Publications by authors named "Sebastian Meyer"

88 Publications

The impact of path estimates in iterative ion CT reconstructions for clinical-like cases.

Phys Med Biol 2021 Apr 23;66(9). Epub 2021 Apr 23.

Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Garching b. München, Germany.

Ion computed tomography (CT) promises to mitigate range uncertainties inherent in the conversion of x-ray Hounsfield units into ion relative stopping power (RSP) for ion beam therapy treatment planning. To improve accuracy and spatial resolution of ion CT by accounting for statistical multiple Coulomb scattering deflection of the ion trajectories from a straight line path (SLP), the most likely path (MLP) and the cubic spline path (CSP) have been proposed. In this work, we use FLUKA Monte Carlo simulations to investigate the impact of these path estimates in iterative tomographic reconstruction algorithms for proton, helium and carbon ions. To this end the ordered subset simultaneous algebraic reconstruction technique was used and coupled with a total variation superiorization (TVS). We evaluate the image quality and dose calculation accuracy in proton therapy treatment planning of cranial patient anatomies. CSP and MLP generally yielded nearly equal image quality with an average RSP relative error improvement over the SLP of 0.6%, 0.3% and 0.3% for proton, helium and carbon ion CT, respectively. Bone and low density materials have been identified as regions of largest enhancement in RSP accuracy. Nevertheless, only minor differences in dose calculation results were observed between the different models and relative range errors of better than 0.5% were obtained in all cases. Largest improvements were found for proton CT in complex scenarios with strong heterogeneities along the beam path. The additional TVS provided substantially reduced image noise, resulting in improved image quality in particular for soft tissue regions. Employing the CSP and MLP for iterative ion CT reconstructions enabled improved image quality over the SLP even in realistic and heterogeneous patient anatomy. However, only limited benefit in dose calculation accuracy was obtained even though an ideal detector system was simulated.
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http://dx.doi.org/10.1088/1361-6560/abf1ffDOI Listing
April 2021

Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab.

Therap Adv Gastroenterol 2021 14;14:1756284820982802. Epub 2021 Jan 14.

Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen, 91054, Germany.

Background: Long-term data on inflammatory bowel disease (IBD) patients switched from originator to biosimilar infliximab SB2 are lacking. The aim of the conducted study was to investigate the effectiveness, immunogenicity and safety of a large prospectively followed-up IBD patient cohort that was entirely switched from originator infliximab to biosimilar SB2 treatment.

Methods: This was a prospective, single-center, longitudinal, observational study describing clinical outcomes in IBD patients, over an 80-week period following switch from originator infliximab to SB2. Primary outcome measures were change of disease activity [Harvey-Bradshaw Index for Crohn's disease (CD), partial Mayo Score for ulcerative colitis (UC)], C-reactive protein (CRP), infliximab trough levels (TLs), anti-drug antibodies (ADAs) and adverse events.

Results: One hundred and forty-four IBD patients (94 CD, 50 UC), with median duration of 30.5 months' (range 2-110) treatment with originator infliximab were evaluated. Mean change of disease activity compared with baseline was -0.9 (SD 2.6), -0.4 (2.2) and -0.4 (2.0) in CD; 0.1 (1.1), 0.1 (1.1) and 0.1 (1.3) in UC patients at weeks 24, 48 and 72. Median infliximab TLs were 6.2 µg/ml (interquartile range 2.3-12.2), 5.0 µg/ml (2.7-10.0), 6.6 µg/ml (3.5-12.4) and 5.1 µg/ml (2.7-10.9) at baseline and weeks 24, 48 and 72. Median CRP levels were within normal ranges throughout the study. After the switch, 9.8% of the patients developed new ADAs. Persistence on SB2 was 90% (95% confidence interval 0.85-0.95), 79% (0.72-0.86), 72% (0.64-0.80) at weeks 26, 52 and 78. Serious adverse events occurred in 11 patients.

Conclusion: Over the individual patient follow-up of 80 weeks, switch to biosimilar SB2 from originator infliximab does not result in increased disease activity or changed immunogenicity patterns. The switch to SB2 was well tolerated.
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http://dx.doi.org/10.1177/1756284820982802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812413PMC
January 2021

Escape from natural enemies depends on the enemies, the invader, and competition.

Ecol Evol 2020 Oct 11;10(19):10818-10828. Epub 2020 Sep 11.

Terrestrial Ecology Research Group Department of Ecology and Ecosystem Management School of Life Sciences Weihenstephan Technical University of Munich Freising Germany.

The enemy release hypothesis (ERH) attributes the success of some exotic plant species to reduced top-down effects of natural enemies in the non-native range relative to the native range. Many studies have tested this idea, but very few have considered the simultaneous effects of multiple kinds of enemies on more than one invasive species in both the native and non-native ranges. Here, we examined the effects of two important groups of natural enemies-insect herbivores and soil biota-on the performance of (native to Europe but invasive in the USA) and (native to the USA but invasive in Europe) in their native and non-native ranges, and in the presence and absence of competition.In the field, we replicated full-factorial experiments that crossed insecticide, competition, and biogeographic range (Europe vs. USA) treatments. In greenhouses, we replicated full-factorial experiments that crossed soil sterilization, plant-soil feedback, and biogeographic range treatments. We evaluated the effects of experimental treatments on and biomass.The effects of natural enemies were idiosyncratic. In the non-native range and relative to populations in the native range, escaped the negative effects of insect herbivores but not soil biota, depending upon the presence of ; and escaped the negative effects of soil biota but not insect herbivores, regardless of competition. Thus, biogeographic escape from natural enemies depended upon the enemies, the invader, and competition. By explicitly testing the ERH in terms of more than one kind of enemy, more than one invader, and more than one continent, this study enhances our nuanced perspective of how natural enemies can influence the performance of invasive species in their native and non-native ranges.
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http://dx.doi.org/10.1002/ece3.6737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548199PMC
October 2020

Plant traits alone are poor predictors of ecosystem properties and long-term ecosystem functioning.

Nat Ecol Evol 2020 12 5;4(12):1602-1611. Epub 2020 Oct 5.

Institute of Ecology and Evolution, University Jena, Jena, Germany.

Earth is home to over 350,000 vascular plant species that differ in their traits in innumerable ways. A key challenge is to predict how natural or anthropogenically driven changes in the identity, abundance and diversity of co-occurring plant species drive important ecosystem-level properties such as biomass production or carbon storage. Here, we analyse the extent to which 42 different ecosystem properties can be predicted by 41 plant traits in 78 experimentally manipulated grassland plots over 10 years. Despite the unprecedented number of traits analysed, the average percentage of variation in ecosystem properties jointly explained was only moderate (32.6%) within individual years, and even much lower (12.7%) across years. Most other studies linking ecosystem properties to plant traits analysed no more than six traits and, when including only six traits in our analysis, the average percentage of variation explained in across-year levels of ecosystem properties dropped to 4.8%. Furthermore, we found on average only 12.2% overlap in significant predictors among ecosystem properties, indicating that a small set of key traits able to explain multiple ecosystem properties does not exist. Our results therefore suggest that there are specific limits to the extent to which traits per se can predict the long-term functional consequences of biodiversity change, so that data on additional drivers, such as interacting abiotic factors, may be required to improve predictions of ecosystem property levels.
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http://dx.doi.org/10.1038/s41559-020-01316-9DOI Listing
December 2020

The results of biodiversity-ecosystem functioning experiments are realistic.

Nat Ecol Evol 2020 11 24;4(11):1485-1494. Epub 2020 Aug 24.

Department of Geography, University of Zürich, Zürich, Switzerland.

A large body of research shows that biodiversity loss can reduce ecosystem functioning. However, much of the evidence for this relationship is drawn from biodiversity-ecosystem functioning experiments in which biodiversity loss is simulated by randomly assembling communities of varying species diversity, and ecosystem functions are measured. This random assembly has led some ecologists to question the relevance of biodiversity experiments to real-world ecosystems, where community assembly or disassembly may be non-random and influenced by external drivers, such as climate, soil conditions or land use. Here, we compare data from real-world grassland plant communities with data from two of the largest and longest-running grassland biodiversity experiments (the Jena Experiment in Germany and BioDIV in the United States) in terms of their taxonomic, functional and phylogenetic diversity and functional-trait composition. We found that plant communities of biodiversity experiments cover almost all of the multivariate variation of the real-world communities, while also containing community types that are not currently observed in the real world. Moreover, they have greater variance in their compositional features than their real-world counterparts. We then re-analysed a subset of experimental data that included only ecologically realistic communities (that is, those comparable to real-world communities). For 10 out of 12 biodiversity-ecosystem functioning relationships, biodiversity effects did not differ significantly between the full dataset of biodiversity experiments and the ecologically realistic subset of experimental communities. Although we do not provide direct evidence for strong or consistent biodiversity-ecosystem functioning relationships in real-world communities, our results demonstrate that the results of biodiversity experiments are largely insensitive to the exclusion of unrealistic communities and that the conclusions drawn from biodiversity experiments are generally robust.
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http://dx.doi.org/10.1038/s41559-020-1280-9DOI Listing
November 2020

The role of Monte Carlo simulation in understanding the performance of proton computed tomography.

Z Med Phys 2020 Aug 11. Epub 2020 Aug 11.

Department of Radiation Oncology, Department of Medical Physics, University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium, (DKTK), Munich, Germany; Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München (LMU Munich), Garching b. München, Germany.

Proton computed tomography (pCT) is a promising tomographic imaging modality allowing direct reconstruction of proton relative stopping power (RSP) required for proton therapy dose calculation. In this review article, we aim at highlighting the role of Monte Carlo (MC) simulation in pCT studies. After describing the requirements for performing proton computed tomography and the various pCT scanners actively used in recent research projects, we present an overview of available MC simulation platforms. The use of MC simulations in the scope of investigations of image reconstruction, and for the evaluation of optimal RSP accuracy, precision and spatial resolution omitting detector effects is then described. In the final sections of the review article, we present specific applications of realistic MC simulations of an existing pCT scanner prototype, which we describe in detail.
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http://dx.doi.org/10.1016/j.zemedi.2020.06.006DOI Listing
August 2020

Patient-specific CT calibration based on ion radiography for different detector configurations in H, He and C ion pencil beam scanning.

Phys Med Biol 2020 12 22;65(24):245014. Epub 2020 Dec 22.

Department of Medical Physics - Experimental Physics, Ludwig-Maximilians-Universität München, Munich, Germany. Author to whom any correspondence should be addressed.

The empirical conversion of the treatment planning x-ray computed tomography (CT) image to ion stopping power relative to water causes dose calculation inaccuracies in ion beam therapy. A patient-specific calibration of the CT image is enabled by the combination of an ion radiography (iRad) with the forward-projection of the empirically converted CT image along the estimated ion trajectories. This work investigated the patient-specific CT calibration for list-mode and integration-mode detector configurations, with reference to a ground truth ion CT (iCT) image. Analytical simulations of idealized carbon ion and proton trajectories in a numerical anthropomorphic phantom and realistic Monte Carlo simulations of proton, helium and carbon ion pencil beam scanning in a clinical CT image of a head-and-neck patient were considered. Controlled inaccuracy and noise levels were applied to the calibration curve and to the iRad, respectively. The impact of the selection of slices and angles of the iRads, as well as the choice of the optimization algorithm, were investigated. Accurate and robust CT calibration was obtained in analytical simulations of straight carbon ion trajectories. Analytical simulations of non-straight proton trajectories due to scattering suggested limitations for integration-mode but not for list-mode. To make the most of integration-mode, a dedicated objective function was proposed, demonstrating the desired accuracy for sufficiently high proton statistics in analytical simulations. In clinical data the inconsistencies between the iRad and the forward-projection of the ground truth iCT image were in the same order of magnitude as the applied inaccuracies (up to 5%). The accuracy of the CT calibration were within 2%-5% for integration-mode and 1%-3% for list-mode. The feasibility of successful patient-specific CT calibration depends on detector technologies and is primarily limited by these above mentioned inconsistencies that slightly penalize protons over helium and carbon ions due to larger scattering and beam spot size.
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http://dx.doi.org/10.1088/1361-6560/aba319DOI Listing
December 2020

Discovery of Magnetic Single- and Triple-q States in Mn/Re(0001).

Phys Rev Lett 2020 Jun;124(22):227203

Department of Physics, University of Hamburg, 20355 Hamburg, Germany.

We experimentally verify the existence of two model-type magnetic ground states that were previously predicted but so far unobserved. We find them in Mn monolayers on the Re(0001) surface using spin-polarized scanning tunneling microscopy. For fcc stacking of Mn the collinear row-wise antiferromagnetic state occurs, whereas for hcp Mn a three-dimensional spin structure appears, which is a superposition of three row-wise antiferromagnetic states known as the triple-q state. Density-functional theory calculations elucidate the subtle interplay of different magnetic interactions to form these spin structures and provide insight into the role played by relativistic effects.
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http://dx.doi.org/10.1103/PhysRevLett.124.227203DOI Listing
June 2020

Deformable image registration of the treatment planning CT with proton radiographies in perspective of adaptive proton therapy.

Phys Med Biol 2021 02 5;66(4):045008. Epub 2021 Feb 5.

Department of Medical Physics - Experimental Physics, Ludwig-Maximilians-Universität München, Munich, Germany. Author to whom any correspondence should be addressed.

The purpose of this work is to investigate the potentiality of using a limited number of in-room proton radiographies to compensate anatomical changes in adaptive proton therapy. The treatment planning CT is adapted to the treatment delivery scenario relying on 2D-3D deformable image registration (DIR). The proton radiographies, expressed in water equivalent thickness (WET) are simulated for both list-mode and integration-mode detector configurations in pencil beam scanning. Geometrical and analytical simulations of an anthropomorphic phantom in the presence of anatomical changes due to breathing are adopted. A Monte Carlo simulation of proton radiographies based on a clinical CT image in the presence of artificial anatomical changes is also considered. The accuracy of the 2D-3D DIR, calculated as root mean square error, strongly depends on the considered anatomical changes and is considered adequate for promising adaptive proton therapy when comparable to the accuracy of conventional 3D-3D DIR. In geometrical simulation, this is achieved with a minimum of eight/nine radiographies (more than 90% accuracy). Negligible improvement (sim1%) is obtained with the use of 180 radiographies. Comparing different detector configurations, superior accuracy is obtained with list-mode than integration-mode max (WET with maximum occurrence) and mean (average WET weighted by occurrences). Moreover, integration-mode max performs better than integration-mode mean. Results are minimally affected by proton statistics. In analytical simulation, the anatomical changes are approximately compensated (about 60%-70% accuracy) with two proton radiographies and minor improvement is observed with nine proton radiographies. In clinical data, two proton radiographies from list-mode have demonstrated better performance than nine from integration-mode (more than 100% and about 50%-70% accuracy, respectively), even avoiding the finer grid spacing of the last numerical optimization stage. In conclusion, the choice of detector configuration as well as the amount and complexity of the considered anatomical changes determine the minimum number of radiographies to be used.
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http://dx.doi.org/10.1088/1361-6560/ab8fc3DOI Listing
February 2021

Optimization and performance study of a proton CT system for pre-clinical small animal imaging.

Phys Med Biol 2020 08 13;65(15):155008. Epub 2020 Aug 13.

Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Garching b. München, Germany. Current affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.

Proton computed tomography (pCT) promises to reduce or even eliminate range uncertainties inherent in the conversion of Hounsfield units into relative stopping power (RSP) for proton therapy treatment planning. This is of particular interest for proton irradiation studies in animal models due to the high precision required and uncertainties in tissue properties. We propose a dedicated single-particle tracking pCT system consisting of low material budget floating strip Micromegas detectors for tracking and a segmented time-projection-chamber with vertical Mylar absorbers, functioning as a range telescope. Based on Monte Carlo simulations of a realistic in silico beam and detector implementation, a geometrical optimization of the system components was conducted to safeguard an ideal operation close to intrinsic performance limits at 75 MeV. Moreover, the overall imaging capabilities relevant for pre-clinical proton therapy treatment planning were evaluated for a mouse model. In order to minimize extrinsic uncertainties in the estimated proton trajectories, a spacing of the two tracking planes of at least 7 cm is required in both tracking detectors. Additionally, novel in-house developed and produced aluminum-based readout electrodes promise superior performance with around 3 mm spatial resolution due to the reduced material budget. Concerning the range telescope, an absorber thickness within 500 µm to 750 µm was found to yield the best compromise between water-equivalent path length resolution and complexity of the detector instrumentation, still providing sub-0.5% RSP accuracy. The optimized detector configuration enables better than 2% range accuracy for proton therapy treatment planning in pre-clinical data sets. This work outlines the potential of pCT for small animal imaging. The performance of the proposed and optimized system provides superior treatment planning accuracy compared to conventional x-ray CT. Thus, pCT can play an important role in translational and pre-clinical cancer research.
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http://dx.doi.org/10.1088/1361-6560/ab8afcDOI Listing
August 2020

Experimental comparison of clinically used ion beams for imaging applications using a range telescope.

Phys Med Biol 2020 07 27;65(15):155004. Epub 2020 Jul 27.

Ludwig-Maximilians-Universität München, Department of Experimental Physics, Munich, Germany. Current address: Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Current address: Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD) and Heidelberg University Hospital (UKHD), Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany. Current address: German Cancer Consortium (DKTK) Core-Center Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany. Current address: Clinical Cooperation Unit Radiation Oncology, Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Oncology (NCRO), Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany. Current address: Department of Physics and Astronomy, Heidelberg University, Heidelberg, Germany.

In particle therapy, the x-ray based treatment planning converting photon attenuation values to relative stopping power ratio (RSP) introduces clinically relevant range uncertainties. Recently, novel imaging technologies using transmission ion beams have been investigated to directly assess the water equivalent thickness (WET) of tissue, showing improved accuracy in RSP reconstruction, while potentially reducing the imaging dose. Due to their greater availability, protons have been mostly used for ion imaging. To this end, in this work, the influence of three ion species (protons, helium and carbon ions) on the image quality of radiographic WET retrieval has been explored with a dedicated experimental setup and compared to Monte Carlo (MC) simulations. Three phantom setups with different tissue interfaces and features have been irradiated with clinically validated proton, helium and carbon ion pencil beams under comparable imaging dose and beam settings at the Heidelberg Ion-Beam Therapy Center. Ion radiographies (iRADs) were acquired with an integration mode detector, that functions as a range telescope with 61 parallel plate ionization chambers. For comparison, experiments were reproduced in-silico with FLUKA MC simulations. Carbon ions provide iRADs with highest image quality in terms of normalized root mean square error, followed by helium ions and protons. All ions show similar capabilities of resolving WET for the considered phantoms, as shown by the similar average relative error < 3%. Besides for the slab phantom, MC simulations yielded better results than the experiment, indicating potential improvement of the experimental setup. Our results showed that the ability to resolve the WET is similar for all particles, intrinsically limited by the granularity of the detector system. While carbon ions are best suited for acquiring iRADs with the investigated integration mode detector, helium ions are put forward as a less technical challenging alternative.
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http://dx.doi.org/10.1088/1361-6560/ab87f6DOI Listing
July 2020

Ultraplexing: increasing the efficiency of long-read sequencing for hybrid assembly with k-mer-based multiplexing.

Genome Biol 2020 03 14;21(1):68. Epub 2020 Mar 14.

Institute of Medical Microbiology and Hospital Hygiene, University Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Hybrid genome assembly has emerged as an important technique in bacterial genomics, but cost and labor requirements limit large-scale application. We present Ultraplexing, a method to improve per-sample sequencing cost and hands-on time of Nanopore sequencing for hybrid assembly by at least 50% compared to molecular barcoding while maintaining high assembly quality. Ultraplexing requires the availability of Illumina data and uses inter-sample genetic variability to assign reads to isolates, which obviates the need for molecular barcoding. Thus, Ultraplexing can enable significant sequencing and labor cost reductions in large-scale bacterial genome projects.
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http://dx.doi.org/10.1186/s13059-020-01974-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071681PMC
March 2020

Transfontanellar Contrast-Enhanced Ultrasound for Monitoring Brain Perfusion During Neonatal Heart Surgery.

Circ Cardiovasc Imaging 2020 03 2;13(3):e010073. Epub 2020 Mar 2.

Department of Pediatrics and Adolescent Medicine (F.K., A.P.R., A.N., W.R., J.W., J.J.), Friedrich-Alexander-University (FAU) of Erlangen-Nuremberg, Erlangen, Germany.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010073DOI Listing
March 2020

Forecasting Flu Activity in the United States: Benchmarking an Endemic-Epidemic Beta Model.

Int J Environ Res Public Health 2020 02 21;17(4). Epub 2020 Feb 21.

Institute of Medical Informatics, Biometry, and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.

Accurate prediction of flu activity enables health officials to plan disease prevention and allocate treatment resources. A promising forecasting approach is to adapt the well-established endemic-epidemic modeling framework to time series of infectious disease proportions. Using U.S. influenza-like illness surveillance data over 18 seasons, we assessed probabilistic forecasts of this new beta autoregressive model with proper scoring rules. Other readily available forecasting tools were used for comparison, including Prophet, (S)ARIMA and kernel conditional density estimation (KCDE). Short-term flu activity was equally well predicted up to four weeks ahead by the beta model with four autoregressive lags and by KCDE; however, the beta model runs much faster. Non-dynamic Prophet scored worst. Relative performance differed for seasonal peak prediction. Prophet produced the best peak intensity forecasts in seasons with standard epidemic curves; otherwise, KCDE outperformed all other methods. Peak timing was best predicted by SARIMA, KCDE or the beta model, depending on the season. The best overall performance when predicting peak timing and intensity was achieved by KCDE. Only KCDE and naive historical forecasts consistently outperformed the equal-bin reference approach for all test seasons. We conclude that the endemic-epidemic beta model is a performant and easy-to-implement tool to forecast flu activity a few weeks ahead. Real-time forecasting of the seasonal peak, however, should consider outputs of multiple models simultaneously, weighing their usefulness as the season progresses.
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http://dx.doi.org/10.3390/ijerph17041381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068443PMC
February 2020

Biodiversity increases multitrophic energy use efficiency, flow and storage in grasslands.

Nat Ecol Evol 2020 03 24;4(3):393-405. Epub 2020 Feb 24.

Department of Biosciences, University of Salzburg, Salzburg, Austria.

The continuing loss of global biodiversity has raised questions about the risk that species extinctions pose for the functioning of natural ecosystems and the services that they provide for human wellbeing. There is consensus that, on single trophic levels, biodiversity sustains functions; however, to understand the full range of biodiversity effects, a holistic and multitrophic perspective is needed. Here, we apply methods from ecosystem ecology that quantify the structure and dynamics of the trophic network using ecosystem energetics to data from a large grassland biodiversity experiment. We show that higher plant diversity leads to more energy stored, greater energy flow and higher community-energy-use efficiency across the entire trophic network. These effects of biodiversity on energy dynamics were not restricted to only plants but were also expressed by other trophic groups and, to a similar degree, in aboveground and belowground parts of the ecosystem, even though plants are by far the dominating group in the system. The positive effects of biodiversity on one trophic level were not counteracted by the negative effects on adjacent levels. Trophic levels jointly increased the performance of the community, indicating ecosystem-wide multitrophic complementarity, which is potentially an important prerequisite for the provisioning of ecosystem services.
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http://dx.doi.org/10.1038/s41559-020-1123-8DOI Listing
March 2020

On the functional relationship between biodiversity and economic value.

Sci Adv 2020 01 29;6(5):eaax7712. Epub 2020 Jan 29.

Institute of Forest Management, Department of Ecology and Ecosystem Management, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany.

Biodiversity's contribution to human welfare has become a key argument for maintaining and enhancing biodiversity in managed ecosystems. The functional relationship between biodiversity () and economic value () is, however, insufficiently understood, despite the premise of a positive-concave relationship that dominates scientific and political arenas. Here, we review how individual links between biodiversity, ecosystem functions (), and services affect resulting relationships. Our findings show that relationships are more variable, also taking negative-concave/convex or strictly concave and convex forms. This functional form is driven not only by the underlying relationship but also by the number and type of ecosystem services and their potential trade-offs considered, the effects of inputs, and the type of utility function used to represent human preferences. Explicitly accounting for these aspects will enhance the substance and coverage of future valuation studies and allow more nuanced conclusions, particularly for managed ecosystems.
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http://dx.doi.org/10.1126/sciadv.aax7712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989135PMC
January 2020

Alloying and Processing Effects on the Microstructure, Mechanical Properties, and Degradation Behavior of Extruded Magnesium Alloys Containing Calcium, Cerium, or Silver.

Materials (Basel) 2020 Jan 15;13(2). Epub 2020 Jan 15.

Magnesium Innovation Centre (MagIC), Helmholtz-Zentrum Geesthacht, Max-Planck-Str. 1, D21502 Geesthacht, Germany.

Magnesium alloys attract attention as degradable implant materials due to their adjustable corrosion properties and biocompatibility. In the last few decades, especially wrought magnesium alloys with enhanced mechanical properties have been developed, with the main aim of increasing ductility and formability. Alloying and processing studies allowed demonstrating the relationship between the processing and the microstructure development for many new magnesium alloys. Based on this experience, magnesium alloy compositions need adjustment to elements improving mechanical properties while being suitable for biomaterial applications. In this work, magnesium alloys from two Mg-Zn series with Ce (ZE) or Ca (ZX) as additional elements and a series of alloys with Ag and Ca (QX) as alloying elements are suggested. The microstructure development was studied after the extrusion of round bars with varied processing parameters and was related to the mechanical properties and the degradation behavior of the alloys. Grain refinement and texture weakening mechanisms could be improved based on the alloy composition for enhancing the mechanical properties. Degradation rates largely depended on the nature of second phase particles rather than on the grain size, but remained suitable for biological applications. Furthermore, all alloy compositions exhibited promising cytocompatibility.
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http://dx.doi.org/10.3390/ma13020391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013469PMC
January 2020

A multitrophic perspective on biodiversity-ecosystem functioning research.

Adv Ecol Res 2019 23;61:1-54. Epub 2019 Jul 23.

Department of Biology, Marquette University, Milwaukee, WI USA.

Concern about the functional consequences of unprecedented loss in biodiversity has prompted biodiversity-ecosystem functioning (BEF) research to become one of the most active fields of ecological research in the past 25 years. Hundreds of experiments have manipulated biodiversity as an independent variable and found compelling support that the functioning of ecosystems increases with the diversity of their ecological communities. This research has also identified some of the mechanisms underlying BEF relationships, some context-dependencies of the strength of relationships, as well as implications for various ecosystem services that mankind depends upon. In this paper, we argue that a multitrophic perspective of biotic interactions in random and non-random biodiversity change scenarios is key to advance future BEF research and to address some of its most important remaining challenges. We discuss that the study and the quantification of multitrophic interactions in space and time facilitates scaling up from small-scale biodiversity manipulations and ecosystem function assessments to management-relevant spatial scales across ecosystem boundaries. We specifically consider multitrophic conceptual frameworks to understand and predict the context-dependency of BEF relationships. Moreover, we highlight the importance of the eco-evolutionary underpinnings of multitrophic BEF relationships. We outline that FAIR data (meeting the standards of findability, accessibility, interoperability, and reusability) and reproducible processing will be key to advance this field of research by making it more integrative. Finally, we show how these BEF insights may be implemented for ecosystem management, society, and policy. Given that human well-being critically depends on the multiple services provided by diverse, multitrophic communities, integrating the approaches of evolutionary ecology, community ecology, and ecosystem ecology in future BEF research will be key to refine conservation targets and develop sustainable management strategies.
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http://dx.doi.org/10.1016/bs.aecr.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944504PMC
July 2019

Electrical Detection of Domain Walls and Skyrmions in Co Films Using Noncollinear Magnetoresistance.

Phys Rev Lett 2019 Dec;123(23):237205

Department of Physics, University of Hamburg, 20355 Hamburg, Germany.

A large noncollinear magnetoresistance (NCMR) is observed for Rh/Co atomic bilayers on Ir(111) using scanning tunneling microscopy and spectroscopy. The effect is 20% at the Fermi energy and large in a broad energy range. The NCMR can be used to electrically detect nanometer-scale domain walls and skyrmions directly in the tunnel current without the need for a differential measurement. The NCMR results from changes in the density of states of noncollinear spin textures with respect to the ferromagnetic state. Density functional theory calculations reveal that they originate from spin mixing between majority d_{xz} and minority p_{z} states.
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http://dx.doi.org/10.1103/PhysRevLett.123.237205DOI Listing
December 2019

Systemic availability of lipophilic organic UV filters through dermal sunscreen exposure.

Environ Int 2019 11 27;132:105068. Epub 2019 Aug 27.

Friedrich-Alexander Universität Erlangen-Nürnberg, Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Henkestr. 9-11, 91054 Erlangen, Germany. Electronic address:

Background: Chemical UV filters are common components in sunscreens and cosmetic products and used to protect the skin against harmful effects of sunlight like sunburn. However, the effectiveness of sunscreens in the prevention of skin cancer is in some parts still controversial. Meanwhile, questions about negative effects of the chemical UV filters on human health arise and request an effective risk assessment. Real-life exposure data in humans after application of these products are still rare. Thus, we explored whether and to what extent UV filters are absorbed through the skin into the human body.

Material And Methods: Plasma and urine samples from 20 healthy volunteers were collected before, during and after a real-life exposure scenario (1st application: 2 mg/cm; 2nd and 3rd (after 2 and 4 h): 1 mg/cm each) using a commercial sunscreen formulation for one day. These samples were analyzed for their content of the currently prominent UV filters octocrylene and avobenzone as well as 2-cyano-3,3-diphenylacrylic acid (CDAA) as the main octocrylene metabolite by using different liquid chromatography electrospray-ionization tandem mass spectrometric procedures.

Results: Following dermal sunscreen exposure, avobenzone, octocrylene and CDAA reached concentrations up to 11 μg/L, 25 μg/L and 1352 μg/L in plasma. In urine detection rates of avobenzone and octocrylene were low while CDAA showed a high detection rate and reached up to 5207 μg/g creatinine. Kinetic models could be fitted for octocrylene and CDAA in plasma and CDAA in urine. Concentration peaks were reached between 10 and 16 h after first application and half-life periods were in the range of 1.5 to 2 days. The lipophilic UV filter octocrylene and its metabolite CDAA showed a much slower elimination than other more hydrophilic UV filters. Concordantly, the metabolite CDAA in particular showed a markedly increased renal excretion over the whole sampling period and indicated high internal exposure to OC.

Discussion: Real-life sunscreen usage leads to considerable bioavailability of organic UV filters and their metabolites which is rarely seen for other environmental exposures. A combined monitoring of the parent compound and its metabolites is important to fully address internal exposure to the UV filter in humans. Considering the kinetic profiles a prolonged systemic release due to depot formation in skin and a potential accumulation through multi-day exposure is presumed. High in-vivo loads call for a critical toxicological assessment of the UV filters and their metabolites.
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http://dx.doi.org/10.1016/j.envint.2019.105068DOI Listing
November 2019

Isolated zero field sub-10 nm skyrmions in ultrathin Co films.

Nat Commun 2019 Aug 23;10(1):3823. Epub 2019 Aug 23.

Institute of Theoretical Physics and Astrophysics, Christian-Albrechts-Universität zu Kiel, Leibnizstrasse 15, 24098, Kiel, Germany.

Due to their exceptional topological and dynamical properties magnetic skyrmions-localized stable spin structures-show great promise for spintronic applications. To become technologically competitive, isolated skyrmions with diameters below 10 nm stable at zero magnetic field and at room temperature are desired. Despite finding skyrmions in a wide spectrum of materials, the quest for a material with these envisioned properties is ongoing. Here we report zero field isolated skyrmions at T = 4 K with diameters below 5 nm observed in the virgin ferromagnetic state coexisting with 1 nm thin domain walls in Rh/Co atomic bilayers on Ir(111). These spin structures are investigated by spin-polarized scanning tunneling microscopy and can also be detected using non-spin-polarized tips via the noncollinear magnetoresistance. We demonstrate that sub-10 nm skyrmions are stabilized in these ferromagnetic Co films at zero field due to strong frustration of exchange interaction, together with Dzyaloshinskii-Moriya interaction and large magnetocrystalline anisotropy.
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http://dx.doi.org/10.1038/s41467-019-11831-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707282PMC
August 2019

Toxicokinetics of urinary 2-ethylhexyl salicylate and its metabolite 2-ethyl-hydroxyhexyl salicylate in humans after simulating real-life dermal sunscreen exposure.

Arch Toxicol 2019 09 22;93(9):2565-2574. Epub 2019 Aug 22.

Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Henkestr. 9-11, 91054, Erlangen, Germany.

Chemical UV filters are common components in sunscreens and cosmetic products. The question of adverse health risks is not completely resolved, partly owing to lacking human data from dermal exposure, which are essential for sound risk assessment. Therefore, we investigated the urinary toxicokinetics of 2-ethylhexyl salicylate (EHS) after a 1-day dermal real-life sunscreen application scenario. Twenty human volunteers were dermally exposed to a commercial sunscreen for 9 h under real-life conditions (2 mg/cm body surface area; double re-application; corresponding to 3.8 g EHS). Urine samples were analyzed for EHS and one of its specific metabolites 2-ethyl-5-hydroxyhexyl salicylate (5OH-EHS) using a two-dimensional liquid chromatographic electrospray-ionization tandem mass spectrometric procedure. EHS and 5OH-EHS were excreted after sunscreen application and reached up to 525 µg/g and 213 µg/g creatinine, respectively. The toxicokinetic models showed concentration peaks between 7 and 8 h after first application. First-phase terminal half-lives were 8-9 h. For 5OH-EHS, a second-phase terminal half-life could be determined (87 h). EHS and 5OH-EHS showed a faster elimination with 70-80% of the overall excretion occurring within 24 h after application compared to more lipophilic UV filters. Cumulative excreted amounts over 24 h reached up to 334 µg EHS and 124 µg of 5OH-EHS. Simulated real-life sunscreen use for 1 day leads to the bioavailability of the UV filter EHS in humans. The kinetic profiles with a prolonged systemic availability indicate a skin depot and make accumulation during consecutive multi-day exposure likely.
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http://dx.doi.org/10.1007/s00204-019-02537-zDOI Listing
September 2019

Towards a novel small animal proton irradiation platform: the SIRMIO project.

Acta Oncol 2019 Oct 4;58(10):1470-1475. Epub 2019 Jul 4.

Department of Medical Physics, Ludwig-Maximilians-Universität München (LMU Munich) , Munich , Germany.

Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with multi-modal anatomical image guidance and verification of the actual treatment delivery. This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for imaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies.
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http://dx.doi.org/10.1080/0284186X.2019.1630752DOI Listing
October 2019

Advanced Optical Programming of Individual Meta-Atoms Beyond the Effective Medium Approach.

Adv Mater 2019 Jul 27;31(29):e1901033. Epub 2019 May 27.

I. Institute of Physics (IA), RWTH Aachen University, D-52056, Aachen, Germany.

Nanometer-thick active metasurfaces (MSs) based on phase-change materials (PCMs) enable compact photonic components, offering adjustable functionalities for the manipulation of light, such as polarization filtering, lensing, and beam steering. Commonly, they feature multiple operation states by switching the whole PCM fully between two states of drastically different optical properties. Intermediate states of the PCM are also exploited to obtain gradual resonance shifts, which are usually uniform over the whole MS and described by effective medium response. For programmable MSs, however, the ability to selectively address and switch the PCM in individual meta-atoms is required. Here, simultaneous control of size, position, and crystallization depth of the switched phase-change material (PCM) volume within each meta-atom in a proof-of-principle MS consisting of a PCM-covered Al-nanorod antenna array is demonstrated. By modifying optical properties locally, amplitude and light phase can be programmed at the meta-atom scale. As this goes beyond previous effective medium concepts, it will enable small adaptive corrections to external aberrations and fabrication errors or multiple complex functionalities programmable on the same MS.
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http://dx.doi.org/10.1002/adma.201901033DOI Listing
July 2019

Citalopram Improves Obsessive-Compulsive Crossword Puzzling in Frontotemporal Dementia.

Case Rep Neurol 2019 Jan-Apr;11(1):94-105. Epub 2019 Mar 19.

Neurology Department, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.

Behavioral variant frontotemporal dementia (bvFTD) is characterized by severe changes in personality/behavior. Recent studies have provided evidence that a decrease in serotonin receptors and neuronal loss in the raphe nuclei play a role in the bvFTD pathology. Serotonergic antidepressants have been reported to diminish behavioral disturbances in bvFTD, particularly repetitive behaviors, disinhibition, apathy, sexually inappropriate behaviors, and hyperorality. Here, we present the case of an 80-year-old Caucasian male patient with clinically and biomarker supported bvFTD ("probable" bvFTD; disease-specific alterations in F-fluorodesoxyglucose positron emission tomography and magnetic resonance imaging). The patient exhibited behavioral disinhibition, apathy, a loss of empathy, perseverative behavior during testing, hyperorality, changes in diet, and executive deficits in neuropsychological testing. Remarkably, he failed in solving crosswords by systematically filling in the blanks by letters in alphabetical order (A, B, C, D, etc.), indicating obsessive-compulsive behavior. One year later, the patient visited the clinic again for a follow-up investigation. He had taken 20 mg of citalopram per day for 1 consecutive year. Remarkably, he had regained the ability to fill in crossword puzzles correctly, although the neuropsychiatric inventory showed overall only small improvement in behavioral impairment. A regimen of 20 mg citalopram per day over the course of 1 year led to a specific improvement in one of the bvFTD core symptoms, obsessive-compulsive behavior, most pronounced in solving crossword puzzles. This case contributes to the understanding of the neuropharmacological correlates of bvFTD and supports the treatment of bvFTD's behavioral symptoms with selective serotonin reuptake inhibitors.
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http://dx.doi.org/10.1159/000495561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465705PMC
March 2019

Analytical simulator of proton radiography and tomography for different detector configurations.

Phys Med 2019 Mar 8;59:92-99. Epub 2019 Mar 8.

Faculty of Physics, Department of Medical Physics, Experimental Physics, Ludwig-Maximilians-Universität München, Munich, Germany.

Purpose: An analytical simulator of ion Radiography (iRad) and Computed Tomography (iCT) for protons is proposed to serve as imaging benchmark for different detector configurations.

Methods: The analytical simulator is applied to an anthropomorphic phantom and provides iRad and iCT benchmarks. Proton trajectories are traced relying on the Most Likely Path (MLP) algorithm. To simulate the proton trajectories the Multiple Coulomb Scattering (MCS) model embedded in the MLP algorithm is extended to non-uniform water equivalent materials according to variable substitution in the well-known statistical description in uniform water. The proton trajectories are instead estimated relying on the typical assumption of uniform water, thus causing intrinsic inaccuracies of the MLP algorithm. In this work the analytical simulator is used to explore and firstly compare the imaging performances of list-mode and integration-mode detector configurations with proton pencil beam scanning.

Results: The intrinsic inaccuracies of the MLP algorithm affect the imaging performances of list-mode detector configuration, which nevertheless remains superior to integration-mode detector configuration for iCTs. For relatively higher proton statistics, comparable or better imaging performances are offered by integration-mode detector configuration for iRads (upto 29.2% of WET difference). Uncertainties of proton trajectories due to beam spot size are shown to compromise the imaging performances of integration-mode detector configuration, but also to affect the accuracy of the MLP algorithm for list-mode detector configuration.

Conclusions: Based on MCS model in non-uniform water equivalent materials, the proposed simulation environment can serve for development and testing of dedicated imaging methodologies prior to and in combination with realistic Monte Carlo simulations.
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http://dx.doi.org/10.1016/j.ejmp.2019.03.002DOI Listing
March 2019

Plant diversity alters the representation of motifs in food webs.

Nat Commun 2019 03 15;10(1):1226. Epub 2019 Mar 15.

German Center for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Deutscher Platz 5e, 04103, Leipzig, Germany.

Changes in the diversity of plant communities may undermine the economically and environmentally important consumer species they support. The structure of trophic interactions determines the sensitivity of food webs to perturbations, but rigorous assessments of plant diversity effects on network topology are lacking. Here, we use highly resolved networks from a grassland biodiversity experiment to test how plant diversity affects the prevalence of different food web motifs, the smaller recurrent sub-networks that form the building blocks of complex networks. We find that the representation of tri-trophic chain, apparent competition and exploitative competition motifs increases with plant species richness, while the representation of omnivory motifs decreases. Moreover, plant species richness is associated with altered patterns of local interactions among arthropod consumers in which plants are not directly involved. These findings reveal novel structuring forces that plant diversity exerts on food webs with potential implications for the persistence and functioning of multitrophic communities.
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http://dx.doi.org/10.1038/s41467-019-08856-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420570PMC
March 2019

Dosimetric accuracy and radiobiological implications of ion computed tomography for proton therapy treatment planning.

Phys Med Biol 2019 06 12;64(12):125008. Epub 2019 Jun 12.

Department of Medical Physics, Ludwig-Maximilians-Universität München, Garching b. München, Germany. The author to whom correspondence may be addressed.

Ion computed tomography (iCT) represents a potential replacement for x-ray CT (xCT) in ion therapy treatment planning to reduce range uncertainties, inherent in the semi-empirical conversion of xCT information into relative stopping power (RSP). In this work, we aim to quantify the increase in dosimetric accuracy associated with using proton-, helium- and carbon-CT compared to conventional xCT for clinical scenarios in proton therapy. Three cases imaged with active beam-delivery using an ideal single-particle-tracking detector were investigated using FLUKA Monte-Carlo (MC) simulations. The RSP accuracy of the iCTs was evaluated against the ground truth at similar physical dose. Next, the resulting dosimetric accuracy was investigated by using the RSP images as a patient model in proton therapy treatment planning, in comparison to common uncertainties associated with xCT. Finally, changes in relative biological effectiveness (RBE) with iCT particle type/spectrum were investigated by incorporating the repair-misrepair-fixation (RMF) model into FLUKA, to enable first insights on the associated biological imaging dose. Helium-CT provided the lowest overall RSP error, whereas carbon-CT offered the highest accuracy for bone and proton-CT for soft tissue. For a single field, the average relative proton beam-range variation was  -1.00%, +0.09%, -0.08% and  -0.35% for xCT, proton-, helium- and carbon-CT, respectively. Using a 0.5%/0.5mm gamma-evaluation, all iCTs offered comparable accuracy with a better than 99% passing rate, compared to 83% for xCT. The RMF model predictions for RBE for cell death relative to a diagnostic xCT spectrum were 0.82-0.85, 0.85-0.89 and 0.97-1.03 for proton-, helium-, and carbon-CT, respectively. The corresponding RBE for DNA double-strand break induction was generally below one. iCT offers great clinical potential for proton therapy treatment planning by providing superior dose calculation accuracy as well as lower physical and potentially biological dose exposure compared to xCT. For the investigated dose level and ideal detector, proton-CT and helium-CT yielded the best performance.
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http://dx.doi.org/10.1088/1361-6560/ab0fdfDOI Listing
June 2019

A meta food web for invertebrate species collected in a European grassland.

Ecology 2019 06 29;100(6):e02679. Epub 2019 Mar 29.

Institute of Ecology and Evolution, Friedrich Schiller University Jena, Dornburger Strasse 159, Jena, D-07743, Germany.

Patterns of feeding interactions between species are thought to influence the stability of communities and the flux of nutrients and energy through ecosystems. However, surprisingly few well-resolved food webs allow us to evaluate factors that influence the architecture of species interactions. We constructed a meta food web consisting of 714 invertebrate species collected over 9 years of suction and pitfall sampling campaigns in the Jena Experiment, a long-term grassland biodiversity experiment located in Jena, Germany. We summarize information on the 51,496 potential trophic links, which were established using information on diet specificity and species traits that typically constrain feeding interactions (trophic group, body size, and vertical stratification). The list of species identities, traits, and link-derivation rules will be useful not only for tests of plant diversity effects on food web structure within the Jena Experiment, but also for considering consistent construction of food webs from empirical data, and for comparisons of network structure across ecosystems. No copyright or proprietary restrictions are associated with the use of this data set other than citation of this Data Paper.
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http://dx.doi.org/10.1002/ecy.2679DOI Listing
June 2019

Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation.

Gastroenterology 2019 03 16;156(4):1082-1097.e11. Epub 2018 Nov 16.

First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Background & Aims: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice.

Methods: We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2 mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2 to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied.

Results: Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2 mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2 mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation.

Conclusion: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.
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http://dx.doi.org/10.1053/j.gastro.2018.11.029DOI Listing
March 2019