The orphan G protein-coupled receptor GPR17: its pharmacology and function in recombinant and primary cell expression systems

The reconstitution of myelin sheaths, so called remyelination, represents an innovative therapeutic goal in multiple sclerosis (MS), the most common inflammatory-demyelinating disease of the central nervous system (CNS). Recently, the orphan G protein-coupled receptor (GPCR) GPR17, which is predominantly expressed in oligodendrocytes, has been identified as inhibitor of oligodendroglial differentiation, arresting oligodendrocytes in an immature, non-myelinating stage. Moreover, GPR17 expression is upregulated in human MS tissues, suggesting a key role of this receptor during the remyelination impairment that occurs in MS. However, the downstream signaling pathway connecting GPR17 to oligodendroglial maturation arrest is still poorly understood. The present work confirms that GPR17 activation by the small molecule agonist MDL29,951 results in a reduction of mature oligodendrocytes in vitro, evident by their decreased intracellular myelin basic protein (MBP) levels. The GPR17-mediated maturation block is crucially triggered by the Gαi/o pathway, which leads to an inhibition of two signaling cascades: (i) the adenylyl cyclase (AC)-cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA)–cAMP response element-binding protein (CREB), and (ii) the AC-cAMP-exchange protein directly activated by cAMP (EPAC). Remarkably, these findings demonstrate for the first time an involvement of EPAC on oligodendrocyte myelination. In conclusion, GPR17 but also its downstream signaling effectors as elucidated in this study provides several drug targets to influence oligodendrocyte differentiation. Furthermore, knowledge about GPR17 pharmacology would benefit greatly from the identification of both its endogenous ligand(s) and/or selective antagonists. The activation of GPR17 by cysteinyl-leukotriene and purinergic ligands (UDP, UDP-gal, UDP-glc, LTC4, and LTD4) is ten years after its initial publication still controversially discussed. In line with other laboratories that did not validate GPR17 as dualistic receptor for both ligand families, the data of the present work obtained in (i) G protein rearrangement, (ii) β-arrestin recruitment, and (iii) ERK1/2 phosphorylation assays confirm that GPR17 must still be regarded as an orphan receptor. Additionally, the present work invalidates the P2Y12 antagonists ticagrelor and cangrelor as GPR17 inhibitors. However, investigations on two structurally related CysLT2 receptor antagonists, HAMI3379 and Cay10633, strongly suggest that their basic chemical scaffolds will serve as valuable starting point for the generation of more potent and selective GPR17 antagonists to inhibit signaling of this orphan receptor in MS

A consistent picture?

In times of declining party identification, political parties need to persuade and mobilize their voters from election to election. Setting topics in such a way that voters are convinced to cast their vote has become an essential prerequisite for success in modern election campaigns. Social media are suitable for this, as parties can set their own topics or highlight the topics most important to the voters and communicate them to a large audience in organic posts or target specific voter groups with ads. While tendencies of issue ownership in posts on Facebook are repeatedly shown empirically, there is a lack of studies investigating which strategies parties follow in their investment decisions on Facebook ads. Based on theoretical expectations derived from the literature about digital political marketing and issue prioritization in election campaigns, this article investigates whether parties communicated consistently on Facebook with regard to the issues they set in organic posts, sponsored posts, and ads during the 2021 German federal election campaign. The results of a manual quantitative content analysis (n = 1,029 posts, n = 1,197 sponsored posts, n = 2,643 ads) show that parties focused on issue ownership in their posts. Still, their investments in sponsored posts and ads followed different strategies. Here, most parties highlighted social policy, contradicting issue ownership for some parties. The article provides novel insights into digital campaigning and discusses the extent to which parties can engage audiences beyond their organic reach within party-affiliated audiences

Missed opportunity to connect with European citizens? Europarties’ communication on Facebook during the 2019 European election campaign

The digitization of political communication and major transformations in the European Union (EU) have altered the conditions for European election campaigns. Whereas national political parties remain highly visible political actors in the EU, Europarties attract relatively little attention from the media and citizens. Social media could provide Europarties with an opportunity to raise awareness among European citizens. In our study, we investigated the social media campaign strategies of Europarties by conducting a manual quantitative content analysis comparing their Facebook posts with the posts of national parties from 12 European countries, focusing on the communication elements used to inform and mobilize citizens, especially in relation to the lead candidates. Our results revealed that some Europarties employed the concept of European lead candidates by emphasizing their candidates in their Facebook posts. However, in their relative inactivity on Facebook compared with national parties, Europarties did not seem to counteract the oft-cited lack of a European public sphere

A Thermo‐ and mechanoresponsive cyano‐substituted oligo(p‐phenylene vinylene) derivative with five emissive states

Multiresponsive materials that display predefined photoluminescence color changes upon exposure to different stimuli are attractive candidates for advanced sensing schemes. Herein, we report a cyano-substituted oligo(p-phenylene vinylene) (cyano-OPV) derivative that forms five different solvent-free solid-state molecular assemblies, luminescence properties of which change upon thermal and mechanical stimulation. Single-crystal X-ray structural analysis suggested that tolyl groups introduced at the termini of solubilizing side-chains of the cyano-OPV play a pivotal role in its solid-state arrangement. Viewed more broadly, this report shows that the introduction of competing intermolecular interactions into excimer-forming chromophores is a promising design strategy for multicolored thermo- and mechanoresponsive luminescent materials

Keep Them Engaged! Investigating the Effects of Self-centered Social Media Communication Style on User Engagement in 12 European Countries

On Facebook, patterns of user engagement largely shape what types of political contents citizens can see on the platform. Higher engagement leads to higher visibility. Therefore, one of the major goals of political actors' Facebook communication is to produce content with the potential to provoke user engagement, and thereby increase their own visibility. This study introduces the concept of self-centered social media communication style which focuses on 'salient' and 'owned' issues with populist and negative appeals and investigates how user engagement is related to its main elements. We also explore how users' receptivity to these content-related factors is shaped by country context. More specifically, we hypothesize that users are more likely to react, comment on and share posts focusing on salient topics or issues 'owned' by parties rather than more permanent policy issues, and posts including populist appeals and negativity. Further, we test how these effects are moderated by geographical regions and the level of party system polarization. We manually coded 9,703 Facebook posts of 68 parties from 12 European countries in the context of the 2019 European elections. Our findings show that users are more likely to engage with immigration-related, domestic, populist and negative posts, but react less to posts dealing with environmental or economic issues. While issue ownership does not play a significant role for user engagement, country context plays a minor role. However, some populist appeals are more effective in more polarized countries

Religion and Popular Music

The interactions between popular music and religion are manyfold and highly complex. Popular music as an important part of popular culture is a means of communication. Music can transmit not only emotions and a sense of community but also religious knowledge, knowledge that leaves diverse traces in different times and places. In the end, whether we extract religious meaning from popular music and what that meaning is depend on our background and on our capacity to contextualise symbols, motives and narratives – and also on the media used to convey these references. By analysing Florence + The Machines song “Big God” and its music video we will address some of the questions that arise while working in the field of popular music and religion

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression

Culturing of Melanocytes from the Equine Hair Follicle Outer Root Sheath

Hair follicles harbor a heterogeneous regenerative cell pool and represent a putative low-to-non-invasively available source of stem cells. We previously reported a technology for culturing human melanocytes from the hair follicle outer root sheath (ORS) for autologous pigmentation of tissue engineered skin equivalents. This study translated the ORS technology to horses. We de-veloped a culture of equine melanocytes from the ORS (eMORS) from equine forelock hair follicles cultured by means of an analogue human hair follicle-based in vitro methodology. The procedure was adjusted to equine physiology by addition of equine serum to the culture medium. The hair follicles were isolated by macerating forelock skin rests, enzymatically digested and subjected to air-medium-interface cultivation method. The procedure resulted in differentiated equine melanocytes, which exhibited typical morphology, presence of melanosomes, expression of cytoskeleton proteins vimentin, α-SMA, Sox2, S100ß and tyrosinase as well as tyrosinase activity followed by production of melanin. According to all assessed parameters, eMORS could be ranked as partially melanotic melanocytes. The results of the study offer an experimental base for further insight into hair follicle biology in equine and for comparative studies of hair follicles across different species

Cognitive behavioural therapy for insomnia does not appear to have a substantial impact on early markers of cardiovascular disease: A preliminary randomized controlled trial

According to the World Health Organization, cardiovascular diseases are the leading cause of death in the world. Therefore, early prevention of these diseases is a public health priority. Epidemiological data suggest that insomnia may be a modifiable risk factor for cardiovascular diseases. A randomized controlled trial in a sample of insomnia patients without cardiovascular disease was conducted to investigate the effects of insomnia treatment on early markers of cardiovascular diseases assessed by 24‐hr ambulatory blood pressure, heart rate and heart rate variability monitoring, and morning fasting blood samples. Forty‐six patients with insomnia disorder were randomized to cognitive behavioural therapy for insomnia (CBT‐I; n = 23) or a waitlist control condition (n = 23). Contrary to the hypothesis, intention‐to‐treat analyses did not show any significant treatment effects on early markers of cardiovascular disease (d = 0.0–0.6) despite successful insomnia treatment (d = 1.3). Potential methodological and conceptual reasons for these negative findings are discussed. Future studies might include larger sample sizes that are at risk of cardiovascular diseases and focus on other cardiovascular markers