. We show explicitly that for the boundary field theory this implies the emergence of an UV length scale (related to the size of the brane), which decouples in the IR, where conformal invariance is restored. We also show that at high temperatures the system undergoes a phase transition. Whereas at small temperature the Schwarzschild-AdS BB is stable, above a critical temperature the scale covariant, scalar-dressed BB solution, becomes energetically preferred. We calculate the critical exponent z and the hyperscaling violation parameter of the scalar-dressed phase. In particular we show that the hyperscaling violation parameter is always negative. We also show that the above features are not a peculiarity of the exact integrable model of Ref.[1], but are a quite generic feature of Einstein-scalar and Einstein-Maxwell-scalar gravity models for which the squared-mass of the scalar field is positive and the potential vanishes exponentially as the scalar field goes to minus infinity.Comment: 20 pages, 4 figures. In the revised version it has been pointed out that the Einstein-scalar gravity model considered in the paper also arises as compactification of black p-branes with smeared charge

Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein

Several canonical translocations produce oncofusion genes that can initiate acute myeloid leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase (TurboID) in-frame with 3 favorable-risk AML oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11) and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their nuclear localization. However, CBFB::MYH11-TurboID-interacting proteins were largely cytoplasmic, probably because of an interaction of the MYH11 domain with several cytoplasmic myosin-related proteins. Using a variety of methods, we showed that the CBFB domain of CBFB::MYH11 sequesters RUNX1 in cytoplasmic aggregates; these findings were confirmed in primary human AML cells. Paradoxically, CBFB::MYH11 expression was associated with increased RUNX1/2 expression, suggesting the presence of a sensor for reduced functional RUNX1 protein, and a feedback loop that may attempt to compensate by increasing RUNX1/2 transcription. These findings may have broad implications for AML pathogenesis

Food-web structure in relation to environmental gradients and predator-prey ratios in tank-bromeliad ecosystems

Little is known of how linkage patterns between species change along environmental gradients. The small, spatially discrete food webs inhabiting tank-bromeliads provide an excellent opportunity to analyse patterns of community diversity and food-web topology (connectance, linkage density, nestedness) in relation to key environmental variables (habitat size, detrital resource, incident radiation) and predators: prey ratios. We sampled 365 bromeliads in a wide range of understorey environments in French Guiana and used gut contents of invertebrates to draw the corresponding 365 connectance webs. At the bromeliad scale, habitat size (water volume) determined the number of species that constitute food-web nodes, the proportion of predators, and food-web topology. The number of species as well as the proportion of predators within bromeliads declined from open to forested habitats, where the volume of water collected by bromeliads was generally lower because of rainfall interception by the canopy. A core group of microorganisms and generalist detritivores remained relatively constant across environments. This suggests that (i) a highly-connected core ensures food-web stability and key ecosystem functions across environments, and (ii) larger deviations in food-web structures can be expected following disturbance if detritivores share traits that determine responses to environmental changes. While linkage density and nestedness were lower in bromeliads in the forest than in open areas, experiments are needed to confirm a trend for lower food-web stability in the understorey of primary forests

Individual Differences in Processing Speed and Working Memory Speed as Assessed with the Sternberg Memory Scanning Task

The Sternberg Memory Scanning (SMS) task provides a measure of processing speed (PS) and working memory retrieval speed (WMS). In this task, participants are presented with sets of stimuli that vary in size. After a delay, one item is presented, and participants indicate whether or not the item was part of the set. Performance is assessed by speed and accuracy for both the positive (item is part of the set) and the negative trials (items is not part of the set). To examine the causes of variation in PS and WMS, 623 adult twins and their siblings completed the SMS task. A non-linear growth curve (nLGC) model best described the increase in reaction time with increasing set size. Genetic analyses showed that WMS (modeled as the Slope in the nLGC model) has a relatively small variance which is not due to genetic variation while PS (modeled as the Intercept in the nLGC model) showed large individual differences, part of which could be attributed to additive genetic factors. Heritability was 38% for positive and 32% for negative trials. Additional multivariate analyses showed that the genetic effects on PS for positive and negative trials were completely shared. We conclude that genetic influences on working memory performance are more likely to act upon basic processing speed and (pre)motoric processes than on the speed with which an item is retrieved from short term memory