Recent Submissions

  • Journal Article

    Single-plant GWAS coupled with bulk segregant analysis allows rapid identification and corroboration of plant-height candidate SNPs 

    Gyawali, Abiskar; Shrestha, Vivek; Guill, Katherine E; Flint-Garcia, Sherry; Beissinger, Timothy M
    BMC Plant Biology. 2019 Oct 08;19(1):412
    Abstract Background Genome wide association studies (GWAS) are a powerful tool for identifying quantitative trait loci (QTL) and causal single nucleotide polymorphisms (SNPs)/genes associated with various important traits in crop species. Typically, GWAS in crops are performed using a panel of inbred lines, where multiple replicates of the same inbred are measured and the average phenotype is taken as the response variable. Here we describe and evaluate single plant GWAS (sp-GWAS) for performing a GWAS on individual plants, which does not require an association panel of inbreds. Instead sp-GWAS relies on the phenotypes and genotypes from individual plants sampled from a randomly mating population. Importantly, we demonstrate how sp-GWAS can be efficiently combined with a bulk segregant analysis (BSA) experiment to rapidly corroborate evidence for significant SNPs. Results In this study we used the Shoepeg maize landrace, collected as an open pollinating variety from a farm in Southern Missouri in the 1960’s, to evaluate whether sp-GWAS coupled with BSA can efficiently and powerfully used to detect significant association of SNPs for plant height (PH). Plant were grown in 8 locations across two years and in total 768 individuals were genotyped and phenotyped for sp-GWAS. A total of 306 k polymorphic markers in 768 individuals evaluated via association analysis detected 25 significant SNPs (P ≤ 0.00001) for PH. The results from our single-plant GWAS were further validated by bulk segregant analysis (BSA) for PH. BSA sequencing was performed on the same population by selecting tall and short plants as separate bulks. This approach identified 37 genomic regions for plant height. Of the 25 significant SNPs from GWAS, the three most significant SNPs co-localize with regions identified by BSA. Conclusion Overall, this study demonstrates that sp-GWAS coupled with BSA can be a useful tool for detecting significant SNPs and identifying candidate genes. This result is particularly useful for species/populations where association panels are not readily available.
    View Document Abstract
  • Journal Article

    Bayesian localization of CNV candidates in WGS data within minutes 

    Wiedenhoeft, John; Cagan, Alex; Kozhemyakina, Rimma; Gulevich, Rimma; Schliep, Alexander
    Algorithms for Molecular Biology. 2019 Sep 23;14(1):20
    Abstract Background Full Bayesian inference for detecting copy number variants (CNV) from whole-genome sequencing (WGS) data is still largely infeasible due to computational demands. A recently introduced approach to perform Forward–Backward Gibbs sampling using dynamic Haar wavelet compression has alleviated issues of convergence and, to some extent, speed. Yet, the problem remains challenging in practice. Results In this paper, we propose an improved algorithmic framework for this approach. We provide new space-efficient data structures to query sufficient statistics in logarithmic time, based on a linear-time, in-place transform of the data, which also improves on the compression ratio. We also propose a new approach to efficiently store and update marginal state counts obtained from the Gibbs sampler. Conclusions Using this approach, we discover several CNV candidates in two rat populations divergently selected for tame and aggressive behavior, consistent with earlier results concerning the domestication syndrome as well as experimental observations. Computationally, we observe a 29.5-fold decrease in memory, an average 5.8-fold speedup, as well as a 191-fold decrease in minor page faults. We also observe that metrics varied greatly in the old implementation, but not the new one. We conjecture that this is due to the better compression scheme. The fully Bayesian segmentation of the entire WGS data set required 3.5 min and 1.24 GB of memory, and can hence be performed on a commodity laptop.
    View Document Abstract
  • Journal Article

    The first fungal laccase with an alkaline pH optimum obtained by directed evolution and its application in indigo dye decolorization 

    Yin, Qiang; Zhou, Gang; Peng, Can; Zhang, Yinliang; Kües, Ursula; Liu, Juanjuan; Xiao, Yazhong; Fang, Zemin
    AMB Express. 2019 Sep 18;9(1):151
    Abstract Engineering of fungal laccases with optimum catalytic activity at alkaline pH has been a long-lasting challenge. In this study, a mutant library containing 3000 clones was obtained by error-prone PCR to adapt the optimum pH of a fungal laccase Lcc9 from the basidiomycete Coprinopsis cinerea. After three rounds of functional screening, a mutant with three amino acid changes (E116K, N229D, I393T) named PIE5 was selected. PIE5 showed an optimum pH of 8.5 and 8.0 against guaiacol and 2,6-DMP when expressed in Pichia pastoris, representing the first fungal laccase that possesses an optimum pH at an alkaline condition. Site directed mutagenesis disclosed that N229D contributed the most to the optimum pH increment. A single N229D mutation caused an increase in optimum pH by 1.5 units. When used in indigo dye decolorization, PIE5 efficiently decolorized 87.1 ± 1.1% and 90.9 ± 0.3% indigo dye at the optimum conditions of pH 7.0–7.5 and 60 °C, and with either methyl 3,5-dimethoxy-4-hydroxybenzoate or 2,2′-azino-bis(3-ethylbenzothazoline-6-sulfonate) as the mediator. In comparison, the commercially available fungal laccase TvLac from Trametes villosa decolorized 84.3 ± 1.8% of indigo dye under its optimum conditions (opt. pH 5.0 and 60 °C). The properties of an alkaline-dependent activity and the high indigo dye decolorization ability (1.3-fold better than the parental Lcc9) make the new fungal laccase PIE5 an alternative for specific industrial applications.
    View Document Abstract
  • Journal Article

    How I wean patients from veno-venous extra-corporeal membrane oxygenation 

    Vasques, Francesco; Romitti, Federica; Gattinoni, Luciano; Camporota, Luigi
    Critical Care. 2019 Sep 18;23(1):316
    View Document
  • Journal Article

    An ethical comparison of living kidney donation and surrogacy: understanding the relational dimension 

    Beier, Katharina; Wöhlke, Sabine
    Philosophy, Ethics, and Humanities in Medicine. 2019 Sep 18;14(1):13
    Abstract Background The bioethical debates concerning living donation and surrogacy revolve around similar ethical questions and moral concepts. Nevertheless, the ethical discourses in both fields grew largely isolated from each other. Methods Based on a review of ethical, sociological and anthropological research this paper aims to link the ethical discourses on living kidney donation and surrogacy by providing a comparative analysis of the two practices’ relational dimension with regard to three aspects, i.e. the normative role of relational dynamics, social norms and gender roles, and reciprocity. Based on this analysis, we derive conclusions for the framing of living organ donation and surrogacy in ethical theory and practice. Results First, our analysis emphasizes the relevance of acknowledging the complex relational implications of living kidney donation and surrogacy. Underestimating this relational dimension may not only lead to individual crises but endanger existing as well as newly emerging familial relationships. Second, we point out differences in the normative assessment of social norms and gender roles in the ethical debates about living kidney donation and surrogacy. In particular, we show how different evaluations of altruism affect the understanding of autonomy in both contexts. In addition, we sensitize for biased perceptions of gender roles. Finally, we argue that challenges resulting from unresolved reciprocity are an issue in living kidney donation and surrogacy independent of whether the exchange of body parts or bodily services is framed as a gift or commercial exchange. By pointing out the limits of financial compensation, we stress the relevance of non-material, relational rewards as potential remedy.
    View Document Abstract
  • Journal Article

    Model-based myocardial T1 mapping with sparsity constraints using single-shot inversion-recovery radial FLASH cardiovascular magnetic resonance 

    Wang, Xiaoqing; Kohler, Florian; Unterberg-Buchwald, Christina; Lotz, Joachim; Frahm, Jens; Uecker, Martin
    Journal of Cardiovascular Magnetic Resonance. 2019 Sep 19;21(1):60
    Abstract Background This study develops a model-based myocardial T1 mapping technique with sparsity constraints which employs a single-shot inversion-recovery (IR) radial fast low angle shot (FLASH) cardiovascular magnetic resonance (CMR) acquisition. The method should offer high resolution, accuracy, precision and reproducibility. Methods The proposed reconstruction estimates myocardial parameter maps directly from undersampled k-space which is continuously measured by IR radial FLASH with a 4 s breathhold and retrospectively sorted based on a cardiac trigger signal. Joint sparsity constraints are imposed on the parameter maps to further improve T1 precision. Validations involved studies of an experimental phantom and 8 healthy adult subjects. Results In comparison to an IR spin-echo reference method, phantom experiments with T1 values ranging from 300 to 1500 ms revealed good accuracy and precision at simulated heart rates between 40 and 100 bpm. In vivo T1 maps achieved better precision and qualitatively better preservation of image features for the proposed method than a real-time CMR approach followed by pixelwise fitting. Apart from good inter-observer reproducibility (0.6% of the mean), in vivo results confirmed good intra-subject reproducibility (1.05% of the mean for intra-scan and 1.17, 1.51% of the means for the two inter-scans, respectively) of the proposed method. Conclusion Model-based reconstructions with sparsity constraints allow for single-shot myocardial T1 maps with high spatial resolution, accuracy, precision and reproducibility within a 4 s breathhold. Clinical trials are warranted.
    View Document Abstract
  • Monograph

    DINI-Zertifikat für Open-Access-Publikationsdienste 2019 

    Müller, Uwe; Scholze, Frank; Vierkant, Paul; Arning, Ursula; Beucke, Daniel; Blumtritt, Ute; Bove, Karolin; Braun, Kim; Deppe, Arvid Sönke; Deinzer, Gernot; et al.
    Fenner, MartinKlotz-Berendes, BrunoMeinecke, IsabellaPampel, HeinzSchirrwagen, JochenSeveriens, ThomasSummann, FriedrichSteinke, TobiasTullney, MarcoVoigt, MichaelaWalger, WalgerWeimar, AlexanderWolf, Stefan
    DINI Schriften 3-de; Version 6.0
    Deutsche initiative für netzwerkinformation e. V., 2019
    Das Publikationswesen ist ein wesentlicher Stützpfeiler des wissenschaftlichen Erkenntnisfortschritts und der Wissenschaft insgesamt. Zu seinen Kennzeichen gehören a. die Organisation einer effektiven Kommunikation zwischen Forschenden (zwischen Autor*innen und allen potenziellen Rezipient*innen, d. h. die Sicherstellung einer adäquaten Verbreitung), b. ein hohes Maß an Vertrauenswürdigkeit, das den Nutzenden des Publikationswesens (d.h. den Forschenden) vermittelt wird (z.B. in Bezug auf das Prioritätsrecht, die Wahrung des Urheberrechts sowie die Authentizität und die inhaltliche Qualität wissenschaftlicher Arbeiten), sowie c. Nachhaltigkeit und Nachprüfbarkeit (dauerhafte Zitierbarkeit und langfristige Verfügbarkeit, Nachvollziehbarkeit von einzelnen Schritten auf dem Weg zur Veröffentlichung). Mit dem vorliegenden Kriterienkatalog werden diese allgemeinen Erwartungen an das wissenschaftliche Publizieren in konkrete Mindestanforderungen übersetzt, die an Open-Access-Publikationsdienste zu stellen sind.
    View Document Abstract
  • Journal Article

    Using peer education to improve diabetes management and outcomes in a low-income setting: a randomized controlled trial 

    Seuring, Till; Marthoenis; Rhode, Sabrina; Rogge, Lisa; Rau, Holger; Besançon, Stéphane; Zufry, Hendra; Sofyan, Hizir; Vollmer, Sebastian
    Trials. 2019 Sep 02;20(1):548
    Abstract Background Diabetes is an important health burden in Indonesia. However, diabetes management and treatment remain poor, with most people with diabetes in Indonesia not achieving the recommended blood glucose levels. Peer education may have particular potential in low-income settings in complementing diabetes care without being a large additional strain on the health system. Methods/design This cluster randomized controlled trial aims to identify the effect of the implementation of peer education for patients with type 2 diabetes on diabetes-related outcomes in Aceh, Indonesia, which will complement the diabetes treatment provided at primary-care health posts (puskesmas). Altogether, 29 puskesmas were recruited in Banda Aceh and Aceh Besar, each of which was randomly assigned to either the control or the intervention group. Then, 534 people with diabetes were identified and recruited through their respective puskesmas. The intervention consists of up to two peer education groups per puskesmas, which are led by previously trained people with diabetes. Peer education sessions are held every month for 18 months, with follow-up data being collected 9 and 18 months after the first peer education session. The main objective is to improve diabetes management and the health behavior of participants receiving peer education to reduce their average blood glucose levels as measured by glycated hemoglobin (HbA1c) levels. Secondary outcomes are the effects of peer education on lipid levels, waist circumference, blood pressure, quality of life, treatment adherence, diabetes knowledge, physical activity, and dietary diversity. Data sources for the measurement of outcomes include patient and health facility surveys and biomarker measurements. An economic evaluation will be conducted to assess the cost-effectiveness of the intervention. Discussion This trial will contribute to the evidence on the effectiveness and cost-effectiveness of peer education in improving diabetes management in a low-income setting in Indonesia and in other comparable contexts. Trial registration ISRCTN registry, ISRCTN68253014 . Registered on 18 February 2019.
    View Document Abstract
  • Journal Article

    Pragmatic randomised trial of a smartphone app (NRT2Quit) to improve effectiveness of nicotine replacement therapy in a quit attempt by improving medication adherence: results of a prematurely terminated study 

    Herbec, Aleksandra; Brown, Jamie; Shahab, Lion; West, Robert; Raupach, Tobias
    Trials. 2019 Sep 02;20(1):547
    Abstract Background Nicotine replacement therapy (NRT) bought over the counter (OTC) appears to be largely ineffective for smoking cessation, which may be partially explained by poor adherence. We developed and evaluated the NRT2Quit smartphone app (for iOS) designed to improve quit attempts with OTC NRT by improving adherence to the medications. Methods This study was a pragmatic double-blind randomised controlled trial with remote recruitment through leaflets distributed to over 300 UK-based community pharmacies. The study recruited adult daily smokers (≥10 cigarettes per day) who bought NRT, wanted to quit smoking, downloaded NTR2Quit and completed the registration process within the app. Participants were automatically randomly assigned within the app to the intervention (full) version of NRT2Quit or to its control (minimal) versions. The primary outcome was biochemically verified 4-week abstinence assessed at 8-week follow-up using Russell Standard criteria and intention to treat. Bayes factors were calculated for the cessation outcome. Secondary outcomes were self-reported abstinence, NRT use, app use and satisfaction with the app. Results The study under-recruited. Only 41 participants (3.5% of the target sample) were randomly assigned to NRT2Quit (n = 16) or the control (n = 25) app versions between March 2015 and September 2016. The follow-up rate was 51.2%. The intervention participants had numerically higher biochemically verified quit rates (25.0% versus 8.0%, P = 0.19, odds ratio = 3.83, 0.61–24.02). The calculated Bayes factor, 1.92, showed that the data were insensitive to test for the hypothesis that the intervention app version aided cessation. The intervention participants had higher median logins (2.5 versus 0, P = 0.01) and were more likely to use NRT at follow-up (100.0% versus 28.6%, P = 0.03) and recommend NRT2Quit to others (100.0% versus 28.6%, P = 0.01). Conclusions Despite very low recruitment, there was preliminary but inconclusive evidence that NRT2Quit may improve short-term abstinence and adherence among smokers using NRT. Well-powered studies on NRT2Quit are needed, but different recruitment methods will be required to engage smokers through community pharmacies or other channels. Trial registration ISRCTN ISRCTN33423896 , prospectively registered on 22 March 2015.
    View Document Abstract
  • Journal Article

    Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer 

    Conradi, Lena-Christin; Spitzner, Melanie; Metzger, Anna-Lena; Kisly, Merle; Middel, Peter; Bohnenberger, Hanibal; Gaedcke, Jochen; Ghadimi, Michael B; Liersch, Torsten; Rüschoff, Joseph; et al.
    Beißbarth, TimKönig, AlexanderGrade, Marian
    BMC Cancer. 2019 Sep 05;19(1):880
    Abstract Background Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptors HER-2 and HER-3 in the three cell lines LS513, LS1034 and SW837. Methods Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation. Results The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5-fluorouracil and oxaliplatin. Finally, high expression of HER-3 was detected in 121 of 172 locally advanced rectal cancers (70.3%). In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors’ mode of action, as targeting HER-2 alone is not sufficient. Conclusion Since HER-2 and HER-3 are expressed in a relevant number of patients, targeting both receptors may represent a promising therapeutic strategy for CRC.
    View Document Abstract
  • Journal Article

    Dissecting global air traffic data to discern different types and trends of transnational human mobility 

    Gabrielli, Lorenzo; Deutschmann, Emanuel; Natale, Fabrizio; Recchi, Ettore; Vespe, Michele
    EPJ Data Science. 2019 Aug 30;8(1):26
    Abstract Human mobility across national borders is a key phenomenon of our time. At the global scale, however, we still know relatively little about the structure and nature of such transnational movements. This study uses a large dataset on monthly air passenger traffic between 239 countries worldwide from 2010 to 2018 to gain new insights into (a) mobility trends over time and (b) types of mobility. A time series decomposition is used to extract a trend and a seasonal component. The trend component permits—at a higher level of granularity than previous sources—to examine the development of mobility between countries and to test how it is affected by policy and infrastructural changes, economic developments, and violent conflict. The seasonal component allows, by measuring the lag between initial and return motion, to discern different types of mobility, from tourism to seasonal work migration. Moreover, the exact shape of seasonal mobility patterns is extracted, allowing to identify regular mobility peaks and nadirs throughout the year. The result is a unique classification of trends and types of mobility for a global set of country pairs. A range of implications and possible applications are discussed.
    View Document Abstract
  • Journal Article

    The anatomy and development of the nervous system in Magelonidae (Annelida) – insights into the evolution of the annelid brain 

    Beckers, Patrick; Helm, Conrad; Bartolomaeus, Thomas
    BMC Evolutionary Biology. 2019 Aug 28;19(1):173
    Abstract Background The annelid anterior central nervous system is often described to consist of a dorsal prostomial brain, consisting of several commissures and connected to the ventral ganglionic nerve cord via circumesophageal connectives. In the light of current molecular phylogenies, our assumptions on the primary design of the nervous system in Annelida has to be reconsidered. For that purpose we provide a detailed investigation of the adult nervous system of Magelonidae – a putatively basally branching annelid family - and studied early stages of the development of the latter. Results Our comparative investigation using an integrative morphological approach shows that the nervous system of Magelonidae is located inside the epidermis. The brain is composed of an anterior compact neuropil and posteriorly encircles the prostomial coelomic cavities. From the brain two lateral medullary cords branch off which fuse caudally. Prominent brain structures such as nuchal organs, ganglia or mushroom bodies are absent and the entire nervous system is medullary. Our investigations also contradict previous investigations and present an updated view on established assumptions and descriptions. Conclusion The comprehensive dataset presented herein enables a detailed investigation of the magelonid anterior central nervous system for the first time. The data reveal that early in annelid evolution complexity of brains and anterior sensory structures rises. Polymorphic neurons in clusters and distinct brain parts, as well as lateral organs - all of which are not present in outgroup taxa and in the putative magelonid sister group Oweniidae - already evolved in Magelonidae. Commissures inside the brain, ganglia and nuchal organs, however, most likely evolved in the stem lineage of Amphinomidae + Sipuncula and Pleistoannelida (Errantia+ Sedentaria). The investigation demonstrates the necessity to continuously question established descriptions and interpretations of earlier publications and the need for transparent datasets. Our results also hint towards a stronger inclusion of larval morphology and developmental investigations in order to understand adult morphological features, not only in Annelida.
    View Document Abstract
  • Journal Article

    Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial 

    König, Laila; Dreyling, Martin; Dürig, Jan; Engelhard, Marianne; Hohloch, Karin; Viardot, Andreas; Witzens-Harig, Mathias; Kieser, Meinhard; Klapper, Wolfram; Pott, Christiane; et al.
    Herfarth, Klaus
    Trials. 2019 Aug 30;20(1):544
    Abstract Background Large field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30–40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy. Methods/design The GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the “full dose” of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach. Discussion The goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial. Trial registration EudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520 .
    View Document Abstract
  • Journal Article

    Attitudes and beliefs of academic librarians in Germany and the USA 

    Kramer, Stefan; Horstmann, Wolfram
    The purpose of this study is to understand, compare, and contrast professional experiences, attitudes, and beliefs among personnel in academic libraries in the USA and in Germany. Notable findings include differences in: respondents’ professional backgrounds; services offered by, and perceived adequacy and support of, respondents’ libraries; and views of the library profession and its future. Future studies could extend these comparisons to librarians in other countries, beyond Germany and the USA.
    View Document Abstract
  • Journal Article

    Evaluation of an optimized metal artifact reduction algorithm for flat-detector angiography compared to DSA imaging in follow-up after neurovascular procedures 

    Amelung, Nadine; Maus, Volker; Behme, Daniel; Papageorgiou, Ismini E; Leyhe, Johanna R; Knauth, Michael; Psychogios, Marios N
    BMC Medical Imaging. 2019 Aug 14;19(1):66
    Abstract Background Flat detector CT – angiography (FDCTA) has become a valuable imaging tool in post- and peri-interventional imaging after neurovascular procedures. Metal artifacts produced by radiopaque implants like clips or coils still impair image quality. Methods FDCTA was performed in periprocedural or follow-up imaging of 21 patients, who had received neurovascular treatment. Raw data was sent to a dedicated workstation and subsequently a metal artifact reduction algorithm (MARA) was applied. Two neuroradiologists examined the images. Results Application of MARA improved image appearance and led to a significant reduction of metal artifacts. After application of MARA only 8 datasets (34% of the images) were rated as having many or extensive artifacts, before MARA 15 (65%) of the images had extensive or many artifacts. Twenty percent more cases of reperfusion were diagnosed after application of MARA, congruent to the results of digital subtraction angiography (DSA) imaging. Also 3 (13% of datasets) images, which could not be evaluated before application of MARA, could be analyzed after metal artifact reduction and reperfusion could be excluded. Conclusion Application of MARA improved image evaluation, reduced the extent of metal artifacts, and more cases of reperfusion could be detected or excluded, congruent to DSA imaging.
    View Document Abstract
  • Journal Article

    A little bit of sex prevents mutation accumulation even in apomictic polyploid plants 

    Hodač, Ladislav; Klatt, Simone; Hojsgaard, Diego; Sharbel, Timothy F; Hörandl, Elvira
    BMC Evolutionary Biology. 2019 Aug 14;19(1):170
    Abstract Background In the absence of sex and recombination, genomes are expected to accumulate deleterious mutations via an irreversible process known as Muller’s ratchet, especially in the case of polyploidy. In contrast, no genome-wide mutation accumulation was detected in a transcriptome of facultative apomictic, hexaploid plants of the Ranunculus auricomus complex. We hypothesize that mutations cannot accumulate in flowering plants with facultative sexuality because sexual and asexual development concurrently occurs within the same generation. We assume a strong effect of purging selection on reduced gametophytes in the sexual developmental pathway because previously masked recessive deleterious mutations would be exposed to selection. Results We test this hypothesis by modeling mutation elimination using apomictic hexaploid plants of the R. auricomus complex. To estimate mean recombination rates, the mean number of recombinants per generation was calculated by genotyping three F1 progeny arrays with six microsatellite markers and character incompatibility analyses. We estimated the strength of purging selection in gametophytes by calculating abortion rates of sexual versus apomictic development at the female gametophyte, seed and offspring stage. Accordingly, we applied three selection coefficients by considering effects of purging selection against mutations on (1) male and female gametophytes in the sexual pathway (additive, s = 1.000), (2) female gametophytes only (s = 0.520), and (3) on adult plants only (sporophytes, s = 0.212). We implemented recombination rates into a mathematical model considering the three different selection coefficients, and a genomic mutation rate calculated from genome size of our plants and plant-specific mutation rates. We revealed a mean of 6.05% recombinants per generation. This recombination rate eliminates mutations after 138, 204 or 246 generations, depending on the respective selection coefficients (s = 1.000, 0.520, and 0.212). Conclusions Our results confirm that the empirically observed frequencies of facultative recombination suffice to prevent accumulation of deleterious mutations via Muller’s ratchet even in a polyploid genome. The efficiency of selection is in flowering plants strongly increased by acting on the haplontic (reduced) gametophyte stage.
    View Document Abstract
  • Journal Article

    Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer’s disease tau 

    Brendel, Matthias; Deussing, Maximilian; Blume, Tanja; Kaiser, Lena; Probst, Federico; Overhoff, Felix; Peters, Finn; von Ungern-Sternberg, Barbara; Ryazanov, Sergey; Leonov, Andrei; et al.
    Griesinger, ChristianZwergal, AndreasLevin, JohannesBartenstein, PeterYakushev, IgorCumming, PaulBoening, GuidoZiegler, SibylleHerms, JochenGiese, ArminRominger, Axel
    Alzheimer's Research & Therapy. 2019 Aug 01;11(1):67
    Abstract Background Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer’s disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study. Methods Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings. Results Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex − 53%, p < 0.001; hippocampus − 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001). Conclusion Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.
    View Document Abstract
  • Journal Article

    Which features of subjective cognitive decline are related to amyloid pathology? Findings from the DELCODE study 

    Miebach, Lisa; Wolfsgruber, Steffen; Polcher, Alexandra; Peters, Oliver; Menne, Felix; Luther, Katja; Incesoy, Enise; Priller, Josef; Spruth, Eike; Altenstein, Slawek; et al.
    Buerger, KatharinaCatak, CihanJanowitz, DanielPerneczky, RobertUtecht, JuliaLaske, ChristophBuchmann, MartinaSchneider, AnjaFliessbach, KlausKalbhen, PascalHeneka, Michael TBrosseron, FredericSpottke, AnnikaRoy, NinaTeipel, Stefan JKilimann, IngoWiltfang, JensBartels, ClaudiaDüzel, EmrahDobisch, LauraMetzger, CoralineMeiberth, DixRamirez, AlfredoJessen, FrankWagner, Michael
    Alzheimer's Research & Therapy. 2019 Jul 31;11(1):66
    Abstract Background Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. Methods We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. Results Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. Conclusions Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
    View Document Abstract
  • Journal Article

    Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner 

    French, Timothy; Düsedau, Henning P; Steffen, Johannes; Biswas, Aindrila; Ahmed, Norus; Hartmann, Susanne; Schüler, Thomas; Schott, Björn H; Dunay, Ildiko R
    Journal of Neuroinflammation. 2019 Jul 29;16(1):159
    Abstract Background It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes. Methods Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation. Results Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism. Conclusion Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.
    View Document Abstract
  • Journal Article

    Aged mice show an increased mortality after anesthesia with a standard dose of ketamine/xylazine 

    Schuetze, Sandra; Manig, Anja; Ribes, Sandra; Nau, Roland
    Laboratory Animal Research. 2019 Jul 24;35(1):8
    Abstract Geriatric animal models are crucial for a better understanding and an improved therapy of age-related diseases. We observed a high mortality of aged mice after anesthesia with a standard dose of ketamine/xylazine, an anesthetic regimen frequently used in laboratory veterinary medicine. C57BL/6-N mice at the age of 2.14 ± 0.23 months (young mice) and 26.31 ± 2.15 months (aged mice) were anesthetized by intraperitoneal injection of 2 mg ketamine and 0.2 mg xylazine. 4 of 26 aged mice (15.4%) but none of 26 young mice died within 15 min after injection of the anesthetics. The weight of aged mice was significantly higher than that of young mice (32.8 ± 5.4 g versus 23.2 ± 3.4 g, p < 0.0001). Thus, aged mice received lower doses of anesthetics in relation to their body weight which are within the lower range of doses recommended in the literature or even beneath. There were no differences between deceased and surviving aged mice concerning their sex, weight and their motor performance prior to anesthesia. Our data clearly show an age-related increase of mortality upon anesthesia with low standard doses of ketamine/xylazine. Assessment of weight and motor performance did not help to predict vulnerability of aged mice to the anesthetics. Caution is necessary when this common anesthetic regimen is applied in aged mice: lower doses or the use of alternative anesthetics should be considered to avoid unexpected mortality. The present data from our geriatric mouse model strongly corroborate an age-adjusted reduction of anesthetic doses to reduce anesthesia-related mortality in aged individuals.
    View Document Abstract

View more