Activin-A is a pro-inflammatory regulator in type-2-driven upper airway disease.

It is undeniably one of the greatest findings in biology that (with some very minor exceptions) every cell in the body possesses the whole genetic information needed to generate a complete individual. Today, this concept has been so thoroughly assimilated that we struggle to still see how surprising this finding actually was: all cellular phenotypes naturally occurring in one person are generated from genetic uniformity, and thus are per definition epigenetic. Transcriptional mechanisms are clearly critical for developing and protecting cell identities, because a mis-expression of few or even single genes can efficiently induce inappropriate cellular programmes. However, how transcriptional activities are molecularly controlled and which of the many known epigenomic features have causal roles remains unclear. Today, clarification of this issue is more pressing than ever because profiling efforts and epigenome-wide association studies (EWAS) continuously provide comprehensive datasets depicting epigenomic differences between tissues and disease states. In this commentary, we propagate the idea of a widespread follow-up use of epigenome editing technology in EWAS studies. This would enable them to address the questions of which features, where in the genome, and which circumstances are essential to shape development and trigger disease states

Fluorescent and bioluminescent calcium indicators with tuneable colors and affinities

We introduce a family of bright, rhodamine-based calcium indicators with tuneable affinities and colors. The indicators can be specifically localized to different cellular compartments and are compatible with both fluorescence and bioluminescence readouts through conjugation to HaloTag fusion proteins. Importantly, their increase in fluorescence upon localization enables no-wash live-cell imaging, which greatly facilitates their use in biological assays. Applications as fluorescent indicators in rat hippocampal neurons include the detection of single action potentials and of calcium fluxes in the endoplasmic reticulum (ER). Applications as bioluminescent indicators include the recording of the pharmacological modulation of nuclear calcium in high-throughput-compatible assays. The versatility and remarkable ease of use of these indicators make them powerful tools for bioimaging and bioassays

Phylogeography and demographic history of the black kite Milvus migrans, a widespread raptor in Eurasia, Australia and Africa

The black kite Milvus migrans, one of the most common raptor species, shows great flexibility as regards food resources and breeding sites. While black kite subspecies are found all over Eurasia, Africa and Australia, it has been poorly studied outside of Europe, with virtually nothing known about the phylogeny of populations in Asia, India, Africa or Australia. We analysed 85 published black kite nucleotide sequences and ca 660 new sequences from the ranges of the main black kite subspecies using a non-invasive method of DNA extraction from moulted feathers. In doing so, we evaluated genetic diversity and population affinities and reconstructed their demographic histories. Populations from Europe, northern Asia and India all had separate haplogroups of the mitochondrial cytochrome b gene. The European and North Asian subspecies were isolated in the Pleistocene and spread across the northern Palearctic following climate amelioration, forming a broad intergradation zone from western Siberia and Kazakhstan to eastern Europe. Representatives of the European, North Asian and Indian haplogroups were found in Pakistan, where they probably breed. The Australasian population separated from the Indian population relatively recently and carries one of the two Indian major haplotypes. We found support for the assumption that the African yellow-billed kite differs from the black kite at the species level. Further, the yellow-billed kite contains at least two genetically distant mitochondrial lineages with ranges that do not correspond with its traditional subspecies ranges. Based on these data, we were able to outline the general pattern of black kite phylogeography over its entire range, making it possible to evaluate the evolutionary history of the species as a whole

Supplementary Material for: Activin-A Is a Pro-Inflammatory Regulator in Type-2-Driven Upper Airway Disease

<b><i>Background:</i></b> Allergic upper airway disease involves pro-inflammatory type-2 cytokines such as IL-5 and regulatory tissue repair mediators, in particular transforming growth factor (TGF)-β₁. The TGF-β-superfamily member activin-A displays multiple biological functions and shares certain signalling pathways with TGF-β₁. We aimed to examine the coregulation of mucosal activin-A and TGF-β₁ in acute allergic and chronic Th2-driven upper airway disease. <b><i>Methods:</i></b> We investigated mucosal cytokine expression profiles and kinetics using RT-PCR after nasal allergen challenges in patients with seasonal allergic rhinitis. Furthermore, we analysed mucosal specimens from patients with chronic upper airway disease with nasal polyps using ELISPOTs and confocal microscopy. In addition, we stimulated nasal mucosa ex vivo from patients with nasal polyps as well as primary nasal cell cultures from healthy donors. <b><i>Results:</i></b> Mucosal activin-A expression revealed increasing correlation with IL-5 and TGF-β₁ at 0.25, 6, and 24 h, respectively, and was significantly upregulated at 6 h after allergen challenge. The correlated expression was found to be more pronounced in chronic disease with nasal polyps, showing substantially (48-fold) increased activin-A-producing cells in nasal polyps by ELISPOT, while submucosal downstream signalling as determined by confocal microscopy was decreased. Ex vivo stimulations of nasal tissue suggested that activin-A and TGF-β₁ mutually regulate each other’s expression at the mRNA level and, when combined, enhance IL-5 expression. <b><i>Conclusion:</i></b> Activin-A in allergic upper airway disease acts as a pro-inflammatory mediator and TGF-β₁ modifier. Our data in the upper airways oppose the view of potentially anti-inflammatory properties in contrast to lymphatic compartments