Veränderung der Muskarin-(M2)-Rezeptor-Gi-Protein-Adenylatzyklase-Interaktion in den respiratorischen Segmenten der Atemwege bei der Recurrent Airway Obstruction (RAO) des Pferdes

Muskarin-cholinerge und adrenerge Rezeptoren des autonomen Nervensystems im Respirationstrakt spielen sowohl bei der physiologischen Regulation der Atemwegsfunktion als auch bei der Entstehung und Behandlung wiederkehrender obstruktiver Atemwegserkrankungen (RAO) des Pferdes eine wichtige Rolle. Im Wesentlichen sorgen diese Rezeptorsysteme für eine Relaxation und bzw. oder Kontraktion der glatten Atemwegsmuskulatur. Bei einer Erkrankung der Atemwege wird eine Störung der Balance beider Rezeptorsysteme vermutet. Neuere Forschungsergebnisse belegen, dass zum einen der β–adrenerge Rezeptor-Gs-Protein-Adenylatzyklase-Signalweg im Respirationstrakt RAO-erkrankter Pferde beeinträchtigt ist. Gleichzeitig war die Verteilung und Dichte der muskarin-cholinergen Rezeptoren unverändert. Die Signaltransduktionswege, insbesondere die des muskarin-cholinergen Rezeptorsystems, wurden jedoch bisher noch nicht ausreichend untersucht. Membranen des Lungenparenchyms sowie des Tracheal- und Bronchialepithels mit der darunter liegenden glatten Muskulatur gesunder und RAO-erkrankter Pferde wurden hinsichtlich der Funktionalität der M2- Rezeptor-Gi-Protein-AC-Kopplungsmechanismen mittels 35S-GTPγS-Bindungsstudien untersucht. Mit verschiedenen muskarin-cholinergen Agonisten und den Substanzen N-Ethylmaleimid (NEM) und Pertussistoxin (PTX) wurde die M2-Rezeptor-Gi-Protein-Kopplung überprüft. Vorher war die Ermittlung der Konzentrationen von Na+ (200 mmol/l), Mg2+ (10 mmol/l) und GDP (10 μmol/l) zur Etablierung einer optimierten 35S-GTPγS-Bindung notwendig. Es konnte gezeigt werden, dass die Basalbindung und die Agonisten-stimulierte 35S-GTPγS-Bindung zeitabhängig ist und eine Inkubationszeit festgelegt werden musste, bei der eine hohe relative Stimulation gemessen werden konnte. Diese Inkubationszeit lag bei 120 min bei einer Temperatur von 30°C. Bis zu diesem Zeitpunkt stieg die relative Stimulation der 35S-GTPγS-Bindung. Die muskarin-cholinergen Agonisten Oxotremorin M, Carbachol und Acetylcholin waren in der Lage die 35S-GTPγS-Bindung in allen untersuchten Segmenten bei gesunden und bei an RAO-erkrankten Pferden zu stimulieren, wobei Oxotremorin M die 35S-GTPγS-Bindung stärker als Carbachol und Acetylcholin stimulierte. Die maximale relative Stimulation lag in den Bronchien bei 126 %, in der Trachea bei 104 % und in der Lunge bei 41 %. Diese segmentabhängige Stimulierbarkeit der 35S-GTPγS-Bindung entspricht der Dichte der M2-muskarin-cholinergen Rezeptoren, die an Gi-Proteine gekoppelt sind. Bei an RAO-erkrankten Pferden konnte eine tendenziell stärkere Agonisten-stimulierte Interaktion zwischen den M2-muskarincholinergen Rezeptoren und Gi-Proteinen gemessen werden (Bronchien 141 % und Lunge 78 %) als bei gesunden Pferden. Dies könnte mit einer erhöhten Anzahl an Bindungsstellen für 35S-GTPγS begründet sein, was eine erhöhte Menge an Gi-Proteinen im erkrankten Gewebe bedeuten würde. Hierfür spricht die Hemmung der 35S-GTPγS-Bindung mit NEM und PTX, die die Agonisten-vermittelte 35S-GTPγS-Bindung im Gewebe von an RAO-erkrankten Pferden schwächer hemmte als im Gewebe von gesunden Pferden. Die indirekte Messung der AC-Aktivität zeigte eine segmentabhängige Reduzierung der cAMP-Produktion von Trachea über Bronchien bis hin zur Lunge. Oxotremorin M hemmte die Forskolin-vermittelte cAMPProduktion, und PTX war in der Lage diese durch Entkopplung der Gi-Proteine vom M2-Rezeptor zu hemmen. Ein weiterer Hinweis auf die erhöhte Menge von Gi-Proteinen im Gewebe RAO-erkrankter Pferde war die gemessene Reduzierung der Forskolin-induzierten cAMP-Produktion. In der vorliegenden Arbeit wurde erstmalig die Methode zur Messung der Rezeptorinteraktion mit korrespondierenden G-Proteinen - die 35S-GTPγS-Bindung - in Geweben des Respirationstrakts von Pferden etabliert. Die Stimulation mit muskarin-cholinergen Agonisten führte zu einer erhöhten 35S-GTPγS-Bindung bei an RAO-erkrankten Pferden. Außerdem konnte bei RAO eine Reduzierung der Forskolin-induzierten cAMP-Produktion beobachtet werden. Diese Ergebnisse deuten auf eine erhöhte Gi-Proteinmenge hin. Somit verschiebt sich bei RAO das Gi/Gs-Gleichgewicht auf Seite des Gi-Protein-vermittelten Signalwegs. Diese Veränderung des M2-Rezeptor-Gi-Protein-Signalwegs trägt, wie auch die Verschiebung des muskarincholinergen/ adrenergen Gleichgewichts durch β-Adrenozeptor-Downregulation, letztendlich zur bronchokonstriktorischen Aktivität bei RAO bei. Die Ergebnisse dieser Arbeit liefern somit die Grundlage für ein Evidenz-basiertes Konzept der Pharmakotherapie der RAO des Pferdes mit Muskarin-M2-selektiven Antagonisten zusätzlich zur etablierten Basistherapie mit β2-Sympathomimetika, insbesondere wenn gegenüber diesen bereits eine Toleranz besteht

Das österreichische Wahljahr 2004

'2004 fanden in Österreich mehrere Wahlen statt, die einige machtpolitische Veränderungen ergaben. Der Beitrag befasst sich mit den Ergebnissen der Landtagswahlen in Kärnten, Salzburg und Vorarlberg, der Bundespräsidentschaftswahl und der Wahl zum Europäischen Parlament. Forschungsfragen sind die Veränderungen im Wahlverhalten, zentrale Wahlmotive, die Bedeutung der Parteien bzw. ihrer KandidatInnen und die Gründe der niedrigen Wahlbeteiligung. Schließlich werden das Phänomen der ehemaligen FPÖ-WählerInnen, der Erfolg der Liste Hans-Peter Martin sowie die Perspektiven für die einzelnen Parteien bzw. mögliche Koalitionsbildungen analysiert.' (Autorenreferat)'In 2004, there were several elections in Austria that resulted in some shifts of political power. Our article focuses on the outcome of regional elections in Carinthia, Salzburg and Vorarlberg, the federal presidential election, and the European Parliament elections. Research questions are the changes in voting behaviour, elections motives, the role of parties and their candidates, and reasons for the low voter turnout. Finally, the phenomenon of 'former voters' of the so-called Freedom Party (FPOE), the success of the Hans-Peter Martin list, and possible coalition perspectives for the individual parties are analysed.' (author's abstract)

Effect of Twitter investor engagement on cryptocurrencies during the COVID-19 pandemic

This study aims to examine whether the prices and returns of two cryptocurrencies, Dogecoin and Ethereum, are affected by Twitter engagement following the COVID-19 pandemic. We use the autoregressive integrated moving average with explanatory variables model to integrate the effects of investor attention and engagement on Dogecoin and Ethereum returns using data from December 31, 2020, to May 12, 2021. The results provide evidence supporting the hypothesis of a strong effect of Twitter investor engagement on Dogecoin returns; however, no potential impact is identified for Ethereum. These findings add to the growing evidence regarding the effect of social media on the cryptocurrency market and have useful implications for investors and corporate investment managers concerning investment decisions and trading strategies

Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Effects of Protein Load Prior to the Main Meal of the Day: A Pilot Trial

Background: High protein diets increase satiety and may decrease energy intake. Many overweight people overeat in the evening. We hypothesized that ingesting protein prior to the evening meal may limit successive calorie intake and generate weight loss. Aims: To explore whether protein pre-load before the evening meal will lead to weight loss compared to eating as usual. Methods: 129 adults with a Body Mass Index (BMI) ≥25 reporting eating large evening meals were randomized to either consume a 20 g protein bar 30 minutes before their evening meal daily for two weeks (Protein pre-loading (PP) arm) or not (No protein pre-loading (NP) arm). Hunger ratings were recorded, immediately prior to each evening meal. Participants returned at the end of weeks one and two to provide their weight and rating of hunger and any changes in evening food consumption since baseline. Results: There was no significant difference in weight loss between the study arms (Week1 PP: -0.13 kg, [SD=0.74] vs. NP: -0.06 kg, [SD=0.75], not significant (NS); Week2 PP: +0.06 kg, [SD=0.82] vs. NP: -0.005 kg, [SD=0.82], NS). Participants in the PP arm reported less hunger before evening meals than those in the NP arm (Week1: 4.97 [SD=0.94] vs. 3.72[SD=0.65], p < .0011; Week2: 4.95 [SD=0.94] vs. 3.69[SD=0.71], p < .001). They also reported eating less at their evening meals (Week1: 2.59[SD=0.53] vs. 2.11[SD=0.54], p < .001; Week2: 2.63[SD=0.49] vs. 2.10[SD=0.50], p < .001). Conclusion: Consuming 20 g of protein before the evening meal reduced hunger and self-reported food intake in the evening, but had no effect on weight

Effects of reduced-risk nicotine-delivery products on smoking prevalence and cigarette sales: an observational study

BACKGROUND: It is not currently clear what impact alternative nicotine-delivery products (electronic cigarettes, heated tobacco products and snus) have on smoking rates and cigarette sales. OBJECTIVE: To assess whether access to these products promotes smoking in the population. DESIGN AND DATA SOURCES: We examined associations of alternative nicotine product use and sales with smoking rates and cigarette sales overall, and in different age and socioeconomic groups, and compared smoking prevalence over time in countries with contrasting regulations of these products. For electronic cigarettes, we examined data from countries with historically similar smoking trajectories but differing current electronic cigarette regulations (United Kingdom and United States of America vs. Australia, where sales of nicotine-containing electronic cigarettes are banned); for heated tobacco, we used data from countries with state tobacco monopolies, where cigarette and heated tobacco sales data are available (Japan, South Korea), and for snus we used data from Sweden. ANALYSIS METHODS: We pre-specified dynamic time series analyses to explore associations between use and sales of alternative nicotine-delivery products and smoking prevalence and cigarette sales, and time series analyses to compare trends of smoking prevalence in countries with different nicotine product policies. RESULTS: Because of data and analysis limitations (see below), results are only tentative and need to be interpreted with caution. Only a few findings reached statistical significance and for most results the Bayes factor indicated inconclusive evidence. We did not find an association between rates of smoking and rates of the use of alternative nicotine products. The increase in heated tobacco product sales in Japan was accompanied by a decrease in cigarette sales. The decline in smoking prevalence seems to have been slower in Australia than in the United Kingdom overall, and slower than in both the United Kingdom and the United States of America among young people and also in lower socioeconomic groups. The decline in cigarette sales has also accelerated faster in the United Kingdom than in Australia. LIMITATIONS: Most of the available data had insufficient data points for robust time series analyses. The assumption of our statistical approach that causal interactions are more likely to be detected when longer-term changes are screened out may not apply for short time series and in product interaction scenarios, where short-term fluctuations can be caused by, for example, fluctuations in prosperity or product supplies. In addition, due to dual use, prevalence figures for smoking and alternative product use overlap. The ecological study design limits the causal inferences that can be made. Longer time periods are needed for any effects of exclusive use of the new products on smoking prevalence to emerge. CONCLUSIONS: We detected some indications that alternative nicotine products are competing with cigarettes rather than promoting smoking and that regulations that allow their sales are associated with a reduction rather than an increase of smoking, but the findings are inconclusive because of insufficient data points and issues with the assumptions of the pre-specified statistical analyses. FUTURE WORK: As further prevalence and sales data emerge the analyses will become more informative. Accessing sales figures in particular is the current research priority. STUDY REGISTRATION: The project is registered on Open Science Framework https://osf.io/bd3ah. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR129968) and will be published in full in Public Health Research; Vol. 11, No. 7. See the NIHR Journals Library website for further project information

E-cigarette use in public places: striking the right balance

First paragraph: The availability, marketing and use of electronic cigarettes or nicotine vapourisers is subject to a range of regulations across different countries, varying from the prohibition of sales and use, to little or no regulation. The most common approach adopted in countries that permit some use of e-cigarettes has been to adapt existing laws or frameworks designed for tobacco products to include e-cigarettes. This can include extending bans on tobacco advertising to e-cigarettes, applying the same age of sale laws or taxing e-cigarettes like tobacco. In some jurisdictions including many Canadian provinces and US states, existing smoke-free public places laws have also been amended to include e-cigarettes, so that vaping is prohibited wherever tobacco cannot be used&mdash;including enclosed public places, workplaces and some outdoor areas. But is this the right approach, and is it supported by research evidence

Initial ratings of different types of e-cigarettes and relationships between product appeal and nicotine delivery

AIMS: Little is known about features of e-cigarettes (EC) that facilitate or hinder the switch from smoking to vaping. We tested eight brands of EC to determine how nicotine delivery and other product characteristics influence user's initial reactions. METHODS: Fifteen vapers tested each product after overnight abstinence from both smoking and vaping. At each session, participant's vaped ad lib for 5 min. Blood samples were taken at baseline and at 2, 4, 6, 8, 10 and 30 min after starting vaping. Participants rated the products on a range of characteristics. The products tested included six 'cig-a-like' and two refillable products, one with variable voltage. We also tested participants' own EC. RESULTS: All products significantly reduced urges to smoke. Refillable products delivered more nicotine and received generally superior ratings in terms of craving relief, subjective nicotine delivery, throat hit and vapour production but in overall ratings, they were joined by a cig-a-like, Blu. Participants puffed more on low nicotine delivery products. Participants' estimates of nicotine delivery from different EC were closely linked to 'throat hit'. Nicotine delivery was less important in the initial product ratings than draw resistance, mouthpiece comfort and effects on reducing urge to smoke. CONCLUSIONS: All EC products reduced urges to smoke. Refillable products received generally more favourable ratings than 'cig-a-likes' with similar nicotine content. Perception of nicotine delivery was guided by throat sensations. Lower nicotine delivery was associated with more frequent puffing. The first impressions of EC products are guided less by nicotine delivery than by sensory signals

Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors

Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to treat B-cell lymphoma and autoimmune diseases. We describe the discovery and optimization of (1s,4s)-N,N′-diaryl cyclohexane-1,4-diamines, a novel series of allosteric MALT1 inhibitors, resulting in compound 8 with single digit micromolar cell potency. X-ray analysis confirms that this compound binds to an induced allosteric site in MALT1. Compound 8 is highly selective and has an excellent in vivo rat PK profile with low clearance and high oral bioavailability, making it a promising lead for further optimization