DNA origami nanorulers and emerging reference structures

The DNA origami technique itself is considered a milestone of DNA nanotechnology and DNA origami nanorulers represent the first widespread application of this technique. DNA origami nanorulers are used to demonstrate the capabilities of techniques and are valuable training samples. They have meanwhile been developed for a multitude of microscopy methods including optical microscopy, atomic force microscopy, and electron microscopy, and their unique properties are further exploited to develop point-light sources, brightness references, nanophotonic test structures, and alignment tools for correlative microscopy. In this perspective, we provide an overview of the basics of DNA origami nanorulers and their increasing applications in fields of optical and especially super-resolution fluorescence microscopy. In addition, emerging applications of reference structures based on DNA origami are discussed together with recent developments

The Anthropocene is best understood as an ongoing, intensifying, diachronous event

Current debate on the status and character of the Anthropocene is focussed on whether this interval of geological time should be designated as a formal unit of epoch/series rank in the International Chronostratigraphic Chart/Geological Time Scale, or whether it is more appropriate for it to be considered as an informal ‘event’ comparable in significance with other major transformative events in deeper geological time. The case for formalizing the Anthropocene as a chronostratigraphical unit with a base at approximately 1950 CE is being developed by the Anthropocene Working Group of the Subcommission on Quaternary Stratigraphy. Here we outline the alternative position and explain why the time-transgressive nature of human impact on global environmental systems that is reflected in the recent stratigraphical record means that the Anthropocene is better seen not as a series/epoch with a fixed lower boundary, but rather as an unfolding, transforming and intensifying geological event

A cosmopolitan temptation

For some, the transnationalization of political action and communicative space in the European Union heralds an emergent cosmopolitan order. Need that be so? There are supranational institutions in the EU as well as transnational political and cultural spaces and cross-border communicative flows. However, the Union's member states remain key controllers of citizenship rights and purveyors of collective identities. And for many purposes they still maintain strongly bounded national public spheres. Because the EU's overall character as a polity remains unresolved, this has consequences for the organization of communicative spaces. The EU is a field of tensions and contradictions that is inescapably rooted in institutional realities. Wishful thinking about cosmopolitanism can get in the way of clear analysis

Digital phenotyping: Towards replicable findings with comprehensive assessments and integrative models in bipolar disorders

Background: Digital phenotyping promises to unobtrusively obtaining a continuous and objective input of symptomatology from patients\u27 daily lives. The prime example are bipolar disorders, as smartphone parameters directly reflect bipolar symptomatology. Empirical studies, however, have yielded inconsistent findings. We believe that three main shortcomings have to be addressed to fully leverage the potential of digital phenotyping: short assessment periods, rare outcome assessments, and an extreme fragmentation of parameters without an integrative analytical strategy. Methods: To demonstrate how to overcome these shortcomings, we conducted frequent (biweekly) dimensional and categorical expert ratings and daily self-ratings over an extensive assessment period (12 months) in 29 patients with bipolar disorder. Digital phenotypes were monitored continuously. As an integrative analytical strategy, we used structural equation modelling to build latent psychopathological outcomes (mania, depression) and latent digital phenotype predictors (sleep, activity, communicativeness). Outcomes: Combining gold-standard categorical expert ratings with dimensional self and expert ratings resulted in two latent outcomes (mania and depression) with statistically meaningful factor loadings that dynamically varied over 299 days. Latent digital phenotypes of sleep and activity were associated with same-day latent manic psychopathology, suggesting that psychopathological alterations in bipolar disorders relate to domains (latent variables of sleep and activity) and not only to specific behaviors (such as the number of declined incoming calls). The identification of latent psychopathological outcomes that dimensionally vary on a daily basis will enable to empirically determine which combination of digital phenotypes at which days prior to an upcoming episode are viable as digital prodromal predictors. (DIPF/Orig.

Digital phenotyping: towards replicable findings with comprehensive assessments and integrative models in bipolar disorders

Background: Digital phenotyping promises to unobtrusively obtaining a continuous and objective input of symptomatology from patients’ daily lives. The prime example are bipolar disorders, as smartphone parameters directly reflect bipolar symptomatology. Empirical studies, however, have yielded inconsistent findings. We believe that three main shortcomings have to be addressed to fully leverage the potential of digital phenotyping: short assessment periods, rare outcome assessments, and an extreme fragmentation of parameters without an integrative analytical strategy. Methods: To demonstrate how to overcome these shortcomings, we conducted frequent (biweekly) dimensional and categorical expert ratings and daily self-ratings over an extensive assessment period (12 months) in 29 patients with bipolar disorder. Digital phenotypes were monitored continuously. As an integrative analytical strategy, we used structural equation modelling to build latent psychopathological outcomes (mania, depression) and latent digital phenotype predictors (sleep, activity, communicativeness). Outcomes: Combining gold-standard categorical expert ratings with dimensional self and expert ratings resulted in two latent outcomes (mania and depression) with statistically meaningful factor loadings that dynamically varied over 299 days. Latent digital phenotypes of sleep and activity were associated with same-day latent manic psychopathology, suggesting that psychopathological alterations in bipolar disorders relate to domains (latent variables of sleep and activity) and not only to specific behaviors (such as the number of declined incoming calls). The identification of latent psychopathological outcomes that dimensionally vary on a daily basis will enable to empirically determine which combination of digital phenotypes at which days prior to an upcoming episode are viable as digital prodromal predictors

Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin

Background. Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. Objectives. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI+) and IgE- positive (IgE+) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. Study design. In a double-blind study, CSU patients aged 18‑75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks. Changes in disease activity were assessed by use of the weekly Urticaria Activity Score (UAS7). Circulating IgE levels, basophil numbers and levels of expression of FcεRI+ and IgE+ cells in the skin and in blood basophils were determined. Results. Patients receiving omalizumab showed a significantly greater decrease in UAS7 compared with patients receiving placebo. At Week 12 the mean difference in UAS7 between treatment groups was -14.82 (p=0.0027), consistent with previous studies. Total IgE levels in serum were increased after omalizumab treatment and remained elevated up to Week 12. Free IgE levels decreased after omalizumab treatment. Mean levels of FcεRI+ skin cells in patients treated with omalizumab 300 mg were decreased at Week 12 compared with baseline in the dermis of both non-lesional and lesional skin, reaching levels comparable with those seen in healthy volunteers (HVs). There were no statistically significant changes in mean FcɛRI+ cell levels in the placebo group. Similar results were seen for changes in IgE+ cells, although the changes were not statistically significant. The level of peripheral blood basophils increased immediately after treatment start and returned to Baseline values after the follow-up period. The levels of FcεRI and IgE expression on peripheral blood basophils were rapidly reduced by omalizumab treatment up to Week 12. Conclusions. Treatment with omalizumab resulted in rapid clinical benefits in patients with CSU. Treatment with omalizumab was associated with reduction in FcɛRI+ and IgE+ basophils and intradermal cells

Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants.

Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR/Cas9, we find that F0 mouse embryos modeling one PLCB4 variant have facial defects recapitulating those observed in hypomorphic Ednra mouse models, including a bone that we identify as an atavistic change in the posterior palate/oral cavity. Remarkably, we have identified a similar osseous phenotype in a child with ARCND2. Our results identify the disease mechanism of ARCND2, demonstrate that the PLCB4 variants cause craniofacial differences and illustrate how minor changes in signaling within NCCs may have driven evolutionary changes in jaw structure and function. This article has an associated First Person interview with the first author of the paper

A practical solution: the Anthropocene is a geological event, not a formal epoch

The Anthropocene has yet to be defined in a way that is functional both to the international geological community and to the broader fields of environmental and social sciences. Formally defining the Anthropocene as a chronostratigraphical series and geochronological epoch with a precise global start date would drastically reduce the Anthropocene’s utility across disciplines. Instead, we propose the Anthropocene be defined as a geological event, thereby facilitating a robust geological definition linked with a scholarly framework more useful to and congruent with the many disciplines engaging with human-environment interactions. Unlike formal epochal definitions, geological events can recognize the spatial and temporal heterogeneity and diverse social and environmental processes that interact to produce anthropogenic global environmental changes. Consequently, an Anthropocene Event would incorporate a far broader range of transformative human cultural practices and would be more readily applicable across academic fields than an Anthropocene Epoch, while still enabling a robust stratigraphic characterization