Independent and Interdependent Immunoregulatory Effects of IL-27, IFN-β, and IL-10 in the Suppression of Human Th17 Cells and Murine Experimental Autoimmune Encephalomyelitis

IFN-ß, IL-27, and IL-10 have been shown to exert a range of similar immunoregulatory effects in murine and human experimental systems, particularly in Th1- and Th17-mediated models of autoimmune inflammatory disease. In this study we sought to translate some of our previous findings in murine systems to human in vitro models and delineate the interdependence of these different cytokines in their immunoregulatory effects. We demonstrate that human IL-27 upregulates IL-10 in T cell-activated PBMC cultures and that IFN-ß drives IL-27 production in activated monocytes. IFN-ß-driven IL-27 is responsible for the upregulation of IL-10, but not IL-17 suppression, by IFN-ß in human PBMCs. Surprisingly, IL-10 is not required for the suppression of IL-17 by either IL-27 or IFN-ß in this model or in de novo differentiating Th17 cells, nor is IL-27 signaling required for the suppression of experimental autoimmune encephalomyelitis (EAE) by IFN-ß in vivo. Furthermore, and even more surprisingly, IL-10 is not required for the suppression of Th17-biased EAE by IL-27, in sharp contrast to Th1-biased EAE. In conclusion, IFN-ß and IL-27 both induce human IL-10, both suppress human Th17 responses, and both suppress murine EAE. However, IL-27 signaling is not required for the therapeutic effect of IFN-ß in EAE. Suppression of Th17-biased EAE by IL-27 is IL-10-independent, in contrast to its mechanism of action in Th1-biased EAE. Taken together, these findings delineate a complex set of interdependent and independent immunoregulatory mechanisms of IFN-ß, IL-27, and IL-10 in human experimental models and in murine Th1- and Th17-driven autoimmunity.

Inflammatory bowel disease, gut bacteria and probiotic therapy

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD) and both diseases lead to high morbidity and health care costs. Complex interactions between the immune system, enteric commensal bacteria and host genotype are thought to underlie the development of IBD although the precise aetiology of this group of diseases is still unknown. The understanding of the composition and complexity of the normal gut microbiota has been greatly aided by the use of molecular methods and is likely to be further increased with the advent of metagenomics and metatranscriptomics approaches, which will allow an increasingly more holistic assessment of the microbiome with respect to both diversity and function of the commensal gut microbiota. Studies thus far have shown that the intestinal microbiota drives the development of the gut immune system and can induce immune homeostasis as well as contribute to the development of IBD. Probiotics which deliver some of the beneficial immunomodulatory effects of the commensal gut microbiota and induce immune homeostasis have been proposed as a suitable treatment for mild to moderate IBD. This review provides an overview over the current understanding of the commensal gut microbiota, its interactions with the mucosal immune system and its capacity to induce both gut homeostasis as well as dysregulation of the immune system. Bacterial-host events, including interactions with pattern recognition receptors (PRRs) expressed on epithelial cells and dendritic cells (DCs) and the resultant impact on immune responses at mucosal surfaces will be discussed. (C) 2009 Elsevier GmbH. All rights reserved.

Double-detonation sub-Chandrasekhar supernovae: Synthetic observables for minimum helium shell mass models

In the double-detonation scenario for Type Ia supernovae, it is suggested that a detonation initiates in a shell of helium-rich material accreted from a companion star by a sub-Chandrasekhar-mass white dwarf. This shell detonation drives a shock front into the carbon-oxygen white dwarf that triggers a secondary detonation in the core. The core detonation results in a complete disruption of the white dwarf. Earlier studies concluded that this scenario has difficulties in accounting for the observed properties of Type Ia supernovae since the explosion ejecta are surrounded by the products of explosive helium burning in the shell. Recently, however, it was proposed that detonations might be possible for much less massive helium shells than previously assumed (Bildsten et al.). Moreover, it was shown that even detonations of these minimum helium shell masses robustly trigger detonations of the carbon-oxygen core (Fink et al.). Therefore, it is possible that the impact of the helium layer on observables is less than previously thought. Here, we present time-dependent multi-wavelength radiative transfer calculations for models with minimum helium shell mass and derive synthetic observables for both the optical and ? -ray spectral regions. These differ strongly from those found in earlier simulations of sub-Chandrasekhar-mass explosions in which more massive helium shells were considered. Our models predict light curves that cover both the range of brightnesses and the rise and decline times of observed Type Ia supernovae. However, their colors and spectra do not match the observations. In particular, their B - V colors are generally too red. We show that this discrepancy is mainly due to the composition of the burning products of the helium shell of the Fink et al. models which contain significant amounts of titanium and chromium. Using a toy model, we also show that the burning products of the helium shell depend crucially on its initial composition. This leads us to conclude that good agreement between sub-Chandrasekhar-mass explosions and observed Type Ia supernovae may still be feasible but further study of the shell properties is required.

JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone

Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones.

Topoisomerase IIα promotes activation of RNA polymerase I transcription by facilitating pre-initiation complex formation

Type II DNA topoisomerases catalyse DNA double-strand cleavage, passage and re-ligation to effect topological changes. There is considerable interest in elucidating topoisomerase II roles, particularly as these proteins are targets for anti-cancer drugs. Here we uncover a role for topoisomerase IIa in RNA polymerase I-directed ribosomal RNA gene transcription, which drives cell growth and proliferation and is upregulated in cancer cells. Our data suggest that topoisomerase IIa is a component of the initiation-competent RNA polymerase Iß complex and interacts directly with RNA polymerase I-associated transcription factor RRN3, which targets the polymerase to promoter-bound SL1 in pre-initiation complex formation. In cells, activation of rDNA transcription is reduced by inhibition or depletion of topoisomerase II, and this is accompanied by reduced transient double-strand DNA cleavage in the rDNA-promoter region and reduced pre-initiation complex formation. We propose that topoisomerase IIa functions in RNA polymerase I transcription to produce topological changes at the rDNA promoter that facilitate efficient de novo pre-initiation complex formation.

Almost all quantum states have nonclassical correlations

Quantum discord quantifies nonclassical correlations in a quantum system including those not captured by entanglement. Thus, only states with zero discord exhibit strictly classical correlations. We prove that these states are negligible in the whole Hilbert space: typically a state picked out at random has positive discord and, given a state with zero discord, a generic arbitrarily small perturbation drives it to a positive-discord state. These results hold for any Hilbert-space dimension and have direct implications for quantum computation and for the foundations of the theory of open systems. In addition, we provide a simple necessary criterion for zero quantum discord. Finally, we show that, for almost all positive-discord states, an arbitrary Markovian evolution cannot lead to a sudden, permanent vanishing of discord.

Are Alkyl Sulfate-Based Protic and Aprotic Ionic Liquids Stable with Water and Alcohols? A Thermodynamic Approach

The knowledge of the chemical stability as a function of the temperature of ionic liquids (ILs) in the presence of other molecules such as water is crucial prior to developing any no GO industrial application and process involving these novel materials. Fluid phase equilibria and density over a large range of temperature and composition can give basic information on IL purity and chemical stability. The IL scientific community requires accurate measurements accessed from reference data. In this work, the stability of different alkyl sulfate-based ILs in the presence of water and various alcohols (methanol, ethanol, 1-butanol, and 1-octanol) was investigated to understand their stability as a function of temperature up to 423.15 K over the hydrolysis and transesterification reactions, respectively. From this investigation, it was clear that methyl sulfate- and ethyl sulfate-based ILs are not stable in the presence of water, since hydrolysis of the methyl sulfate or ethyl sulfate anions to methanol or ethanol and hydrogenate anion is undoubtedly observed. Such observations could help to explain the differences observed for the physical properties published in the literature by various groups. Furthermore, it appears that a thermodynamic equilibrium process drives these hydrolysis reactions. In other words, these hydrolysis reactions are in fact reversible, providing the possibility to re-form the desired alkyl sulfate anions by a simple transesterification reaction between hydrogen sulfate-based ILs and the corresponding alcohol (methanol or ethanol). Additionally, butyl sulfate- and octyl sulfate-based ILs appear to follow this pattern but under more drastic conditions. In these systems, hydrolysis is observed in both cases after several months for temperatures up to 423 K in the presence of water. Therein, the partial miscibility of hydrogen sulfate-based ILs with long chain alcohols (1-butanol and 1-octanol) can help to explain the enhanced hydrolytic stability of the butyl sulfate- and octyl sulfate-based ILs compared with the methyl or ethyl sulfate systems. Additionally, rapid transesterification reactions are observed during liquid-liquid equilibrium studies as a function of temperature for binary systems of (hydrogen sulfate-based ionic liquids + 1-butanol) and of (hydrogen sulfate-based ionic liquids + 1-octanol). Finally, this atom-efficient catalyst-free transesterification reaction between hydrogen sulfate-based ILs and alcohol was then tested to provide a novel way to synthesize new ILs with various anion structures containing the alkyl sulfate group.

Co-deposition of organic carbon and arsenic in Bengal Delta aquifers.

We present data showing that arsenic (As) was codeposited with organic carbon (OC) in Bengal Delta sediments as As and OC concentrations are highly (p < 0.001) positively correlated in core profiles collected from widely dispersed geographical sites with different sedimentary depositional histories. Analysis of modern day depositional environments revealed that the As/OC correlations observed in cores are due to As retention and high OC inputs in vegetated zones of the deltaic environment. We hypothesize that elevated concentrations of As occur in vegetated wetland sediments due to concentration and retention of arsenate in aerated root zones and animal burrows where copious iron(III) oxides are deposited. On burial of the sediment, degradation of organic carbon from plant and animal biomass detritus provides the reducing conditions to dissolve iron(III) oxides and release arsenite into the porewater. As tubewell abstracted aquifer water is an invaluable resource on which much of Southeast Asia is now dependent, this increased understanding of the processes responsible for As buildup and release will identify, through knowledge of the palaeosedimentary environment, which sediments are at most risk of having high arsenic concentrations in porewater. Our data allow the development of a new unifying hypothesis of how As is mobilized into groundwaters in river flood plains and deltas of Southeast Asia, namely that in these highly biologically productive environments, As and OC are codeposited, and the codeposited OC drives As release from the sediments. We present data showing that arsenic (As) was codeposited with organic carbon (OC) in Bengal Delta sediments as As and OC concentrations are highly (p < 0.001) positively correlated in core profiles collected from widely dispersed geographical sites with different sedimentary depositional histories. Analysis of modern day depositional environments revealed that the As?OC correlations observed in cores are due to As retention and high OC inputs in vegetated zones of the deltaic environment. We hypothesize that elevated concentrations of As occur in vegetated wetland sediments due to concentration and retention of arsenate in aerated root zones and animal burrows where copious iron(III) oxides are deposited. On burial of the sediment, degradation of organic carbon from plant and animal biomass detritus provides the reducing conditions to dissolve iron(III) oxides and release arsenite into the porewater. As tubewell abstracted aquifer water is an invaluable resource on which much of Southeast Asia is now dependent, this increased understanding of the processes responsible for As buildup and release will identify, through knowledge of the palaeosedimentary environment, which sediments are at most risk of having high arsenic concentrations in porewater. Our data allow the development of a new unifying hypothesis of how As is mobilized into groundwaters in river flood plains and deltas of Southeast Asia, namely that in these highly biologically productive environments, As and OC are codeposited, and the codeposited OC drives As release from the sediments.

Parameter studies of fibre laser micro-welding of AISI 316L using Taguchi method

This paper discusses the application of the Taguchi experimental design approach in optimizing the key process parameters for micro-welding of thin AISI 316L foil using the 100W CW fibre laser. A L16 Taguchi experiment was conducted to systematically understand how the power, scanning velocity, focus position, gas flow rate and type of shielding gas affect the bead dimensions. The welds produced in the L16 Taguchi experiment was mainly of austenite cellular-dendrite structure with an average grain size of 5µm. An exact penetration weld with the largest penetration to fusion width ratio was obtained. Among those process parameters, the interaction between power and scanning velocity presented the strongest effect to the penetration to fusion width ratio and the power was found to be the predominantly important factor that drives the interaction with other factors to appreciably affect the bead dimensions.

Estimating Stellar Radial Velocity Variability from Kepler and GALEX: Implications for the radial velocity confirmation of exoplanets.

We cross match the GALEX and Kepler surveys to create a unique dataset with both ultraviolet (UV) measurements and highly precise photometric variability measurements in the visible light spectrum. As stellar activity is driven by magnetic field modulations, we have used UV emission from the magnetically heated gas in the stellar atmosphere to serve as our proxy for the more well-known stellar activity indicator, R' HK . The R' HK approximations were in turn used to estimate the level of astrophysical noise expected in radial velocity (RV) measurements and these were then searched for correlations with photometric variability. We find significant scatter in our attempts to estimate RV noise for magnetically active stars, which we attribute to variations in the phase and strength of the stellar magnetic cycle that drives the activity of these targets. However, for stars we deem to be magnetically quiet, we do find a clear correlation between photometric variability and estimated levels of RV noise (with variability up to ~10 m s–1). We conclude that for these quiet stars, we can use photometric measurements as a proxy to estimate the RV noise expected. As a result, the procedure outlined in this paper may help select targets best-suited for RV follow-up necessary for planet confirmation.

BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptora- negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability.We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. © 2014 American Association for Cancer Research.

Generation of high-energy-density ion bunches by ultraintense laser-cone-target interaction

A scheme in which carbon ion bunches are accelerated to a high energy and density by a laser pulse (∼10 W/cm) irradiating cone targets is proposed and investigated using particle-in-cell simulations. The laser pulse is focused by the cone and drives forward an ultrathin foil located at the cone's tip. In the course of the work, best results were obtained employing target configurations combining a low-Z cone with a multispecies foil transversely shaped to match the laser intensity profile. © 2014 AIP Publishing LLC.

Interacting supernovae from photoionization-confined shells around red supergiant stars

Betelgeuse, a nearby red supergiant, is a runaway star with a powerful stellar wind that drives a bow shock into its surroundings. This picture has been challenged by the discovery of a dense and almost static shell that is three times closer to the star than the bow shock and has been decelerated by some external force. The two physically distinct structures cannot both be formed by the hydrodynamic interaction of the wind with the interstellar medium. Here we report that a model in which Betelgeuse's wind is photoionized by radiation from external sources can explain the static shell without requiring a new understanding of the bow shock. Pressure from the photoionized wind generates a standing shock in the neutral part of the wind and forms an almost static, photoionization-confined shell. Other red supergiants should have significantly more massive shells than Betelgeuse, because the photoionization-confined shell traps up to 35 per cent of all mass lost during the red supergiant phase, confining this gas close to the star until it explodes. After the supernova explosion, massive shells dramatically affect the supernova lightcurve, providing a natural explanation for the many supernovae that have signatures of circumstellar interaction.

In situ electron holography of the dynamic magnetic field emanating from a hard-disk drive writer

The proliferation of mobile devices in society accessing data via the ‘cloud’ is imposing a dramatic increase in the amount of information to be stored on hard disk drives (HDD) used in servers. Forecasts are that areal densities will need to increase by as much as 35% compound per annum and by 2020 cloud storage capacity will be around 7 zettabytes corresponding to areal densities of 2 Tb/in2. This requires increased performance from the magnetic pole of the electromagnetic writer in the read/write head in the HDD. Current state-of-art writing is undertaken by morphologically complex magnetic pole of sub 100 nm dimensions, in an environment of engineered magnetic shields and it needs to deliver strong directional magnetic field to areas on the recording media around 50 nm x 13 nm. This points to the need for a method to perform direct quantitative measurements of the magnetic field generated by the write pole at the nanometer scale. Here we report on the complete in situ quantitative mapping of the magnetic field generated by a functioning write pole in operation using electron holography. Opportunistically, it points the way towards a new nanoscale magnetic field source to further develop in situ Transmission Electron Microscopy.

Rural Migration, Agrarian Change and Institutional Dynamics: Perspectives from the Majority World

Overall, this special issue provides insights into the mutually constitutive ways in which rapid economic development associated with industrialisation drives institutional change, migration and mobility, and, finally, altered relationships between – and conceptions of – rural and urban. The following papers pose important conceptual, normative as well as practical, policy-relevant questions relating to the human consequences of these processes and point to the applications of population research – a central objective of this journal.