Germanizing Europe? The evolution of the European Stability and Growth Pact

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Mas-related G-protein–coupled receptors inhibit pathological pain in mice

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein–coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8–22 (BAM 8–22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8–22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets

Decidual Macrophages Are Significantly Increased in Spontaneous Miscarriages and Over-Express FasL

Decidual macrophages (DM) are the second most abundant population in the fetal-maternal interface. Their role has been so far identified as being local immuno-modulators favoring the maternal tolerance to the fetus. Herein we investigated tissue samples from 11 cases of spontaneous miscarriages and from 9 cases of elective terminations of pregnancy. Using immunohistochemistry and dual immunofluorescence we have demonstrated that in spontaneous miscarriages the DM are significantly increased. Additionally, we noted a significant up-regulation of macrophage FasL expression. Our results further support a dual role for DM during pregnancy and miscarriages. We hypothesize that the baseline DM population in normal pregnancy is in line with an M2 phenotype supporting the ongoing gestation. In contrast, during spontaneous miscarriages, the increased FasL-expressing population could be a part of an M1 phenotype participating in Fas/FasL-related apoptosis. Our results highlight a new aspect of macrophage biology in pregnancy physiology and pathophysiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact

Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites

Drugs that enhance GABAergic inhibition alleviate inflammatory and neuropathic pain after spinal application. This antihyperalgesia occurs mainly through GABAA receptors (GABAARs) containing α2 subunits (α2-GABAARs). Previous work indicates that potentiation of these receptors in the spinal cord evokes profound antihyperalgesia also after systemic administration, but possible synergistic or antagonistic actions of supraspinal α2-GABAARs on spinal antihyperalgesia have not yet been addressed. Here we generated two lines of GABAAR-mutated mice, which either lack α2-GABAARs specifically from the spinal cord, or, which express only benzodiazepine-insensitive α2-GABAARs at this site. We analyzed the consequences of these mutations for antihyperalgesia evoked by systemic treatment with the novel non-sedative benzodiazepine site agonist HZ166 in neuropathic and inflammatory pain. Wild-type mice and both types of mutated mice had similar baseline nociceptive sensitivities and developed similar hyperalgesia. However, antihyperalgesia by systemic HZ166 was reduced in both mutated mouse lines by about 60% and was virtually indistinguishable from that of global point-mutated mice, in which all α2-GABAARs were benzodiazepine insensitive. The major (α2-dependent) component of GABAAR-mediated antihyperalgesia was therefore exclusively of spinal origin, whereas supraspinal α2-GABAARs had neither synergistic nor antagonistic effects on antihyperalgesia. Our results thus indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control. Such drugs may therefore be well-suited for the systemic treatment of different chronic pain conditions

"Ich feg den Staub aus dieser Welt"

Die vorliegende Arbeit stellt drei Shakespeare-Inszenierungen des kürzlich verstorbenen Regisseurs Jürgen Gosch vor. Es handelt sich dabei um keine detaillierten Aufführungsanalysen, sondern um eine vergleichende Darstellung einer Inszenierungsreihe, aus der am Ende eine gewisse Stilistik abgeleitet werden soll. Die theoretische Grundlage für die Beschreibung mehrerer Arbeiten eines einzigen Regisseurs bildet Yvonne Poppeks große Studie „Was ist ein Dorn? Die Shakespeare-Inszenierungen des Theaterregisseurs Dieter Dorn“ (München, 2006). Alle drei Inszenierungen – „Was ihr wollt“ (Düsseldorfer Schauspielhaus, 2007), „Ein Sommernachtstraum“ (Deutsches Theater Berlin, 2007) und „Macbeth“ (Düsseldorfer Schauspielhaus, 2005) hat Gosch gemeinsam mit seinem Ausstatter Johannes Schütz erarbeitet, der in seinen Bühnenbildern wiederholt Zitate aus der Entstehungszeit der Dramen, sowie aus anderen künstlerischen Disziplinen unterbringt. Derartige Querverweise sollen in der Arbeit ebenfalls aufgezeigt werden, etwa anhand von Exkursen über die Arbeiten von Cy Twombly oder Lucian Freud. Die Arbeit versteht sich als ein Beitrag zur deutschsprachigen Shakespeare-Rezeption und versucht außerdem dem Regisseur Jürgen Gosch einen Platz innerhalb der theaterwissenschaftlichen Forschungsliteratur einzuräumen, zumal er von dieser bisher kaum beachtet wurde

HLA-G - evolvement from a trophoblast specific marker to a checkpoint molecule in cancer, a narrative review about the specific role in breast- and gynecological cancer

Human leukocyte antigen G (HLA-G) is known as a non-classical molecule of the major histocompatibility complex class Ib and downregulates the mother's immune response against the fetus during pregnancy, thereby generating immune tolerance. Due to the latter effect, HLA-G is also referred to as an immune checkpoint molecule. Originally identified on extravillous trophoblasts, HLA-G is already known to induce immune tolerance at various stages of the immune response, for example through cell differentiation and proliferation, cytolysis and cytokine secretion. Because of these functions, HLA-G is involved in various processes of cancer progression, but a comprehensive review of the role of HLA-G in gynecologic cancers is lacking. Therefore, this review focuses on the existing knowledge of HLA-G in ovarian cancer, endometrial cancer, cervical cancer and breast cancer. HLA-G is predominantly expressed in cancer tissues adjacent to the extravillous trophoblast. Therefore, modulating its expression in the cancer target tissues of cancer patients could be a potential therapeutic approach to treat these diseases

Using automated patch clamp electrophysiology platforms in pain-related ion channel research: insights from industry and academia

Automated patch clamp (APC) technology was first developed at the turn of the millennium. The increased throughput it afforded promised a new paradigm in ion channel recordings: it offered the potential to overcome the time-consuming, low-throughput bottleneck arising from manual patch clamp (MPC) investigations. This has relevance to the fast-paced development of novel therapies for chronic pain. This review highlights the advances in technology, using select examples, that have facilitated APC usage in both industry and academia. It covers both first generation and the latest developments in second-generation platforms. In addition, it also provides an overview of the pain research field and how APC platforms have furthered our understanding of ion channel research and the development of pharmacological tools and therapeutics. APC platforms have much to offer the ion channel research community and this review highlights areas of 'best practice' for both academia and industry. The impact of APC platforms and the prospects for chronic pain ion channel research and improved therapeutics will be evaluated

The AI Transformation? Unpacking the Impact of AI on Incumbent Business Models

Incumbent firms feel pressured to incorporate artificial intelligence (AI) in their business model (BM) to innovate and stay competitive. While transforming the BM with digital technologies is challenging, AI adds complexity through its countless applications and incomprehensible nature. Unraveling this complexity, we develop a taxonomy to describe and analyze how AI impacts incumbent BMs. The taxonomy builds on extant literature and the analysis of 46 empirical cases. Our findings reveal AI’s roles in enhancing and transforming offerings, key operations, and financial logic. In addition, the taxonomy highlights different ways incumbents provide AI capabilities and data as key resources for the resulting BM. Despite the hype around AI, we critically reflect that most of AI’s impact corresponds to well-known digital BM concepts (e.g., personalization). However, AI technology‘s progress might intensify the effectiveness of those BMs and spur novel opportunities within the known digital BM space

Rapid material development and processing of complex near-net-shaped parts by PIM

A promising fabrication method in view of large-scale production of complex parts is Powder Injection Molding (PIM) which has been intensively investigated at Karlsruhe Institute of Technology (KIT). With its near-net-shape precision the method offers particularly the advantage of cost-saving. PIM as special process allows the mass production of components, the creation of composite and prototype materials. Furthermore it is an ideal tool for scientific investigations for R&D in general, and for developing industrial products for a wide range of applications. This contribution describes the characterization and analyses of prototype materials produced via PIM. The investigation of pure tungsten and oxide or carbide doped tungsten materials comprises the microstructure examination, element allocation, texture analyses, and mechanical testing. In addition, fabricated near-net-shape Langmuir probes for diagnostics for the French tokamak WEST will be presented