Medicinal chemistry and molecular pharmacology of orphan human Mas-related G protein-coupled receptors X2 and X4 (MRGPRX2 and MRGPRX4)

The MRGPRX protein subfamily comprise rhodopsin-like orphan GPCRs, whose endogenous agonists have not been identified yet. They are exclusively expressed in primates, including humans. All Mas-related GPCRs (MRGPRs) were first detected in dorsal root ganglia (DRGs) and trigeminal ganglia (TGs), suggesting a role in pain and itch. The MRGPRX2 subtype and its postulated mouse orthologue MRGPRB2 exhibit unique features being activated by various endogenous and exogenous agonists and due to their predominant expression in mast cells (MCs). Both MRGPRX2 and MRGPRB2 are associated with pseudoallergic reactions, such as asthma, chronic urticaria and skin inflammation. Due to its activation by bile acids and bilirubin, MRGPRX4 has been proposed to the target of high concentrations of these molecules released in cholestasis and being responsible for their provoking of itch. MRGPRX2 and MRGPRX4 represent fundamentally new drug targets. Therefore, the development of potent and selective agonists and antagonists is essential to reveal the (patho)physiological functions of these GPCRs, and validating them as novel drug targets, performing preclinical studies and eventually advance them towards clinical development. In view of the need of new drugs to treat and prevent chronic itch and pain, the design of MRGPRX2, MRGPRB2 and MRGPRX4 ligands represents a crucial step. In this PhD thesis, MRGPRX2, its proposed mouse orthologue MRGPRB2, as well as MRGPRX4 were pharmacologically investigated. Tricyclic benzimidazole derivatives have been identified before as potent MRGPRX2 antagonists, and polar xanthine derivatives as MRGPRX4 agonists with high potency. Structure-activity relationships (SARs) at both GPCRs have been intensively investigated in this study as well as their chemical optimization. This approach resulted in finding the most potent ligands for these GPCRs so far: whereas the MRGPRX2 antagonist CB70 displayed a potency in the nanomolar range (IC50 0.0225 µM in β-arrestin assays), the determined agonistic potency of the MRGPRX4 agonist DM288 was in the high picomolar range (EC50 0.000296 µM in β-arrestin assays). Additionally, tricyclic benzimidazole derivatives were evaluated for their additional antagonism at MRGPRB2 in calcium assays and SAR analysis allowed the identification of the most potent MRGPRB2 antagonist to date (CB70, IC50 0.00169 µM in calcium assays). In order to further characterize CB70, the compound was analyzed for its inhibition mode at MRGPRX2. Several antagonistic hit compounds for MRGPRX4 were evaluated for their potency and selectivity. During the development of calcium and β-arrestin assays for MRGPRX4, a single nucleotide polymorphism (S83L) has been identified in the MRGPRX4 gene that altered the GPCR function and impacted the potency of the investigated MRGPRX4 ligands. Lastly, optimized ligands were tested for their inhibition of mast cell degranulation as well as for their induction of intracellular calcium concentration in stem cell-derived mature human dorsal root ganglia neurons. The successful development of new potent and selective MRGPRX2 and MRGPRX4 ligands will help to further characterize the physiological role of these GPCRs

Pascals Kunst zu überzeugen : Geist und Wirkung der Mathematischen Logik in den Briefen in die Provinz

Die bis in unsere Tage reichende Präsenz der "Briefe in die Provinz" von Blaise Pascal (1623 - 1662) gab Anlass, diese Streitschriften hinsichtlich eines ihnen zugrunde liegenden methodischen Verfahrens zu untersuchen, das auf den Grundregeln der von Pascal betriebenen Mathematischen Logik beruht und das den nachhaltigen Erfolg der "Briefe in die Provinz" erklärt

Anästhesiologische Konzepte bei der Resektion von arteriovenösen Malformationen des Gehirns

Zerebrale arteriovenöse Malformationen (AVM) sind Gefäßfehlbildungen im Gehirn, die in ihrem klinischen Verlauf unter anderem zu intrazerebralen Blutungen führen können. Eine Therapiemöglichkeit ist die mikrochirurgische Resektion. Bei diesen anspruchsvollen Operationen kommt in ausgewählten Fällen die kontrollierte Hypotension zum Einsatz. Hierbei handelt es sich um ein anästhesiologisches Verfahren, bei dem der Blutdruck intraoperativ auf einen mittleren arteriellen Blutdruck von 50-60 mmHg abgesenkt wird, um Blutungen zu reduzieren und ein übersichtlicheres Operationsfeld zu ermöglichen. Die vorliegende Arbeit untersucht retrospektiv den Einsatz und die Umsetzung der kontrollierten Hypotension bei der Resektion von zerebralen AVMs. In erster Linie wird der postoperative neurologische Zustand der Patienten analysiert. Weiterhin wird der intraoperative Blutverlust und der Operationsverlauf untersucht. Es wurden 56 Narkoseprotokolle ausgewertet und eine Einteilung in eine Hypotensions- und eine Kontrollgruppe vorgenommen. Es zeigte sich, dass der Blutdruck in der Hypotensionsphase auf durchschnittlich 57 mmHg abgesenkt wurde. Dies wurde in den meisten Fällen durch eine Vertiefung der Narkose oder die Gabe von Urapidil erreicht. Im Vergleich zeigte sich der Blutverlust in der Hypotensionsgruppe höher und die Operationsdauer länger. Zudem zeigten die Patienten der Hypotensionsgruppe postoperativ tendenziell eher eine neurologische Verschlechterung. In der Analyse wurde das postoperative Auftreten von neurologischen Defiziten am besten durch den arteriellen Mitteldruck der Hypotensionsphase und das Auftreten von postoperativen Hemiparesen durch die Dauer der Hypotensionsphase vorhergesagt. Insgesamt kommt diese Arbeit zu dem Schluss, dass ein notwendiger Einsatz der kontrollierten Hypotension unter strenger Indikation und in seiner Dauer und Ausprägung so kurz und gering wie möglich erfolgen sollte

Schöner wohnen wollen (sollen) : Optimierung als Subjektivierungsweise auf den Titelblättern der Schöner Wohnen in den 1980er- und 1990er-Jahren

Not only can we live beautifully, living can be even more beautiful, that’s what the title of the most famous living magazine in German-speaking countries promises and demands. The editors point at the design of living by using a climax in the title, but furthermore, the focus is on optimizing the act of living. Living, shown in media like Schöner Wohnen, can be revealed as a sociopolitical act, which entangles subjectification, normalization and optimization processes. The cover sheets of Schöner Wohnen between 1980-1999 will be analyzed with regard to their image-text-combinations in order to identify the supposedly private space of living as a place of action for optimization and its representation. The discoursive links between social and political developments and the history of living in this period are specific interests of this article, as well as reflections on the magazine as a medium and its functional mechanisms

Investigation of the chemical composition of plasma-treated water by MidiPLexc and its antimicrobial effect on L. monocytogenes and Pseudomonas fluorescens monospecies suspension cultures

Plasma -generated compounds conceived by microwave -induced plasma (MidiPLexc) were physicochemically investigated in their molecular compositions. Therefore, plasma -treated water (PTW) was generated by treatment with the MidiPLexc within a 1 l glass bottle for a pre -treatment time of 100 s, 300 s and 900 s. The PTW was further investigated in its composition of reactive oxygen/nitrogen species. For this purpose, the hydrogen peroxide (H2O2) concentration of the PTW was determined electrochemically using chronoamperometry, and the anionic components were determined using ion chromatography. As a result, H2O2 concentrations of up to 720 mg l−1 , nitrite concentrations of 1600 mg l−1 and nitrate concentrations of 72.3 mg l−1 could be detected after 900 s pre-treatment time of the water. The compounds obtained by ion chromatography were fractionated and subsequently confirmed by mass spectrometry. Once an overview of the chemical composition of PTW had been obtained, its effects on pathogens like Pseudomonas fluorescens and L. monocytogenes, which are both of particular importance as pathogenic contaminants during food production, were tested. In that process, a maximum reduction in the colony forming units of 4 log10 steps for P. fluorescens and 3 log10 steps for L. monocytogenes could be observed. The LIVE/DEAD assay showed a maximum reduction in the ratio G/R of 67% for P. fluorescens and 38% for L. monocytogenes. In addition, the XTT assay results showed a maximum cell metabolism reduction of 96% for P. fluorescens and 91% for L. monocytogenes

Schöner wohnen wollen (sollen) – Optimierung als Subjektivierungsweise auf den Titelblättern der Schöner Wohnen in den 1980er- und 1990er-Jahren

Not only can we live beautifully, living can be even more beautiful, that’s what the title of the most famous living magazine in German-speaking countries promises and demands. The editors point at the design of living by using a climax in the title, but furthermore, the focus is on optimizing the act of living. Living, shown in media like Schöner Wohnen, can be revealed as a sociopolitical act, which entangles subjectification, normalization and optimization processes. The cover sheets of Schöner Wohnen between 1980-1999 will be analyzed with regard to their image-text-combinations in order to identify the supposedly private space of living as a place of action for optimization and its representation. The discoursive links between social and political developments and the history of living in this period are specific interests of this article, as well as reflections on the magazine as a medium and its functional mechanisms

Programing stimuli-responsiveness of gelatin with electron beams: Basic effects and development of a hydration-controlled biocompatible demonstrator

Biomimetic materials with programmable stimuli responsiveness constitute a highly attractive material class for building bioactuators, sensors and active control elements in future biomedical applications. With this background, we demonstrate how energetic electron beams can be utilized to construct tailored stimuli responsive actuators for biomedical applications. Composed of collagen-derived gelatin, they reveal a mechanical response to hydration and changes in pH-value and ion concentration, while maintaining their excellent biocompatibility and biodegradability. While this is explicitly demonstrated by systematic characterizing an electron-beam synthesized gelatin-based actuator of cantilever geometry, the underlying materials processes are also discussed, based on the fundamental physical and chemical principles. When applied within classical electron beam lithography systems, these findings pave the way for a novel class of highly versatile integrated bioactuators from micro-to macroscales

Determinants of Long-term Protection After Hepatitis B Vaccination in Infancy: A Meta-analysis

Background: The duration of protection after hepatitis B vaccination in early infancy is unclear and may be related to vaccination schedule, dosage, vaccine type and population characteristics. Factors potentially influencing waning immunity were assessed. Methods: A systematic review was performed. The main outcomes were prevalence of anti-hepatits B antibodies >= 10 mIU/mL after primary or booster vaccination. Factors potentially influencing protection were assessed in an adjusted random-effects meta-analysis model by age for both outcomes. Results of both meta-analyses were combined in a prognostic model. Results: Forty-six studies reporting on the anti-hepatits B antibodies >= 10 mIU/mL 5 to 20 years after primary immunization and 29 on booster response were identified. The adjusted meta-analyses identified maternal carrier status (odds ratio OR]: 2.37 1.11; 5.08]), lower vaccine dosage than presently recommended (OR: 0.14 0.06; 0.30]) and gap time between last and preceding dose of the primary vaccine series (OR: 0.44 0.22; 0.86]) as determinants for persistence of anti-hepatits B antibodies >= 10. A lower vaccine dosage was also associated with failure to respond to booster (OR: 0.20 0.10; 0.38]). The prognostic model predicted long-term protection of 90% 77%; 100%] at the age of 17 years for offspring of noncarrier mothers vaccinated with a presently recommended dose and vaccination schedule. Conclusions: Based on meta-analyses, predictors of waning immunity after hepatitis B vaccination in infancy could be identified. A prognostic model for long-term protection after hepatitis B vaccination in infancy was developed

Trade-off for survival: Microbiome response to chemical exposure combines activation of intrinsic resistances and adapted metabolic activity

The environmental microbiota is increasingly exposed to chemical pollution. While the emergence of multi-resistant pathogens is recognized as a global challenge, our understanding of antimicrobial resistance (AMR) development from native microbiomes and the risks associated with chemical exposure is limited. By implementing a lichen as a bioindicator organism and model for a native microbiome, we systematically examined responses towards antimicrobials (colistin, tetracycline, glyphosate, and alkylpyrazine). Despite an unexpectedly high resilience, we identified potential evolutionary consequences of chemical exposure in terms of composition and functioning of native bacterial communities. Major shifts in bacterial composition were observed due to replacement of naturally abundant taxa; e.g. Chthoniobacterales by Pseudomonadales. A general response, which comprised activation of intrinsic resistance and parallel reduction of metabolic activity at RNA and protein levels was deciphered by a multi-omics approach. Targeted analyses of key taxa based on metagenome-assembled genomes reflected these responses but also revealed diversified strategies of their players. Chemical-specific responses were also observed, e.g., glyphosate enriched bacterial r-strategists and activated distinct ARGs. Our work demonstrates that the high resilience of the native microbiota toward antimicrobial exposure is not only explained by the presence of antibiotic resistance genes but also adapted metabolic activity as a trade-off for survival. Moreover, our results highlight the importance of native microbiomes as important but so far neglected AMR reservoirs. We expect that this phenomenon is representative for a wide range of environmental microbiota exposed to chemicals that potentially contribute to the emergence of antibiotic-resistant bacteria from natural environments