Testung potenzieller Therapeutika zur Behandlung nach S-Lost-Exposition in Hautmodellen

Bei dem Hautkampfstoff Schwefellost (S-Lost) handelt es sich um einen chemischen Kampfstoff, der seit dem 1. Weltkrieg in verschiedenen militärischen Konflikten eingesetzt wurde. Trotz der Vereinbarungen durch die Chemiewaffenkonvention S-Lost nicht mehr einzusetzen und die Restbestände zu vernichten, besteht weiterhin die Gefahr einer Verwendung in asymmetrischen Konflikten oder Terrorszenarien. Gut dokumentierte Vergiftungsfälle aus dem Bürgerkrieg in Syrien verdeutlichen, wie wichtig eine intensive Forschung an Therapieoptionen auf diesem Gebiet ist. Die Symptomatik nach einer S-Lost-Exposition betrifft vor allem die Augen, Atemwege und die Haut. Typisch ist eine zeitliche Verzögerung bis zum Einsetzen der ersten Anzeichen einer Intoxikation. Durch eine anhaltende Entzündungsreaktion und Gewebsnekrosen verläuft der Heilungsprozess sehr langsam und es können irreversible Narben und Hautverfärbungen zurückbleiben. Bis heute konnte der molekulare Pathomechanismus von S-Lost nicht vollständig aufgeklärt werden und daher fehlt es an zielgerichteten Behandlungsoptionen. Die derzeitigen therapeutische Ansätze fokussieren sich ausschließlich auf die symptomatische Behandlung von S-Lost-Vergifteten. Im Bereich der Toxikologie sind in vitro Modelle ein wissenschaftlich etablierter Standard. Zur besseren Abbildung der physiologischen Bedingungen und zur Erhöhung der Aussagekraft für eine spätere in vivo Translation, wurde am Institut für Pharmakologie und Toxikologie der Bundeswehr eine Co-Kultur-Testbatterie etabliert. Hierbei handelt es sich um ein Hautmodell bestehend aus der Keratinozyten-Zelllinie HaCaT und der humanen Monozyten-Zelllinie THP-1. Ein standardisiertes Vergiftungsprotokoll mit anschließenden Assays zur Bestimmung der Apoptose und Nekrose sowie den Entzündungsmarkern IL-6 und IL-8 erlaubt eine experimentelle Evaluierung potenzieller S-Lost-Therapeutika. Der Naturstoff Berberin zeigte in einer Studie mit der Testbatterie anti-apoptotische und antientzündliche Eigenschaften. Für Berberin ist kein spezifischer Wirkmechanismus beschrieben, allerdings zeigte es in unterschiedlichen Versuchen eine Vielzahl pharmakologischer Effekte. Die Behandlung eine Stunde nach S-Lost-Exposition führte konzentrationsabhängig zu einer Reduktion der IL-6- und IL-8-Freisetzung sowie zu einer signifikanten Abnahme der Apoptose. Dieses Ergebnis zeigte, dass die pleiotropen Effekte von Berberin eine S-Lost-Intoxikation positiv modulieren können und es möglicherweise eine alternative therapeutische Option zu etablierten Entzündungshemmern darstellen kann. Eine zweite Substanz, die im Wirkstoffscreening zytoprotektive und antiinflammatorische Wirkung zeigte, war der Nekrose-Inhibitor Necrosulfonamid. Entgegen der Erwartung war die Zytoprotektivität nicht auf eine Reduktion der Nekrose zurückzuführen, sondern es kam zu einer Verminderung der Apoptose. Eine signifikante Absenkung der Entzündungsmarker IL-6 und IL-8 konnte in der mit 5 µM Necrosulfonamid behandelten Gruppe für allen Vergiftungsstufen gezeigt werden. Da Necrosulfonamid in erster Linie die über MLKL-induzierte Nekroptose inhibiert und deren Rolle am S-Lost vermittelten Zelltod noch unerforscht ist, zeigten die Untersuchungen, dass eine mechanistische Aufklärung der Nekroptose weitere grundlegende Erkenntnisse über die molekulare Toxizität von S-Lost liefern kann.Sulfur mustard is a chemical warfare agent that was used in various military conflicts since WWI. Despite a ban by the chemical weapons convention, considerable amounts of sulfur mustard are still in stock which results in a potential risk for future use particularly in scenarios of asymmetric warfare and terrorist attacks. Well documented cases from the war in Syria underline the importance of further studies on new therapeutic options in this area. Symptoms of a sulfur mustard exposure target above all the eyes, the respiratory system and the skin. One of the most typical indicators for an intoxication is the latency between exposure and the occurrence of the first symptoms. Due to a chronic inflammation and necrotic tissue damage the wound healing process is slow and eventually results in permanent scare tissue. A lack of therapeutic options is caused by the incomplete understanding of the pathomechanisms of sulfur mustard. Already existing therapies merely focus on symptomatic treatment with the goal to reduce inflammatory reactions. Since skin tissue is sufficient to trigger intoxication, skin models were established as an appropriate approach for testing potential therapeutics. In vitro models are an established scientific method in toxicology. A co-culture model consisting of HaCaT skin cells and the monocytic cell line THP-1 was introduced by the Bundeswehr Institute of Pharmacology and Toxicology as an in vitro test system. With its help, it is possible to mimic a more physiological environment as compared to a mono-culture, and the results are more promising for an in vivo translation. Standardized protocols and assays for necrosis, apoptosis and the inflammation markers IL-6 and IL-8 enable an evaluation of a wide range of potential therapeutics. In a study, Berberine, a naturally occurring substance, showed anti-apoptotic and anti-inflammatory effects. No specific mode of action was described for berberine so far, although, it showed a variety of pharmacological capacities in different studies. Post-treatment after sulfur mustard exposure resulted in a significant reduction of apoptosis and the inflammation markers IL-6 and IL-8. Obviously, Berberine offers an interesting therapeutic option to positively modulate a sulfur mustard intoxication. Another substance with cytoprotective and anti-inflammatory outcome was the necroptosis inhibitor Necrosulfonamide. Unexpectedly, Necrosulfonamide showed anti-apoptotic effects rather than reducing necrosis. Additionally, IL-6 and IL-8 levels were reduced significantly by 5 µM Necrosulfonamide post-treatment. Necrosulfonamide is defined as a MLKL-inhibitor and, thus, reduces necroptotic cell death. Since no research on necroptosis after sulfur mustard exposure exists, these results form a basis for further mechanistical understanding of sulfur mustard-induced cell damage

Testung potenzieller Therapeutika zur Behandlung nach S-Lost-Exposition in Hautmodellen

Bei dem Hautkampfstoff Schwefellost (S-Lost) handelt es sich um einen chemischen Kampfstoff, der seit dem 1. Weltkrieg in verschiedenen militärischen Konflikten eingesetzt wurde. Trotz der Vereinbarungen durch die Chemiewaffenkonvention S-Lost nicht mehr einzusetzen und die Restbestände zu vernichten, besteht weiterhin die Gefahr einer Verwendung in asymmetrischen Konflikten oder Terrorszenarien. Gut dokumentierte Vergiftungsfälle aus dem Bürgerkrieg in Syrien verdeutlichen, wie wichtig eine intensive Forschung an Therapieoptionen auf diesem Gebiet ist. Die Symptomatik nach einer S-Lost-Exposition betrifft vor allem die Augen, Atemwege und die Haut. Typisch ist eine zeitliche Verzögerung bis zum Einsetzen der ersten Anzeichen einer Intoxikation. Durch eine anhaltende Entzündungsreaktion und Gewebsnekrosen verläuft der Heilungsprozess sehr langsam und es können irreversible Narben und Hautverfärbungen zurückbleiben. Bis heute konnte der molekulare Pathomechanismus von S-Lost nicht vollständig aufgeklärt werden und daher fehlt es an zielgerichteten Behandlungsoptionen. Die derzeitigen therapeutische Ansätze fokussieren sich ausschließlich auf die symptomatische Behandlung von S-Lost-Vergifteten. Im Bereich der Toxikologie sind in vitro Modelle ein wissenschaftlich etablierter Standard. Zur besseren Abbildung der physiologischen Bedingungen und zur Erhöhung der Aussagekraft für eine spätere in vivo Translation, wurde am Institut für Pharmakologie und Toxikologie der Bundeswehr eine Co-Kultur-Testbatterie etabliert. Hierbei handelt es sich um ein Hautmodell bestehend aus der Keratinozyten-Zelllinie HaCaT und der humanen Monozyten-Zelllinie THP-1. Ein standardisiertes Vergiftungsprotokoll mit anschließenden Assays zur Bestimmung der Apoptose und Nekrose sowie den Entzündungsmarkern IL-6 und IL-8 erlaubt eine experimentelle Evaluierung potenzieller S-Lost-Therapeutika. Der Naturstoff Berberin zeigte in einer Studie mit der Testbatterie anti-apoptotische und antientzündliche Eigenschaften. Für Berberin ist kein spezifischer Wirkmechanismus beschrieben, allerdings zeigte es in unterschiedlichen Versuchen eine Vielzahl pharmakologischer Effekte. Die Behandlung eine Stunde nach S-Lost-Exposition führte konzentrationsabhängig zu einer Reduktion der IL-6- und IL-8-Freisetzung sowie zu einer signifikanten Abnahme der Apoptose. Dieses Ergebnis zeigte, dass die pleiotropen Effekte von Berberin eine S-Lost-Intoxikation positiv modulieren können und es möglicherweise eine alternative therapeutische Option zu etablierten Entzündungshemmern darstellen kann. Eine zweite Substanz, die im Wirkstoffscreening zytoprotektive und antiinflammatorische Wirkung zeigte, war der Nekrose-Inhibitor Necrosulfonamid. Entgegen der Erwartung war die Zytoprotektivität nicht auf eine Reduktion der Nekrose zurückzuführen, sondern es kam zu einer Verminderung der Apoptose. Eine signifikante Absenkung der Entzündungsmarker IL-6 und IL-8 konnte in der mit 5 µM Necrosulfonamid behandelten Gruppe für allen Vergiftungsstufen gezeigt werden. Da Necrosulfonamid in erster Linie die über MLKL-induzierte Nekroptose inhibiert und deren Rolle am S-Lost vermittelten Zelltod noch unerforscht ist, zeigten die Untersuchungen, dass eine mechanistische Aufklärung der Nekroptose weitere grundlegende Erkenntnisse über die molekulare Toxizität von S-Lost liefern kann.Sulfur mustard is a chemical warfare agent that was used in various military conflicts since WWI. Despite a ban by the chemical weapons convention, considerable amounts of sulfur mustard are still in stock which results in a potential risk for future use particularly in scenarios of asymmetric warfare and terrorist attacks. Well documented cases from the war in Syria underline the importance of further studies on new therapeutic options in this area. Symptoms of a sulfur mustard exposure target above all the eyes, the respiratory system and the skin. One of the most typical indicators for an intoxication is the latency between exposure and the occurrence of the first symptoms. Due to a chronic inflammation and necrotic tissue damage the wound healing process is slow and eventually results in permanent scare tissue. A lack of therapeutic options is caused by the incomplete understanding of the pathomechanisms of sulfur mustard. Already existing therapies merely focus on symptomatic treatment with the goal to reduce inflammatory reactions. Since skin tissue is sufficient to trigger intoxication, skin models were established as an appropriate approach for testing potential therapeutics. In vitro models are an established scientific method in toxicology. A co-culture model consisting of HaCaT skin cells and the monocytic cell line THP-1 was introduced by the Bundeswehr Institute of Pharmacology and Toxicology as an in vitro test system. With its help, it is possible to mimic a more physiological environment as compared to a mono-culture, and the results are more promising for an in vivo translation. Standardized protocols and assays for necrosis, apoptosis and the inflammation markers IL-6 and IL-8 enable an evaluation of a wide range of potential therapeutics. In a study, Berberine, a naturally occurring substance, showed anti-apoptotic and anti-inflammatory effects. No specific mode of action was described for berberine so far, although, it showed a variety of pharmacological capacities in different studies. Post-treatment after sulfur mustard exposure resulted in a significant reduction of apoptosis and the inflammation markers IL-6 and IL-8. Obviously, Berberine offers an interesting therapeutic option to positively modulate a sulfur mustard intoxication. Another substance with cytoprotective and anti-inflammatory outcome was the necroptosis inhibitor Necrosulfonamide. Unexpectedly, Necrosulfonamide showed anti-apoptotic effects rather than reducing necrosis. Additionally, IL-6 and IL-8 levels were reduced significantly by 5 µM Necrosulfonamide post-treatment. Necrosulfonamide is defined as a MLKL-inhibitor and, thus, reduces necroptotic cell death. Since no research on necroptosis after sulfur mustard exposure exists, these results form a basis for further mechanistical understanding of sulfur mustard-induced cell damage

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Recent advances quantifying the large wood dynamics in river basins: New methods and remaining challenges

Citation: Ruiz-Villanueva, V., Piégay, H., Gurnell, A. A., Marston, R. A., & Stoffel, M. (2016). Recent advances quantifying the large wood dynamics in river basins: New methods and remaining challenges. Reviews of Geophysics. doi:10.1002/2015RG000514Large wood is an important physical component of woodland rivers and significantly influences river morphology. It is also a key component of stream ecosystems. However, large wood is also a source of risk for human activities as it may damage infrastructure, block river channels, and induce flooding. Therefore, the analysis and quantification of large wood and its mobility are crucial for understanding and managing wood in rivers. As the amount of large-wood-related studies by researchers, river managers, and stakeholders increases, documentation of commonly used and newly available techniques and their effectiveness has also become increasingly relevant as well. Important data and knowledge have been obtained from the application of very different approaches and have generated a significant body of valuable information representative of different environments. This review brings a comprehensive qualitative and quantitative summary of recent advances regarding the different processes involved in large wood dynamics in fluvial systems including wood budgeting and wood mechanics. First, some key definitions and concepts are introduced. Second, advances in quantifying large wood dynamics are reviewed; in particular, how measurements and modeling can be combined to integrate our understanding of how large wood moves through and is retained within river systems. Throughout, we present a quantitative and integrated meta-analysis compiled from different studies and geographical regions. Finally, we conclude by highlighting areas of particular research importance and their likely future trajectories, and we consider a particularly underresearched area so as to stress the future challenges for large wood research. ©2016. American Geophysical Union

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase