Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3-and viral-induced expression of type i interferons

Toll-like receptors (TLRs) sense pathogen-associated molecules and respond by inducing cytokines and type I interferon. Here we show that genetic ablation of the E3 ubiquitin ligase Pellino3 augmented the expression of type I interferon but not of proinflammatory cytokines in response to TLR3 activation. Pellino3-deficient mice had greater resistance against the pathogenic and lethal effects of encephalomyocarditis virus (EMCV). TLR3 signaling induced Pellino3, which in turn interacted with and ubiquitinated TRAF6. This modification suppressed the ability of TRAF6 to interact with and activate IRF7, resulting in downregulation of type I interferon expression. Our findings highlight a new physiological role for Pellino3 and define a new autoregulatory network for controlling type I interferon expression. © 2012 Nature America, Inc. All rights reserved.

Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-∝

Tumour necrosis factor-a (TNF) can activate NF-?B to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-?B pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.

The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor kappa B (NF-kappa B) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor-associated kinase 2 (IRAK2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.

Modeling target bulk heating resulting from ultra-intense short pulse laser irradiation of solid density targets

Isochoric heating of solid-density matter up to a few tens of eV is of interest for investigating astrophysical or inertial fusion scenarios. Such ultra-fast heating can be achieved via the energy deposition of short-pulse laser generated electrons. Here, we report on experimental measurements of this process by means of time-and space-resolved optical interferometry. Our results are found in reasonable agreement with a simple numerical model of fast electron-induced heating. (C) 2013 AIP Publishing LLC.

Identification of damping in a bridge using a moving instrumented vehicle

In recent years, there has been a significant increase in the number of bridges which are being instrumented and monitored on an ongoing basis. This is in part due to the introduction of bridge management systems designed to provide a high level of protection to the public and early warning if the bridge becomes unsafe. This paper investigates a novel alternative; a low-cost method consisting of the use of a vehicle fitted with accelerometers on its axles to monitor the dynamic behaviour of bridges. A simplified half-car vehicle-bridge interaction model is used in theoretical simulations to test the effectiveness of the approach in identifying the damping ratio of the bridge. The method is tested for a range of bridge spans and vehicle velocities using theoretical simulations and the influences of road roughness, initial vibratory condition of the vehicle, signal noise, modelling errors and frequency matching on the accuracy of the results are investigated.

A drive-by inspection system via vehicle moving force identification

This paper presents a novel method to carry out monitoring of transport infrastructure such as pavements and bridges through the analysis of vehicle accelerations. An algorithm is developed for the identification of dynamic vehicle-bridge interaction forces using the vehicle response. Moving force identification theory is applied to a vehicle model in order to identify these dynamic forces between the vehicle and the road and/or bridge. A coupled half-car vehicle-bridge interaction model is used in theoretical simulations to test the effectiveness of the approach in identifying the forces. The potential of the method to identify the global bending stiffness of the bridge and to predict the pavement roughness is presented. The method is tested for a range of bridge spans using theoretical simulations and the influences of road roughness and signal noise on the accuracy of the results are investigated.

Dynamic Axle Force and Road Profile Identification Using a Moving Vehicle

In the interaction between vehicles, pavements and bridges, it is essential to aim towards a reduction of vehicle axle forces to promote longer pavement life spans and to prevent bridges loads becoming too high. Moreover, as the road surface roughness affects the vehicle dynamic forces, an efficient monitoring of pavement condition is also necessary to achieve this aim. This paper uses a novel algorithm to identify the dynamic interaction forces and pavement roughness from vehicle accelerations in both theoretical simulations and a laboratory experiment; moving force identification theory is applied to a vehicle model for this purpose. Theoretical simulations are employed to evaluate the ability of the algorithm to predict forces over a range of bridge spans and to evaluate the influence of road roughness level on the accuracy of the results. Finally, in addressing the challenge for the real-world problem, the effects of vehicle configuration and speed on the predicted road roughness are also investigated in a laboratory experiment.

Theoretical investigation of the use of a moving vehicle to identify bridge dynamic parameters

Pavements and bridges are subject to a continuous degradation due to traffic aggressiveness, ageing and environmental factors. A rational transport policy requires the monitoring of this transport infrastructure in order to provide adequate maintenance and guarantee the required levels of transport service and safety. This paper investigates the use of an instrumented vehicle fitted with accelerometers on its axles to monitor the dynamics of bridges. A simplified quarter carbridge interaction model is used in theoretical simulations and the natural frequency of the bridge is extracted from the spectra of the vehicle accelerations. The accuracy is better at lower speeds and for smooth road profiles. The structural damping of the bridge was also monitored for smooth and rough road profiles. The magnitude of peaks in the power spectral density of the vehicle accelerations decreased with increasing bridge damping and this decrease was easier to detect the smoother the road profile.