IκBβ acts to inhibit and activate gene expression during the inflammatory response

The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major isoform of IκB, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. Although cells lacking IκBβ have been reported3, 4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6, 7, 8, 9, 10, 11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and c-Rel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9, 10, 11. Here we report that in vivo IκBβ serves both to inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-α (TNF-α). Surprisingly, absence of IκBβ results in a dramatic reduction of TNF-α in response to LPS even though activation of NF-κB is normal. The inhibition of TNF-α messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNF-α promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNF-α. As a result, IκBβ^(−/−) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNF-α production during the inflammatory response

On the Effect of Nb on the Microstructure and Properties of Next Generation Polycrystalline Powder Metallurgy Ni-Based Superalloys

Abstract The effect of Nb on the properties and microstructure of two novel powder metallurgy (P/M) Ni-based superalloys was evaluated, and the results critically compared with the Rolls-Royce alloy RR1000. The Nb-containing alloy was found to exhibit improved tensile and creep properties as well as superior oxidation resistance compared with both RR1000 and the Nb-free variant tested. The beneficial effect of Nb on the tensile and creep properties was due to the microstructures obtained following the post-solution heat treatments, which led to a higher γ′ volume fraction and a finer tertiary γ′ distribution. In addition, an increase in the anti-phase-boundary energy of the γ′ phase is also expected with the addition of Nb, further contributing to the strength of the material. However, these modifications in the γ′ distribution detrimentally affect the dwell fatigue crack-growth behavior of the material, although this behavior can be improved through modified heat treatments. The oxidation resistance of the Nb-containing alloy was also enhanced as Nb is believed to accelerate the formation of a defect-free Cr2O3 scale. Overall, both developmental alloys, with and without the addition of Nb, were found to exhibit superior properties than RR1000.This work was supported by the Rolls-Royce/EPSRC Strategic Partnership under EP/H022309/1, EP/H500375/1 and EP/ M005607/1

Inhibitor of Kappa B Epsilon (IκBε) Is a Non-Redundant Regulator of c-Rel-Dependent Gene Expression in Murine T and B Cells

Inhibitors of kappa B (IκBs) -α, -β and -ε effect selective regulation of specific nuclear factor of kappa B (NF-κB) dimers according to cell lineage, differentiation state or stimulus, in a manner that is not yet precisely defined. Lymphocyte antigen receptor ligation leads to degradation of all three IκBs but activation only of subsets of NF-κB-dependent genes, including those regulated by c-Rel, such as anti-apoptotic CD40 and BAFF-R on B cells, and interleukin-2 (IL-2) in T cells. We report that pre-culture of a mouse T cell line with tumour necrosis factor-α (TNF) inhibits IL-2 gene expression at the level of transcription through suppressive effects on NF-κB, AP-1 and NFAT transcription factor expression and function. Selective upregulation of IκBε and suppressed nuclear translocation of c-Rel were very marked in TNF-treated, compared to control cells, whether activated via T cell receptor (TCR) pathway or TNF receptor. IκBε associated with newly synthesised c-Rel in activated cells and, in contrast to IκBα and -β, showed enhanced association with p65/c-Rel in TNF-treated cells relative to controls. Studies in IκBε-deficient mice revealed that basal nuclear expression and nuclear translocation of c-Rel at early time-points of receptor ligation were higher in IκBε−/− T and B cells, compared to wild-type. IκBε−/− mice exhibited increased lymph node cellularity and enhanced basal thymidine incorporation by lymphoid cells ex vivo. IκBε−/− T cell blasts were primed for IL-2 expression, relative to wild-type. IκBε−/− splenic B cells showed enhanced survival ex vivo, compared to wild-type, and survival correlated with basal expression of CD40 and induced expression of CD40 and BAFF-R. Enhanced basal nuclear translocation of c-Rel, and upregulation of BAFF-R and CD40 occurred despite increased IκBα expression in IκBε−/− B cells. The data imply that regulation of these c-Rel-dependent lymphoid responses is a non-redundant function of IκBε

Augmented Reality Visualization: A Review Of Civil Infrastructure System Applications

In Civil Infrastructure System (CIS) applications, the requirement of blending synthetic and physical objects distinguishes Augmented Reality (AR) from other visualization technologies in three aspects: (1) it reinforces the connections between people and objects, and promotes engineers\u27 appreciation about their working context; (2) it allows engineers to perform field tasks with the awareness of both the physical and synthetic environment; and (3) it offsets the significant cost of 3D Model Engineering by including the real world background. This paper reviews critical problems in AR and investigates technical approaches to address the fundamental challenges that prevent the technology from being usefully deployed in CIS applications, such as the alignment of virtual objects with the real environment continuously across time and space; blending of virtual entities with their real background faithfully to create a sustained illusion of co-existence; and the integration of these methods to a scalable and extensible computing AR framework that is openly accessible to the teaching and research community. The research findings have been evaluated in several challenging CIS applications where the potential of having a significant economic and social impact is high. Examples of validation test beds implemented include an AR visual excavator-utility collision avoidance system that enables workers to see buried utilities hidden under the ground surface, thus helping prevent accidental utility strikes; an AR post-disaster reconnaissance framework that enables building inspectors to rapidly evaluate and quantify structural damage sustained by buildings in seismic events such as earthquakes or blasts; and a tabletop collaborative AR visualization framework that allows multiple users to observe and interact with visual simulations of engineering processes

Augmented reality visualization: A review of civil infrastructure system applications

In Civil Infrastructure System (CIS) applications, the requirement of blending synthetic and physical objects distinguishes Augmented Reality (AR) from other visualization technologies in three aspects: (1) it reinforces the connections between people and objects, and promotes engineers\u27 appreciation about their working context; (2) it allows engineers to perform field tasks with the awareness of both the physical and synthetic environment; and (3) it offsets the significant cost of 3D Model Engineering by including the real world background. This paper reviews critical problems in AR and investigates technical approaches to address the fundamental challenges that prevent the technology from being usefully deployed in CIS applications, such as the alignment of virtual objects with the real environment continuously across time and space; blending of virtual entities with their real background faithfully to create a sustained illusion of co-existence; and the integration of these methods to a scalable and extensible computing AR framework that is openly accessible to the teaching and research community. The research findings have been evaluated in several challenging CIS applications where the potential of having a significant economic and social impact is high. Examples of validation test beds implemented include an AR visual excavator-utility collision avoidance system that enables workers to see buried utilities hidden under the ground surface, thus helping prevent accidental utility strikes; an AR post-disaster reconnaissance framework that enables building inspectors to rapidly evaluate and quantify structural damage sustained by buildings in seismic events such as earthquakes or blasts; and a tabletop collaborative AR visualization framework that allows multiple users to observe and interact with visual simulations of engineering processes

Mobile And Pervasive Construction Visualization Using Outdoor Augmented Reality

This chapter describes the applicability of AR-based visualization for animating dynamic operations modeled and simulated using Discrete Event Simulation (DES). Introduce firstly are developed outdoor AR registration algorithms that use the Global Positioning System (GPS) and electronic compasses to place CAD models with correct pose in users\u27 views. Secondly, an AR animation authoring language called ARVISCOPE is introduced; it is capable of generating animations of arbitrary length and complexity at the operations level of detail using external software processes, such as running DES models. Several examples of pervasive outdoor AR visualization created using the authoring language are presented at the end. These smooth and chronologically accurate animations include an offshore concrete delivery operation, an earthmoving operation, and a structural steel erection operation. © 2012 John Wiley & Sons Ltd