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The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild-type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia.
Multiple antenatal dexamethasone treatment alters brain vessel differentiation in newborn mouse pups
(2015)
Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.
Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway.
Background: SNPs near the interferon lambda (IFNL) 3 gene are predictors for sustained virological response (SVR) in patients with chronic hepatitis C genotype (GT) 1. In addition, a dinucleotide frame shift in ss469415590 was described, which generates IFNL4. In this study, we compared the role of IFNL4 variants with IFNL3-(rs12979860) and IFNL3-(rs8099917) on response to pegylated (PEG)-IFN and Ribavirin (RBV) in patients with chronic hepatitis C GT2/3.
Methods: We recruited 1006 patients with chronic hepatitis C and GT2/3 in a large German registry. A treatment with PEG-IFN and Ribavirin was started by 959 patients. We performed genotyping of IFNL3 (rs12979860, n = 726; rs8099917, n = 687) and of IFNL4 (ss469415590; n = 631).
Results: Both preferable IFNL3 genotypes were associated with RVR (both p<0.0001) rather than with SVR (rs12979860: p = 0.251; rs8099917: p = 0.447). Only RVR was linked to SVR in univariate and multivariate analyzes (both p<0.001). Concordance of genotyping in patients with available serum samples and EDTA blood samples (n = 259) was more than 96% for both IFNL3 SNPs. IFNL3-(rs12979860) correlated with IFNL4: 99.2% of patients with IFNL3-(rs12979860)-CC were IFNL4-(ss469415590)-TT/TT. IFNL3-(rs12979860)-CT was linked with IFNL4-(ss469415590)-TT/ΔG (98.0%) and IFNL3-(rs12979860)-TT was associated with IFNL4-(ss469415590)-ΔG/ΔG (97.6%).
Conclusion: IFNL3 genotyping from serum was highly efficient and can be used as an alternative if EDTA whole blood is not available. In Caucasian GT2/3 patients genotyping for INFL4-(ss469415590) does not lead to additional information for the decision-making process. Importantly, IFNL3 SNPs were not associated with SVR but with RVR. Even in the era of new direct acting antiviral (DAA) therapies, IFNL3 testing may therefore still be considered for naïve GT2/3 patients to decide if dual Peg-IFN/RBV therapy is an option in resource limited regions.
Background & aim: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin.
Methods: HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression.
Results: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12.
Conclusions: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.
The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti-inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 μM, 5 μL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi-LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid.
This paper studies the life cycle consumption-investment-insurance problem of a family. The wage earner faces the risk of a health shock that significantly increases his probability of dying. The family can buy long-term life insurance that can only be revised at significant costs, which makes insurance decisions sticky. Furthermore, a revision is only possible as long as the insured person is healthy. A second important feature of our model is that the labor income of the wage earner is unspanned. We document that the combination of unspanned labor income and the stickiness of insurance decisions reduces the long-term insurance demand significantly. This is because an income shock induces the need to reduce the insurance coverage, since premia become less affordable. Since such a reduction is costly and families anticipate these potential costs, they buy less protection at all ages. In particular, young families stay away from long-term life insurance markets altogether. Our results are robust to adding short-term life insurance, annuities and health insurance.
We consider the continuous-time portfolio optimization problem of an investor with constant relative risk aversion who maximizes expected utility of terminal wealth. The risky asset follows a jump-diffusion model with a diffusion state variable. We propose an approximation method that replaces the jumps by a diffusion and solve the resulting problem analytically. Furthermore, we provide explicit bounds on the true optimal strategy and the relative wealth equivalent loss that do not rely on quantities known only in the true model. We apply our method to a calibrated affine model. Our findings are threefold: Jumps matter more, i.e. our approximation is less accurate, if (i) the expected jump size or (ii) the jump intensity is large. Fixing the average impact of jumps, we find that (iii) rare, but severe jumps matter more than frequent, but small jumps.
Based on a cognitive notion of neo-additive capacities reflecting likelihood insensitivity with respect to survival chances, we construct a Choquet Bayesian learning model over the life-cycle that generates a motivational notion of neo-additive survival beliefs expressing ambiguity attitudes. We embed these neo-additive survival beliefs as decision weights in a Choquet expected utility life-cycle consumption model and calibrate it with data on subjective survival beliefs from the Health and Retirement Study. Our quantitative analysis shows that agents with calibrated neo-additive survival beliefs (i) save less than originally planned, (ii) exhibit undersaving at younger ages, and (iii) hold larger amounts of assets in old age than their rational expectations counterparts who correctly assess their survival chances. Our neo-additive life-cycle model can therefore simultaneously accommodate three important empirical findings on household saving behavior.
This paper investigates systemic risk in the insurance industry. We first analyze the systemic contribution of the insurance industry vis-à-vis other industries by applying 3 measures, namely the linear Granger causality test, conditional value at risk and marginal expected shortfall, on 3 groups, namely banks, insurers and non-financial companies listed in Europe over the last 14 years. We then analyze the determinants of the systemic risk contribution within the insurance industry by using balance sheet level data in a broader sample. Our evidence suggests that i) the insurance industry shows a persistent systemic relevance over time and plays a subordinate role in causing systemic risk compared to banks, and that ii) within the industry, those insurers which engage more in non-insurance-related activities tend to pose more systemic risk. In addition, we are among the first to provide empirical evidence on the role of diversification as potential determinant of systemic risk in the insurance industry. Finally, we confirm that size is also a significant driver of systemic risk, whereas price-to-book ratio and leverage display counterintuitive results.
Abstract: The current Ebola outbreak poses a threat to individual and global public health. Although the disease has been of interest to the scientific community since 1976, an effective vaccination approach is still lacking. This fact questions past global public health strategies, which have not foreseen the possible impact of this infectious disease. To quantify the global research activity in this field, a scientometric investigation was conducted. We analyzed the research output of countries, individual institutions and their collaborative networks. The resulting research architecture indicated that American and European countries played a leading role regarding output activity, citations and multi- and bilateral cooperations. When related to population numbers, African countries, which usually do not dominate the global research in other medical fields, were among the most prolific nations. We conclude that the field of Ebola research is constantly progressing, and the research landscape is influenced by economical and infrastructural factors as well as historical relations between countries and outbreak events.
Author Summary: For the first time in the history of the disease, the Ebola virus left its local setting and affected people not only in isolated rural areas, but reached larger towns and cities leading to worldwide repercussions. This development prompted a joint global response to this health threat. This encompassed not only immediate relief efforts, but also an up search in global research work. In this study, the scientific output in Ebola research available in one of the mayor medical search platforms was characterized. We studied among others the origin of research, the collaboration between countries and the research topics. Partly, the obtained data was weighted against economic parameters. We attained a detailed map of the research activities from the discovery of Ebola in 1976 up to today. Our research provides the first overview of the worldwide Ebola research output. It might help stakeholders in Ebola research to better plan investigations with a global perspective.
Die vorliegende kumulative Dissertation befasst sich mit der Erfassung der Behandlungsintegrität bestehend aus psychotherapeutischer Adhärenz, Kompetenz sowie der Behandlungsdifferenzierung im Rahmen der Psychotherapieforschung. Die Überprüfung, ob Behandlungen bzw. Interventionen so wie intendiert durchgeführt wurden, ist für die Sicherstellung valider Schlussfolgerungen aus einer klinischen Studie von hoher Relevanz.
Die erste Studie untersucht, ob die Erfassung der Behandlungsintegrität ökonomischer gestaltbar ist. Es zeigte sich, dass Beurteilungen der Adhärenz und Kompetenz basierend auf Sitzungssegmenten im Vergleich zu ganzen Sitzungen keine Unterschiede aufweisen hinsichtlich Reliabilität, Validität und Prädiktion des Behandlungserfolgs.
In der zweiten Studie wird die Entwicklung und Validierung einer Adhärenz- und Kompetenzskala vorgestellt. Diese Studie weist zudem auf die Verwendung im Rahmen der Aus- und Weiterbildung von Therapeuten hin.
Die dritte Studie zeigt, dass in Psychotherapiestudien die im Vergleich stehenden Behandlungsbedingungen gut voneinander unterscheidbar sein müssen. Für die Beschreibung der Behandlungsdifferenzierung und -spezifität wurde der Behandlungs-Spezifitäts-Index entwickelt, dessen Eignung bestätigt werden konnte.
Die vierte Studie überprüft, ob sich erfolgreiche von nicht erfolgreichen Therapien hinsichtlich der psychotherapeutischen Kompetenz, Adhärenz und psychotherapeutischen Beziehung unterscheiden. Es zeigte sich, dass Adhärenz eine Voraussetzung für kompetentes Vorgehen darstellt. Kompetenz beeinflusst die psychotherapeutische Beziehung maßgebend, die mitentscheidend für den (Miss-)Erfolg einer Behandlung zu sein scheint.
Insgesamt tragen die Ergebnisse zu einer differenzierteren, spezifischeren und ökonomischeren Erfassung der Behandlungsintegrität innerhalb der Psychotherapieforschung bei. Gleichzeitig erweitern sie den Fokus auf neue Ansätze für zukünftige Forschungen.
Zur Untersuchung der Eigenschaften organischer Halbleiter sollte die Ultrareinigung organischer Materialien durch Zonenschmelzen ermöglicht werden und anschließend dieses Verfahren auf einen neuen molekularen n-Halbleiter, Perfluoranthracen, angewendet werden. Ein Großteil der vorliegenden Arbeit beschäftigte sich daher mit der Konstruktion einer Zonenschmelze. Diese sollte in der Lage sein, laborübliche Mengen organischer Materialien zu reinigen (ca. 0,5-5 g). Ein Eigenbau wurde in Angriff genommen, um eine optimale Anpassung an die zu erwartenden Aufgabenstellungen zu erreichen. Daher wurde das System in einer modularen Bauweise konzipiert, sodass einzelne oder mehrere Heizzonen verwendet werden können und die Apparatur auch später beliebig erweitert werden kann. Zunächst mussten Erfahrungen mit der Wärmezufuhr und Kühlung gesammelt werden und ein verlässlicher Zugmechanismus entwickelt werden, der die Probe in kontrollierter, langsamer Weise durch die Apparatur bewegt. Ein grosses Problem stellte das Bersten der gläsernen Probenbehältnisse beim Zonenschmelzen einiger Substanzen dar. Nach dem erfolgreichen Einsatz verschiedener Puffermaterialien wurde schliesslich ein apparativer Aufbau entwickelt, der auf eine aktive Kühlung verzichtete. Hierdurch konnte die unkontrollierte Sublimation unterbunden werden und das Bersten der Probenbehältnisse wurde unterdrückt. Gleichzeitig musste jedoch sichergestellt werden, dass die Effektivität des Zonenschmelzen auch ohne den Einsatz grosser Temperaturgradienten gegeben war. Die Reinigung verschiedener kommerziell verfügbarer Substanzen wurde getestet und gleichzeitig die Analytik der organischen Verunreinigungen mittels Gaschromatographie im Arbeitskreis etabliert. Das Zonenschmelzen ermöglichte schließlich die Reinigung von Anthracen bis auf 99,97%. In Dibenzothiophen konnten der Anteil der Nebenkomponenten unter die Nachweisgrenze verringert werden. Nach der Herstellung von Perfluoranthracen wurden unterschiedliche Methoden zur Reinigung getestet und schließlich das Zonenschmelzen angewendet. Es war möglich, kleinere Mengen an Perfluoranthracen in einer Reinheit von bis zu 99,11% zu isolieren, was durch reguläre Reinigungsverfahren wie Umkristallisation oder Sublimation nicht erreicht werden konnte. Dennoch limitierte die thermische Instabilität des Materials die Effektivität des Zonenschmelzens.
Weiterhin wurden die optische und elektrochemische Bandlücke von Perfluoranthracen untersucht, um Aussagen über die mögliche Anwendung als n-Halbleiter treffen zu können. Es wurde eine optische Bandlücke von 3,08 eV und eine elektrochemische Bandlücke von 2,82 eV ermittelt. Im Vergleich zu Anthracen wurden niedriger liegende Grenzorbitale bestimmt, was ein Einbringen von Elektronen in das energetisch niedrigste unbesetzte Molekülorbital (LUMO) und somit n-Halbleitung vereinfachen könnte. Schließlich wurde untersucht, ob sich durch die äquimolare Mischung von Anthracen und Perfluoranthracen Mischkristalle herstellen lassen, die Charge-Transfer-Eigenschaften (CT) und eine hohe elektrische Leitfähigkeit aufweisen würden. Hierzu mussten zunächst ausreichend grosse Einkristalle gezüchtet werden, von denen anschliessend die Röntgenkristallstruktur bestimmt wurde. Das einkristalline Material zeigte eine gemischt gestapelte Anordnung (siehe Abbildung 0.2), wie sie für andere Systeme, beispielsweise Benzol/Hexafluorbenzol, bekannt ist. In feldstärkenabhängigen und temperaturabhängigen Messungen wurden danach die elektrischen Eigenschaften des Materials charakterisiert. Es konnten keine Hinweise für CT-Eigenschaften gefunden werden. Dennoch besitzt der Mischkristall im Vergleich zu Anthracen eine etwa 10 12 -fach höhere Leitfähigkeit und erreicht Werte guter anorganischer Halbleiter. Das temperaturabhängige Verhalten selbst zeigt aber keine typisch halbleitenden Charakteristiken, da für die thermisch angeregte Zunahme der Ladungsträgerkonzentration im untersuchten Mischkristall kein lineares Verhalten im Arrhenius-Plot gefunden wurde. Die genauen Leitungsmechanismen bedürfen weiterer Untersuchungen. In nachfolgenden Experimenten könnte die mögliche Anwendbarkeit in elektronischen Anwendungen geklärt werden.
G-Protein-gekoppelte Rezeptoren (GPCR) sind im Immunsystem essentiell für die Verarbeitung von Signalen, die von Chemokinen, Lipiden und anderen Botenstoffen ausgehen. Ihre Existenz gewährleistet, dass Leukozyten sowohl unter physiologischen als auch unter pathophysiologischen Umständen ihren Funktionen als Immunzellen nachkommen können. Grundlegend wichtig für das angeborene Immunsystem sind die GPCR, die die Weiterleitung ihrer Signale über G-Proteine vom Typ Gi vermitteln. Die Migration, Adhäsion und Differenzierung von Leukozyten wird jedoch auch maßgeblich durch G12/13-gekoppelte Rezeptoren reguliert, wobei die kleine GTPase RhoA als Effektormolekül eine wichtige Rolle spielt. Die Bedeutung der G12/13-gekoppelten Signaltransduktion in Makrophagen ist allerdings weitgehend unverstanden. Mit Hilfe einer Mauslinie, in der speziell und ausschließlich in myeloiden Zellen die beiden G-Protein-Untereinheiten Gα12 und Gα13 durch ein konstitutiv aktives Cre-Rekombinase-System inaktiviert wurden (Lys-Gα12/Gα13-KO), sollte nun die Funktion und der genaue Mechanismus des G12/13-gekoppelten Signalweges in Monozyten und Makrophagen aufgeklärt werden und somit neue Erkenntnisse zur Rolle der GPCR im Immunsystem gewonnen werden.
Eine erste Untersuchung der peripheren Immunzellpopulationen des Lys-Gα12/Gα13-KO ergab, dass residente Gewebemakrophagen, im Speziellen die des Peritoneums, in ihrer Anzahl erhöht sind. In einer vertieften Analyse der residenten peritonealen Makrophagen (rpMP) konnte gezeigt werden, dass der Verlust von Gα12/13 zu Veränderung im Zytoskelett der Makrophagen führt. Die Zellen entwickeln einen Phänotyp mit besonders langen und verzweigten Filopodien und zeigen Ein-schränkungen in ihrer basalen Beweglichkeit.
Über diesen morphologischen Befund hinaus, konnte in einer Studie zur Gen-expression in diesen Zellen festgestellt werden, dass Gα12/13-defiziente Makrophagen verstärkt proinflammatorische Gene wie Nos2, die Cyclooxygenase 2 aber auch verschiedene Chemokine wie Cxcl10 oder Cytokine wie Il-6 oder Tnfα exprimieren. Ein ähnlicher Phänotyp in Bezug auf Morphologie und Genexpression wurde bei der Untersuchung von Makrophagen, die aus Knochenmark des Lys-Gα12/Gα13-KO generiert wurden, beobachtet.
Als vermutlich verantwortlicher G12/13-gekoppelter Rezeptor konnte der S1P-Rezeptor-subtyp 2 (S1P2) identifiziert werden. Mit Hilfe von Inhibitoren für die G12/13-gekoppelte Signaltransduktionskaskade konnte gezeigt werden, dass über die kleine GTPase RhoA die NF-κB-abhängige Genaktivität reguliert werden kann. Vermutlich aktiviert RhoA dazu die Rho Kinase ROCK, die wiederum das untergeordnete Effektormolekül Rac1 hemmen kann. Im Falle des Lys-Gα12/Gα13-KO führt eine reduzierte Aktivierung von RhoA insgesamt zu einer eingeschränkten Hemmung dieses Signalweges und im Folgenden zu einer außer Kontrolle geratenen Induktion entzündungsrelevanter Gene und damit einhergehend auch zu einer Veränderung des Milieus in der Bauchhöhle dieser Tiere.
Obwohl die Immunantwort in diesen Tieren auf klassische Pathogene wie Lipopolylsaccharide (LPS) unverändert ist, konnte ein Anstieg an peritonealen B-Zellen festgestellt werden. Diese B-Zellen, insbesondere B1 B-Zellen, sind als wichtige Produzenten von natürlichen Antikörpern gegen endogene Pathogene bekannt. Die Analyse von Plasma aus Lys-Gα12/Gα13-KO-Mäusen ergab einen erhöhten Titer für natürliche Antikörper wie beispielsweise gegen oxidierte Formen von atherogenen Lipoproteinen. Diese Erkenntnis führte zu der Frage, ob die ursprünglich pro-inflammatorischen Veränderungen der peritonealen Makrophagen einen indirekten, positiven Einfluss auf die Entwicklung einer Atherosklerose haben können. Interessanterweise sind die Tiere des Lys-Gα12/Gα13-KO signifikant vor Atherosklerose geschützt und die Existenz der natürlichen Antikörper in atherosklerotischen Läsionen wird als Hinweis für ihre protektive Rolle im Krankheitsverlauf angesehen. In einem therapeutischen Ansatz mit peritonealen Zellen konnte in Atherosklerose-gefährdeten Tieren die Progression dieser Gefäßerkrankung eingedämmt werden.
Die hier durchgeführte Studie hat durch in vitro und in vivo Versuche mit Lys-Gα12/Gα13-KO-Mäusen dazu beitragen, das Verständnis der Rolle der G12/13-gekoppelten Signaltransduktion im Immunsystem zu verbessern.
Die Komplexität der verschiedenen Funktionen einzelner Effektormoleküle einerseits und die Interaktionen unterschiedlicher Immunzellpopulationen andererseits lassen jedoch vermuten, dass noch weitreichende Untersuchungen an GPCR und G-Proteinen nötig sind, um diese für den Organismus bedeutsamen Informationssysteme voll-ständig zu verstehen und weiter therapeutisch nutzbar zu machen.
The crystal structure of the title compound, C25H24N2O2, at 173 K has monoclinic (C2/c) symmetry. The molecule is located on a crystallographic twofold rotation axis with only half a molecule in the asymmetric unit. The imidazolidine ring adopts a twist conformation, with a twist about the ring C—C bond. The crystal structure shows the anticlinal disposition of the two (2-hydroxynaphthalen-1-yl)methyl substituents of the imidazolidine ring. The structure displays two intramolecular O—H⋯N hydrogen bonds, each forming an S(6) ring motif.
In the title salt, [Ag(C27H36N2)2]Cl·C4H8O, the AgI atom is coordinated by two 1,3-bis(2,6-dimethylphenyl)imidazol-2-ylidene ligands. The imidazole rings are inclined to one another by 46.69 (13)° and the benzene rings in each ligand are almost normal to the imdazole ring to which they are attached, with dihedral angles varying from 82.39 (13) to 88.27 (12)°. There are C—H⋯π interactions present in the cation, involving the two ligands, and the solvent molecule is linked to the cation via a C—H⋯O hydrogen bond. In the crystal, molecules are linked by trifurcated C—H⋯(Cl,Cl,Cl) hydrogen bonds, forming slabs parallel to (101). One isopropyl group is disordered over two sets of sites with an occupancy ratio of 0.447 (17):0.553 (17) and the THF molecule is disordered over two positions with an occupancy ratio of 0.589 (6):0.411 (6).
In the title ternary co-crystalline adduct, C7H14N4·2C6H5NO3, molecules are linked by two intermolecular O—H⋯N hydrogen bonds, forming a tricomponent aggregates in the asymmetric unit. The hydrogen-bond formation to one of the N atoms is enough to induce structural stereoelectronic effects in the normal donor→acceptor direction. In the title adduct, the two independent nitrophenol molecules are essentially planar, with maximum deviations of 0.0157 (13) and 0.0039 (13) Å. The dihedral angles between the planes of the nitro group and the attached benzene rings are 4.04 (17) and 5.79 (17)°. In the crystal, aggregates are connected by C—H⋯O hydrogen bonds, forming a supramolecular dimer enclosing an R66(32) ring motif. Additional C—H⋯O intermolecular hydrogen-bonding interactions form a second supramolecular inversion dimer with an R22(10) motif. These units are linked via C—H⋯O and C—H⋯N hydrogen bonds, forming a three-dimensional network.
Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I. We demonstrate that a single salt bridge in the membrane between the transporter associated with antigen processing TAP and the MHC I-specific chaperone tapasin is essential for the assembly of the PLC and for efficient MHC I antigen presentation. Molecular modeling and all-atom molecular dynamics simulations suggest an ionic lock-switch mechanism for the binding of TAP to tapasin, in which an unfavorable uncompensated charge in the ER-membrane is prevented through complex formation. Our findings not only deepen the understanding of the interaction network within the PLC, but also provide evidence for a general interaction principle of dynamic multiprotein membrane complexes in immunity.
Background: The treatment of different skin conditions with spa waters is a long tradition dating back to at least late Hellenism. Interestingly, independent scientific examinations studying the effect of spa waters are scarce.
Objective: In the present in vitro study, we compared the effect of culture media supplemented with (a) thermal spa waters (La Roche-Posay, Avène) and (b) two natural mineral drinking waters (Heppinger, Adelholzener) on physiological parameters in HaCaT keratinocytes.
Methods: The different medium preparations were investigated with regard to cell proliferation and cell damage. Moreover, the impact on inflammation parameters with and without ultraviolet B (UVB) irradiation was examined.
Results: Two popular thermal spring waters were found to suppress cell proliferation and cell damage. Moreover, these waters reversed the induction of interleukin-6, as measured using enzyme-linked immunosorbent assay and promoter transactivation, and the formation of reactive oxygen species after UVB stimulation. Of note, the two natural mineral waters, which are distributed as drinking waters, had some effect on the above-mentioned parameters but to a lesser extent.
Conclusion: In summary, our results show that spa waters, and particularly those derived from thermal springs, reduce parameters associated with inflammation. It seems likely that trace elements such as selenium and zinc are critical for the observed effects.
Incidence rates of clinically significant tinnitus: 10-year trend from a cohort study in England
(2015)
Objective: To investigate the incidence of tinnitus that burdens the health service in England.
Design: This was an observational study of 4.7 million residents of England under 85 years of age who were at risk for developing clinically significant tinnitus (sigT). SigT was defined by a discharge from hospital with a primary diagnosis of tinnitus, or a primary care recording of tinnitus with subsequent related medical follow-up within 28 days. The database used was the Clinical Practice Research Datalink and individual records were linked to additional data from the Hospital Episode Statistics. The observational period was from January 1, 2002 to December 31, 2011. Age-, gender-, and calendar year-specific incidence rates for and cumulative incidences of sigT were estimated and a projection of new cases of sigT between 2012 and 2021 was performed.
Results: There were 14,303 incident cases of sigT identified among 26.5 million person-years of observation. The incidence rate was 5.4 new cases of sigT per 10,000 person-years (95% confidence interval: 5.3 to 5.5). The incidence rate did not depend on gender but increased with age, peaking at 11.4 per 10,000 in the age group 60 to 69 years. The annual incidence rate of sigT increased from 4.5 per 10,000 person-years in 2002 to 6.6 per 10,000 person-years in 2011. The 10-year cumulative incidence of sigT was 58.4 cases (95% confidence interval: 57.4 to 59.4) per 10,000 residents. Nearly 324,000 new cases of sigT are expected to occur in England between 2012 and 2021.
Conclusions: Tinnitus presents a burden to the health care system that has been rising in recent years. Population-based studies provide crucial underpinning evidence; highlighting the need for further research to address issues around effective diagnosis and clinical management of this heterogeneous condition.