Targeting the actin cytoskeleton with natural compounds

Targeting the cytoskeleton (CSK) of cancer cells offers a valuable strategy in cancer therapy. Whereas drugs which address microtubule CSK such as vinca alkaloids or taxanes are well established in the clinic, compounds binding to the actin CSK are still far away from their therapeutical application. One reason might be the lacking knowledge on their mode of cytotoxicity and moreover their tumor specific mechanism of action. We used the myxobacterial compound Chondramide as a tool to first elucidate the mechanisms of cytotoxicity by actin targeting in different breast cancer cells, namely MCF7 and MDA-MB-231. Chondramide inhibits actin filament assembly and dynamics shown by a fluorescence-based analysis (FRAP) in whole cells and leads to apoptosis characterized by phosphatidylserine exposure, release of cytochrome C from mitochondria and finally activation of caspases (-9 and -3). Detailed analysis revealed, that Chondramide induces apoptosis by enhancing the occurrence of mitochondrial permeability transition (MPT). Known MPT-modulators were found to be affected by Chondramide: Hexokinase II (HkII) bound to the voltage dependent anion channel (VDAC) translocated from the outer mitochondrial membrane to the cytosol and the proapoptotic protein Bad was recruited to the mitochondria. Importantly, PKCε, a prosurvival serine/threonine kinase possessing an actin-binding site and known to regulate the HkII/VDAC interaction as well as Bad phosphoylation was identified as the link between actin CSK and apoptosis induction. PKCε which was found overexpressed in breast cancer cells accumulated in actin bundles induced by Chondramide and lost its activity. The second goal of our work was to inform on a potential tumor specific action of actin binding agents such as Chondramide. As the nontumor breast epithelial cell line MCF-10A in fact shows resistance to Chondramide induced apoptosis and notably express very low level of PKCε we claim that trapping PKCε via Chondramide induced actin hyperpolymerization displays tumor cell specificity. Our work provides a link between targeting the ubiquitously occurring actin CSK and selective inhibition of pro-tumorigenic PKCε, thus setting the stage for actin-stabilizing agents as innovative cancer drugs. This is moreover supported by the in vivo efficacy of Chondramide triggered by abrogation of PKCε signaling shown in a xenograft breast cancer model. For the actin targeting compound Doliculide we could show that Doliculide impairs the dynamics of the actin CSK similar to Chondramide. Moreover, it reduces the proliferation rate and migration of cancer cells and also leads to the induction of apoptosis, thus Doliculide is also an interesting lead structure for further preclinical investigations

Slurry-grown duckweed (Spirodela polyrhiza) as a means to recycle nitrogen into feed for rainbow trout fry

Liquid manure from livestock production systems is a major source of nitrogen and phosphorus release from nutrient cycles and a cause of ecosystem eutrophication. Duckweeds, small aquatic plants, may be used to recover N and P from livestock slurry while producing high-quality protein feed. In order to assess N and P uptake efficiency and utility for fish feed, two duckweed species, Landoltia punctata and Spirodela polyrhiza, were grown in controlled climate chambers on two nutrient-rich media: diluted (1:10) cattle slurry and mechanically filtered household sewage. Treatments were in triplicate, each running in four cycles with fresh substrate (one week each). Spirodela polyrhiza exhibited the strongest growth (96 g fresh matter m−2 day−1) and highest protein content (306 g per kg dry matter) on diluted slurry. The weakest growth was found for L. punctata on treated sewage (52 g fresh matter m−2 day−1). Average removal of total provided and utilizable inorganic N from the media was 73.2% and 83.9% for sewage and diluted slurry, respectively. Spirodela polyrhiza grown on diluted slurry was subsequently tested as feed ingredient for rainbow trout (Oncorhynchus mykiss) fry. Two different ingredient levels of S. polyrhiza meal (6.25% and 12.5% of feed) were fed to rainbow trout fry for 4 weeks, during which fish growth, feed and nutrient utilization and gut health were assessed. Feed was accepted, but both duckweed meal treatments resulted in 5–10% poorer growth traits and feed efficiency compared to control. The intestine somatic index was not affected. This is the first time the potential of duckweed as feed for rainbow trout fry has been demonstrated. Furthermore, our experiments found considerable N and P uptake from diluted slurry by S. polyrhiza, which produced protein at a high rate per unit time and area

Evaluating First Experiences with an Educational Computer Game: A multi-Method Approach

This paper presents our evaluation approach for a specific case study, namely the evaluation of an early prototype of an educational game with children aged between 12 and 14 years. The main goal of this initial evaluation study was to explore children’s first impressions and experiences of the game on the one hand and to assess the students’ ideas and wishes for the further development of the game on the other hand. The main challenge for the evaluation activities was the selection of the appropriate methodological approach, taking into account children as a special user group. We opted for a combination of different, mainly qualitative and explorative methods that were reported beneficial for work with children in the human-computer interaction (HCI) field. By presenting our multi-method approach, in particular the different steps and procedure within our study, other researchers can get inspirations for follow up activities when evaluating games with children as well as benefit from our experiences in exploring more collaborative methods and methodological combinations

What can we learn from comparing glacio-hydrological models?

Glacio-hydrological models combine both glacier and catchment hydrology modeling and are used to assess the hydrological response of high-mountain glacierized catchments to climate change. To capture the uncertainties from these model combinations, it is essential to compare the outcomes of several model entities forced with the same climate projections. For the first time, we compare the results of two completely independent glacio-hydrological models: (i) HQsim-GEM and (ii) AMUNDSEN. In contrast to prevailing studies, we use distinct glacier models and glacier initialization times. At first glance, the results achieved for future glacier states and hydrological characteristics in the Rofenache catchment in ötztal Alps (Austria) appear to be similar and consistent, but a closer look reveals clear differences. What can be learned from this study is that low-complexity models can achieve higher accuracy in the calibration period. This is advantageous especially when data availability is weak, and priority is given to efficient computation time. Furthermore, the time and method of glacier initialization play an important role due to different data requirements. In essence, it is not possible to make conclusions about the model performance outside of the calibration period or more specifically in the future. Hence, similar to climate modeling, we suggest considering different modeling approaches when assessing future catchment discharge or glacier evolution. Especially when transferring the results to stakeholders, it is vital to transparently communicate the bandwidth of future states that come with all model results. © 2020 by the authors

Matrix Effects on Photoluminescence and Oxygen Sensitivity of a Molecular Ruby

The molecular ruby analogue [Cr(ddpd)2]3+ (ddpd=N,N’‐dimethyl‐N,N’‐dipyridine‐2‐ylpyridine‐2,6‐diamine) exhibits near infrared (NIR) emission with a high photoluminescence (PL) quantum yield ΦPL of 11 % and a lifetime of 898 μs in deaerated water at room temperature. While ligand‐based control of the photophysical properties has received much attention, influences of the counter anions and microenvironment are still underexplored. In this study, the luminescence properties of the molecular ruby were systematically examined for the counter anions Cl−, Br−, [BF4]−, [PF6]−, [BPh4]−, and [BArF24]− in acetonitrile (MeCN) solution, in crystals, and embedded into polystyrene nanoparticles (PSNP). Stern‐Volmer analyses of the oxygen quenching studies in the intensity and lifetime domain showed the highest oxygen sensitivity of the complexes with the counter anions of [BF4]− and [BArF24]−, which also revealed the longest luminescence lifetimes. Embedding [Cr(ddpd)2][PF6]3 in PSNPs and shielding with poly(vinyl alcohol) yields a strongly NIR‐emissive oxygen‐insensitive material with a record ΦPL of 15.2 % under ambient conditions

High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial

Background: Stereotactic body radiation therapy (SBRT)using intensity-modulated radiotherapy (IMRT) can be a safe modality for treating spinal bone metastasis with enhanced targeting accuracy and an effective method for achieving good tumor control and a rigorous pain response. Methods/design: This is a single-center, prospective randomized controlled trial to evaluate pain relief after RT and consists of two treatment groups with 30 patients in each group. One group will receive single-fraction intensity-modulated RT with 1×24 Gy, and the other will receive fractionated RT with 10×3 Gy. The target parameters will be measured at baseline and at 3 and 6 months after RT. Discussion: The aim of this study is to evaluate pain relief after RT in patients with spinal bone metastases by means of two different techniques: stereotactic body radiation therapy and fractionated RT. The primary endpoint is pain relief at the 3-month time-point after RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. Trial registration ClinicalTrials.gov identifier NCT02358720 (June 2, 2015)

Chemical and dynamical identification of emission outflows during the HALO campaign EMeRGe in Europe and Asia

The number of large urban agglomerations is steadily increasing worldwide. At a local scale, their emissions lead to air pollution, directly affecting people\u27s health. On a global scale, their emissions lead to an increase of greenhouse gases, affecting climate. In this context, in 2017 and 2018, the airborne campaign EMeRGe (Effect of Megacities on the transport and transformation of pollutants on the Regional to Global scales) investigated emissions of European and Asian major population centres (MPCs) to improve the understanding and predictability of pollution outflows. Here, we present two methods to identify and characterise pollution outflows probed during EMeRGe. First, we use a set of volatile organic compounds (VOCs) as chemical tracers to characterise air masses by specific source signals, i.e. benzene from anthropogenic pollution of targeted regions, acetonitrile from biomass burning (BB, primarily during EMeRGe-Asia), and isoprene from fresh biogenic signals (primarily during EMeRGe-Europe. Second, we attribute probed air masses to source regions and estimate their individual contribution by constructing and applying a simple emission uptake scheme for the boundary layer which combines FLEXTRA back trajectories and EDGAR carbon monoxide (CO) emission rates (acronyms are provided in the Appendix). During EMeRGe-Europe, we identified anthropogenic pollution outflows from northern Italy, southern Great Britain, the Belgium–Netherlands–Ruhr (BNR) area and the Iberian Peninsula. Additionally, our uptake scheme indicates significant long-range transport of pollution from the USA and Canada. During EMeRGe-Asia, the pollution outflow is dominated by sources in China and Taiwan, but BB signals from Southeast Asia and India contribute as well. Outflows of pre-selected MPC targets are identified in less than 20 % of the sampling time, due to restrictions in flight planning and constraints of the measurement platform itself. Still, EMeRGe combines in a unique way near- and far-field measurements, which show signatures of local and distant sources, transport and conversion fingerprints, and complex air mass compositions. Our approach provides a valuable classification and characterisation of the EMeRGe dataset, e.g. for BB and anthropogenic influence of potential source regions and paves the way for a more comprehensive analysis and various model studies