Key Role of Splenic Myeloid DCs in the IFN-αβ Response to Adenoviruses In Vivo

The early systemic production of interferon (IFN)-αβ is an essential component of the antiviral host defense mechanisms, but is also thought to contribute to the toxic side effects accompanying gene therapy with adenoviral vectors. Here we investigated the IFN-αβ response to human adenoviruses (Ads) in mice. By comparing the responses of normal, myeloid (m)DC- and plasmacytoid (p)DC-depleted mice and by measuring IFN-αβ mRNA expression in different organs and cells types, we show that in vivo, Ads elicit strong and rapid IFN-αβ production, almost exclusively in splenic mDCs. Using knockout mice, various strains of Ads (wild type, mutant and UV-inactivated) and MAP kinase inhibitors, we demonstrate that the Ad-induced IFN-αβ response does not require Toll-like receptors (TLR), known cytosolic sensors of RNA (RIG-I/MDA-5) and DNA (DAI) recognition and interferon regulatory factor (IRF)-3, but is dependent on viral endosomal escape, signaling via the MAP kinase SAPK/JNK and IRF-7. Furthermore, we show that Ads induce IFN-αβ and IL-6 in vivo by distinct pathways and confirm that IFN-αβ positively regulates the IL-6 response. Finally, by measuring TNF-α responses to LPS in Ad-infected wild type and IFN-αβR^−/− mice, we show that IFN-αβ is the key mediator of Ad-induced hypersensitivity to LPS. These findings indicate that, like endosomal TLR signaling in pDCs, TLR-independent virus recognition in splenic mDCs can also produce a robust early IFN-αβ response, which is responsible for the bulk of IFN-αβ production induced by adenovirus in vivo. The signaling requirements are different from known TLR-dependent or cytosolic IFN-αβ induction mechanisms and suggest a novel cytosolic viral induction pathway. The hypersensitivity to components of the microbial flora and invading pathogens may in part explain the toxic side effects of adenoviral gene therapy and contribute to the pathogenesis of adenoviral disease.     

Framework for assessing the impact of human activities on the environment: the impact of forest harvesting and petroleum drilling on habitat of moose (<Emphasis Type="Italic">Alces alces</Emphasis>) and marten (<Emphasis Type="Italic">Martens americana</Emphasis>)

The environmental changes induced by projects occurring in an area are evaluated by cumulative impact assessments (CIA), which consider the consequences of multiple projects, each insignificant on its own, yet important when evaluated collectively. When future human activities are of interest, the proposed activities are included in CIA using an analytical platform that can supply precise predictions but with asymptotically null accuracy. To compensate for the lack of accuracy we propose a shift in the paradigm governing CIA. The paradigm shift advocates a change in the focus of CIA investigations from the detailed analysis of one unlikely future to the identification of patterns describing the future changes in the environment. To illustrate the paradigm shift, a set of 144 possible and equally likely futures were developed and used to identify the potential impacts of forest harvesting and petroleum drilling on the habitat of moose and marten. The univariate and multivariate analysis of two measures of habitat, namely average habitat suitability index (HSI) and surface of the stands with HSI >0.5, revealed at least three distinct periods in the next 100 years. Multivariate analysis also showed that habitat quality is of immediate importance and marten is sensitive during the first third of the century. Our findings indicate that the spatial and temporal arrangement of the human disturbances could be more important than the magnitude of the disturbance. The attributes associated with significant environmental changes are harvesting age and the investigated environmental elements of an ecosystem, in this case the species habitat.     

Peroxidase involvement in the defense response of red raspberry to Didymella applanata (Niessl/Sacc.)

Peroxidase activity of red raspberry canes was dependent on the cultivar and influenced the subsequent lignification. After inoculation with Didymella applanata, responsible for the spur blight cane disease, the activity of soluble cytoplasmic enzyme increased in the moderately resistant ‘Latham’ and susceptible ‘Malling Promise’, similarly for syringaldazine and guaiacol as hydrogen donors. Systemic induction found in ‘Latham’ was recognized as a symptom of defence mechanism responsible for fungal restriction. Locally enhanced peroxidase activity in the ‘M.Promise’ tissues was related to the local lignification and/or may be associated with the loss of cell integrity caused by pathogen penetration. Pathogen-induced changes of cell wall peroxidases were similar in both cultivars mentioned above. No influence of the infection was found in the high susceptible Zeva cultivar. Using native-PAGE analysis and horizontal starch electrophoresis of soluble fraction five constitutive acidic isoperoxidases were detected in ‘Latham’ and three in ‘M. Promise’. The infection process was accompanied by the appearance of two new anodic isoforms.     

Design and Analysis of a Mutant form of the Ice-Binding Protein from Choristoneura fumiferana

The Protein Journal - Ice-binding proteins are expressed in the cells of some cold adapted organisms, helping them to survive at extremely low temperatures. One of the problems in studying such...