Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery

<p>Abstract</p> <p>Background</p> <p>Adenoviral vectors have provided effective methods for <it>in vivo </it>gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes.</p> <p>Methods</p> <p><it>In vitro</it>, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. <it>In vivo</it>, immunocompetent and athymic mice (n = 3 per group) were twice transduced with an Ad-vector.</p> <p>Results</p> <p>The results show an acute induction of type-I-interferon after <it>in vitro </it>transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response <it>in vivo</it>.</p> <p>Conclusion</p> <p>The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin.</p

‘Fourth places’: the Contemporary Public Settings for Informal Social Interaction among Strangers.

This paper introduces ‘fourth places’ as an additional category of informal social settings alongside ‘third places’ (Oldenburg 1989). Through extensive empirical fieldwork on where and how social interaction among strangers occurs in the public and semi-public spaces of a contemporary masterplanned neighbourhood, this paper reveals that ‘fourth places’ are closely related to ‘third places’ in terms of social and behavioural characteristics, involving a radical departure from the routines of home and work, inclusivity, and social comfort. However, the activities, users, locations and spatial conditions that support them are very different. They are characterized by ‘in-betweenness’ in terms of spaces, activities, time and management, as well as a great sense of publicness. This paper will demonstrate that the latter conditions are effective in breaking the ‘placelessness’ and ‘fortress’ designs of newly designed urban public spaces and that, by doing so, they make ‘fourth places’ sociologically more open in order to bring strangers together. The recognition of these findings problematizes well-established urban design theories and redefines several spatial concepts for designing public space. Ultimately, the findings also bring optimism to urban design practice, offering new insights into how to design more lively and inclusive public spaces. Keywords: ‘Fourth places’, Informal Public Social Settings, Social Interaction, Strangers, Public Space Design

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec