Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria

A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals

Herein, we report a general iminium ion-based catalytic method for the enantioselective conjugate addition of carbon-centered radicals to aliphatic and aromatic enals. The process uses an organic photoredox catalyst, which absorbs blue light to generate radicals from stable precursors, in combination with a chiral amine catalyst, which secures a consistently high level of stereoselectivity. The generality of this catalytic platform is demonstrated by the stereoselective interception of a wide variety of radicals, including non-stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium-ion-based radical trap with an enamine-mediated step, affording stereochemically dense chiral products in one-step

Building professional discourse in emerging markets: Language, context and the challenge of sensemaking

Using ethnographic evidence from the former Soviet republics, this article examines a relatively new and mainly unobserved in the International Business (IB) literature phenomenon of communication disengagement that manifests itself in many emerging markets. We link it to the deficiencies of the local professional business discourse rooted in language limitations reflecting lack of experience with the market economy. This hampers cognitive coherence between foreign and local business entities, adding to the liability of foreignness as certain instances of professional experience fail to find adequate linguistic expression, and complicates cross-cultural adjustments causing multi-national companies (MNCs) financial losses. We contribute to the IB literature by examining cross-border semantic sensemaking through a retrospectively constructed observational study. We argue that a relative inadequacy of the national professional idiom is likely to remain a feature of business environment in post-communist economies for some time and therefore should be factored into business strategies of MNCs. Consequently, we recommend including discursive hazards in the risk evaluation of international projects

Evaluation of the incremental cost to the National Health Service of prescribing analogue insulin

Introduction Insulin analogues have become increasingly popular despite their greater cost compared with human insulin. The aim of this study was to calculate the incremental cost to the National Health Service (NHS) of prescribing analogue insulin preparations instead of their human insulin alternatives. Methods Open-source data from the four UK prescription pricing agencies from 2000 to 2009 were analysed. Cost was adjusted for inflation and reported in UK pounds at 2010 prices. Results Over the 10-year period, the NHS spent a total of £2732 million on insulin. The total annual cost increased from £156 million to £359 million, an increase of 130%. The annual cost of analogue insulin increased from £18.2 million (12% of total insulin cost) to £305 million (85% of total insulin cost), whereas the cost of human insulin decreased from £131 million (84% of total insulin cost) to £51 million (14% of total insulin cost). If it is assumed that all patients using insulin analogues could have received human insulin instead, the overall incremental cost of analogue insulin was £625 million. Conclusion Given the high marginal cost of analogue insulin, adherence to prescribing guidelines recommending the preferential use of human insulin would have resulted in considerable financial savings over the period

Magnetic phase diagram and transport properties of FeGe_2

We have used resistivity measurements to study the magnetic phase diagram of the itinerant antiferromagnet FeGe_2 in the temperature range from 0.3->300 K in magnetic fields up to 16 T. In contrast to theoretical predictions, the incommensurate spin density wave phase is found to be stable at least up to 16 T, with an estimated critical field \mu _0H_c of ~ 30 T. We have also studied the low temperature magnetoresistance in the [100], [110], and [001] directions. The transverse magnetoresistance is well described by a power law for magnetic fields above 1 T with no saturation observed at high fields. We discuss our results in terms of the magnetic structure and the calculated electronic bandstructure of FeGe_2. We have also observed, for the first time in this compound, Shubnikov-de Haas oscillations in the transverse magnetoresistance with a frequency of 190 +- 10 T for a magnetic field along [001].Comment: 13 pages, RevTeX, 7 postscript figures, to appear in Journal of Physics: Condensed Matte

A comparative study of different integrate-and-fire neurons: spontaneous activity, dynamical response, and stimulus-induced correlation

Stochastic integrate-and-fire (IF) neuron models have found widespread applications in computational neuroscience. Here we present results on the white-noise-driven perfect, leaky, and quadratic IF models, focusing on the spectral statistics (power spectra, cross spectra, and coherence functions) in different dynamical regimes (noise-induced and tonic firing regimes with low or moderate noise). We make the models comparable by tuning parameters such that the mean value and the coefficient of variation of the interspike interval match for all of them. We find that, under these conditions, the power spectrum under white-noise stimulation is often very similar while the response characteristics, described by the cross spectrum between a fraction of the input noise and the output spike train, can differ drastically. We also investigate how the spike trains of two neurons of the same kind (e.g. two leaky IF neurons) correlate if they share a common noise input. We show that, depending on the dynamical regime, either two quadratic IF models or two leaky IFs are more strongly correlated. Our results suggest that, when choosing among simple IF models for network simulations, the details of the model have a strong effect on correlation and regularity of the output.Comment: 12 page

Social technologies for online learning: theoretical and contextual issues

Three exemplars are presented of social technologies deployed in educational contexts: wikis; a photo-sharing environment; and a social bookmarking tool. Students were found to engage with the technologies selectively, sometimes rejecting them, in the light of their prior conceptions of education. Some students (a minority in all the studies) were unsympathetic to the educational philosophy underpinning the technology’s adoption. The paper demonstrates, through an examination of in-context use, the importance of socio-cultural factors in relation to education, and the non-deterministic nature of educational technology. The academic study of technology has increasingly called into question the deterministic views which are so pervasive in popular discourse and among policy makers. Instead, socio-cultural factors play a crucial role in shaping and defining technology and educational technology is no exception, as the examples in the paper show. The paper concludes by drawing out some implications of the examples for the use of social technologies in education

Phase-plane analysis of Friedmann-Robertson-Walker cosmologies in Brans-Dicke gravity

We present an autonomous phase-plane describing the evolution of Friedmann-Robertson-Walker models containing a perfect fluid (with barotropic index gamma) in Brans-Dicke gravity (with Brans-Dicke parameter omega). We find self-similar fixed points corresponding to Nariai's power-law solutions for spatially flat models and curvature-scaling solutions for curved models. At infinite values of the phase-plane variables we recover O'Hanlon and Tupper's vacuum solutions for spatially flat models and the Milne universe for negative spatial curvature. We find conditions for the existence and stability of these critical points and describe the qualitative evolution in all regions of the (omega,gamma) parameter space for 0-3/2. We show that the condition for inflation in Brans-Dicke gravity is always stronger than the general relativistic condition, gamma<2/3.Comment: 24 pages, including 9 figures, LaTe

Propagation Failure in Excitable Media

We study a mechanism of pulse propagation failure in excitable media where stable traveling pulse solutions appear via a subcritical pitchfork bifurcation. The bifurcation plays a key role in that mechanism. Small perturbations, externally applied or from internal instabilities, may cause pulse propagation failure (wave breakup) provided the system is close enough to the bifurcation point. We derive relations showing how the pitchfork bifurcation is unfolded by weak curvature or advective field perturbations and use them to demonstrate wave breakup. We suggest that the recent observations of wave breakup in the Belousov-Zhabotinsky reaction induced either by an electric field or a transverse instability are manifestations of this mechanism.Comment: 8 pages. Aric Hagberg: http://cnls.lanl.gov/~aric; Ehud Meron:http://www.bgu.ac.il/BIDR/research/staff/meron.htm