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.

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2–5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and Main Results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse
(mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset ofmore difficult-to-treat, Step 4-5 peoplewith asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the needforfurther, adequately powered, trialsin this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).

Tephrochronology and the extended intimate (integration of ice‐core, marine and terrestrial records) event stratigraphy 8-128kab2k

The comparison of palaeoclimate records on their own independent timescales is central to the work of the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) network. For the North Atlantic region, an event stratigraphy has been established from the high-precision Greenland ice-core records and the integrated GICC05 chronology. This stratotype provides a palaeoclimate signal to which the timing and nature of palaeoenvironmental change recorded in marine and terrestrial archives can be compared. To facilitate this wider comparison, without assuming synchroneity of climatic change/proxy response, INTIMATE has also focussed on the development of tools to achieve this. In particular the use of time-parallel marker horizons e.g. tephra layers (volcanic ash). Coupled with the recent temporal extension of the Greenland stratotype, as part of this special issue, we present an updated INTIMATE event stratigraphy highlighting key tephra horizons used for correlation across Europe and the North Atlantic. We discuss the advantages of such an approach, and the key challenges for the further integration of terrestrial palaeoenvironmental records with those from ice cores and the marine realm.

Economic and social integration the challenge for EU constitutional law

'At a time of crisis and therefore a crucial juncture in European politics, Dagmar Schiek offers us an inspiring vision of the potential of the European Union. In her brilliant study, she exposes the obstacles that economic integration has posed for achievement of social justice, and provides a bold solution. Rejecting more limited models of constitutionalism, she presents a convincing alternative which is socially embedded, allowing space for action by manifold actors at multiple levels of governance.' - Tonia Novitz, University of Bristol, UK. © Dagmar Schiek 2012. All rights reserved.