Protective and Aggravating Effects of Nlrp3 Inflammasome Activation in IBD Models: Influence of Genetic and Environmental Factors

Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1 beta and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora. Methods: To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we in-vestigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment. Results: Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model. Conclusions: The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD. Copyright (C) 2012 S. Karger AG, Base

A unified first-principles study of Gilbert damping, spin-flip diffusion and resistivity in transition metal alloys

Using a formulation of first-principles scattering theory that includes disorder and spin-orbit coupling on an equal footing, we calculate the resistivity $\rho$, spin flip diffusion length $l_{sf}$ and the Gilbert damping parameter $\alpha$ for Ni$_{1-x}$Fe$_x$ substitutional alloys as a function of $x$. For the technologically important Ni$_{80}$Fe$_{20}$ alloy, permalloy, we calculate values of $\rho = 3.5 \pm 0.15$ $\mu$Ohm-cm, $l_{sf}=5.5 \pm 0.3$ nm, and $\alpha= 0.0046 \pm 0.0001$ compared to experimental low-temperature values in the range $4.2-4.8$ $\mu$Ohm-cm for $\rho$, $5.0-6.0$ nm for $l_{sf}$, and $0.004-0.013$ for $\alpha$ indicating that the theoretical formalism captures the most important contributions to these parameters.Comment: Published in Physical Review Letter

Simulation and Experimental Investigation of the Stay Vane Channel Flow in a Reversible Pump Turbine at Off-Design Conditions

This work presents the assessment of the mean flow field and low frequency disturbances in the stay vane channel of a model pump turbine using transient numerical simulations and LDV-based measurements. The focus is laid on transient CFD simulations of characteristic flow states in the stay vane channel when operating at off-design conditions in pump mode. Experimental and numerical investigations obtained a shifting velocity distribution between the shroud and hub of the distributor when continuously increasing the discharge in the part-load range. Simulations captured the occurrence of this changing flow state in the stay vane channel reasonably well. A further increase of the discharge showed a uniformly redistributed mean flow of both hub and shroud side. Monitoring points and integral quantities from measurements and transient simulations were used to interpret the development of transient flow patterns in the stay vane channel at the operating point of strongest asymmetrical flow. During simulation and measurement, a dominant rotating stall inception was observed near the design flow of the pump turbine. At this point where the stall becomes severe, a high level of correlation between the signals of the upper and lower stalled flow in the stay vane channel was calculated. Further simulations for different guide vane positions predicted a strong influence of the guide vane position on the structure of rotating stall

Bacterial artificial chromosomes improve recombinant protein production in mammalian cells

<p>Abstract</p> <p>Background</p> <p>The development of appropriate expression vectors for large scale protein production constitutes a critical step in recombinant protein production. The use of conventional expression vectors to obtain cell lines is a cumbersome procedure. Often, stable cell lines produce low protein yields and production is not stable over the time. These problems are due to silencing of randomly integrated expression vectors by the surrounding chromatin. To overcome these chromatin effects, we have employed a Bacterial Artificial Chromosome (BAC) as expression vector to obtain stable cell lines suitable for protein production.</p> <p>Results</p> <p>In this work, we explore the efficacy of a Bacterial Artificial Chromosome based vector applied to production of the constant region of the human IgG1. Direct comparison of bulk HEK 293 cell cultures generated with a "conventional" vector or with a BAC-based vector showed that the BAC-based vector improved the protein yield by a factor of 10. Further analysis of stable cell clones harboring the BAC-based vector showed that the protein production was directly proportional to the number of integrated BAC copies and that the protein production was stable for at least 30 passages.</p> <p>Conclusion</p> <p>Generation of stable cell clones for protein production using Bacterial Artificial Chromosomes offers a clear advantage over the use of conventional vectors. First, protein production is increased by a factor of 10; second, protein production is stable overtime and third, generation of BAC-based expression vectors does not imply a significant amount of work compare to a conventional vector. Therefore, BAC-based vectors may become an attractive tool for protein production.</p

Micrometre‐sized porous polymer beads as heterogeneous molecular catalysts

Porous polymers have great potential as versatile, chemically stable catalyst supports. Yet, shaping of the resulting powders remains a challenge. Here, we demonstrate the use of suspension polymerisation to design micrometre-sized porous polymers beads containing metal binding sites. The good accessibility of the binding sites ensures high catalytic activity, which is demonstrated for two model reactions: photochemical CO2 reduction and transfer hydrogenation of aromatic ketones. Importantly, the shaping of the host material does not affect the catalytic activity of the active site

A probabilistic approach to the Yang-Mills heat equation

AbstractWe construct a parallel transport U in a vector bundle E, along the paths of a Brownian motion in the underlying manifold, with respect to a time dependent covariant derivative ∇ on E, and consider the covariant derivative ∇0U of the parallel transport with respect to perturbations of the Brownian motion. We show that the vertical part U−1∇0U of this covariant derivative has quadratic variation twice the Yang–Mills energy density (i.e., the square norm of the curvature 2-form) integrated along the Brownian motion, and that the drift of such processes vanishes if and only if ∇ solves the Yang–Mills heat equation. A monotonicity property for the quadratic variation of U−1∇0U is given, both in terms of change of time and in terms of scaling of U−1∇0U. This allows us to find a priori energy bounds for solutions to the Yang–Mills heat equation, as well as criteria for non-explosion given in terms of this quadratic variation

LIFEDATA - a framework for traceable active learning projects

Active Learning has become a popular method for iteratively improving data-intensive Artificial Intelligence models. However, it often presents a significant challenge when dealing with large volumes of volatile data in projects, as with an Active Learning loop. This paper introduces LIFEDATA, a Python- based framework designed to assist developers in implementing Active Learning projects focusing on traceability. It supports seamless tracking of all artifacts, from data selection and labeling to model interpretation, thus promoting transparency throughout the entire model learning process and enhancing error debugging efficiency while ensuring experiment reproducibility. To showcase its applicability, we present two life science use cases. Moreover, the paper proposes an algorithm that combines query strategies to demonstrate LIFEDATA’s ability to reduce data labeling effort

Association between infectious burden, socioeconomic status, and ischemic stroke

Background and aims: Infectious diseases contribute to stroke risk, and are associated with socioeconomic status (SES). We tested the hypotheses that the aggregate burden of infections increases the risk of ischemic stroke (IS) and partly explains the association between low SES and ischemic stroke. Methods: In a case-control study with 470 ischemic stroke patients and 809 age- and sex-matched controls, randomly selected from the population, antibodies against the periodontal microbial agents Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, against Chlamydia pneumonia, Mycoplasma pneumoniae (IgA and IgG), and CagA-positive Helicobacter pylori (IgG) were assessed. Results: IgA seropositivity to two microbial agents was significantly associated with IS after adjustment for SES (OR 1.45 95% CI 1.01-2.08), but not in the fully adjusted model (OR 1.32 95% CI 0.86-2.02). By trend, cumulative IgA seropositivity was associated with stroke due to large vessel disease (LVD) after full adjustment (OR 1.88, 95% CI 0.96e3.69). Disadvantageous childhood SES was associated with higher cumulative seropositivity in univariable analyses, however, its strong impact on stroke risk was not influenced by seroepidemiological data in the multivariable model. The strong association between adulthood SES and stroke was rendered nonsignificant when factors of dental care were adjusted for. Conclusions: Infectious burden assessed with five microbial agents did not independently contribute to ischemic stroke consistently, but may contribute to stroke due to LVD. High infectious burden may not explain the association between childhood SES and stroke risk. Lifestyle factors that include dental negligence may contribute to the association between disadvantageous adulthood SES and stroke. (C) 2016 Elsevier Ireland Ltd. All rights reserved.Peer reviewe