TY - JOUR A1 - Shao, Yi-Ming A1 - Ma, Xiaohua A1 - Paira, Priyankar A1 - Tan, Aaron A1 - Herr, Deron Raymond A1 - Lim, Kah Leong A1 - Ng, Chee Hoe A1 - Venkatesan, Gopalakrishnan A1 - Klotz, Karl-Norbert A1 - Federico, Stephanie A1 - Spalluto, Giampiero A1 - Cheong, Siew Lee A1 - Chen, Yu Zong A1 - Pastorin, Giorgia T1 - Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment JF - PLoS ONE N2 - Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7–11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5–40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM). Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237766 VL - 13 ER - TY - JOUR A1 - Förster, Sabine A1 - Koziol, Uriel A1 - Schäfer, Tina A1 - Duvoisin, Raphael A1 - Cailliau, Katia A1 - Vanderstraete, Mathieu A1 - Dissous, Colette A1 - Brehm, Klaus T1 - The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction JF - PLoS Neglected Tropical Diseases N2 - Background Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-failure. The molecular mechanisms of parasite organ tropism towards the liver and influences of liver cytokines and hormones on parasite development are little studied to date. Methodology/Principal findings We show that the E. multilocularis larval stage expresses three members of the fibroblast growth factor (FGF) receptor family with homology to human FGF receptors. Using the Xenopus expression system we demonstrate that all three Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which are present in the liver. In all three cases, activation could be prevented by addition of the tyrosine kinase (TK) inhibitor BIBF 1120, which is used to treat human cancer. At physiological concentrations, acidic and basic FGF significantly stimulated the formation of metacestode vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the parasite’s mitogen activated protein kinase signalling system was stimulated upon addition of human FGF. The survival of metacestode vesicles and parasite stem cells were drastically affected in vitro in the presence of BIBF 1120. Conclusions/Significance Our data indicate that mammalian FGF, which is present in the liver and upregulated during fibrosis, supports the establishment of the Echinococcus metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling system. These data are valuable for understanding molecular mechanisms of organ tropism and host-parasite interaction in AE. Furthermore, our data indicate that the parasite’s FGF signalling systems are promising targets for the development of novel drugs against AE. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228190 VL - 13 ER - TY - JOUR A1 - Nagy, Dóra A1 - Cusumano, Paola A1 - Andreatta, Gabriele A1 - Martin Anduaga, Ane A1 - Hermann-Luibl, Christiane A1 - Reinhard, Nils A1 - Gesto, João A1 - Wegener, Christian A1 - Mazzotta, Gabriella A1 - Rosato, Ezio A1 - Kyriacou, Charalambos P. A1 - Helfrich-Förster, Charlotte A1 - Costa, Rodolfo T1 - Peptidergic signaling from clock neurons regulates reproductive dormancy in Drosophila melanogaster JF - PLoS Genetics N2 - With the approach of winter, many insects switch to an alternative protective developmental program called diapause. Drosophila melanogaster females overwinter as adults by inducing a reproductive arrest that is characterized by inhibition of ovarian development at previtellogenic stages. The insulin producing cells (IPCs) are key regulators of this process, since they produce and release insulin-like peptides that act as diapause-antagonizing hormones. Here we show that in D. melanogaster two neuropeptides, Pigment Dispersing Factor (PDF) and short Neuropeptide F (sNPF) inhibit reproductive arrest, likely through modulation of the IPCs. In particular, genetic manipulations of the PDF-expressing neurons, which include the sNPF-producing small ventral Lateral Neurons (s-LNvs), modulated the levels of reproductive dormancy, suggesting the involvement of both neuropeptides. We expressed a genetically encoded cAMP sensor in the IPCs and challenged brain explants with synthetic PDF and sNPF. Bath applications of both neuropeptides increased cAMP levels in the IPCs, even more so when they were applied together, suggesting a synergistic effect. Bath application of sNPF additionally increased Ca2+ levels in the IPCs. Our results indicate that PDF and sNPF inhibit reproductive dormancy by maintaining the IPCs in an active state. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231681 VL - 15 ER - TY - JOUR A1 - Li, Ying H. A1 - Liu, Xianhui A1 - Vanselow, Jens T. A1 - Zheng, Haiyan A1 - Schlosser, Andreas A1 - Chiu, Joanna C. T1 - O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression JF - PLoS Genetics N2 - Circadian clocks coordinate time-of-day-specific metabolic and physiological processes to maximize organismal performance and fitness. In addition to light and temperature, which are regarded as strong zeitgebers for circadian clock entrainment, metabolic input has now emerged as an important signal for clock entrainment and modulation. Circadian clock proteins have been identified to be substrates of O-GlcNAcylation, a nutrient sensitive post-translational modification (PTM), and the interplay between clock protein O-GlcNAcylation and other PTMs is now recognized as an important mechanism by which metabolic input regulates circadian physiology. To better understand the role of O-GlcNAcylation in modulating clock protein function within the molecular oscillator, we used mass spectrometry proteomics to identify O-GlcNAcylation sites of PERIOD (PER), a repressor of the circadian transcriptome and a critical biochemical timer of the Drosophila clock. In vivo functional characterization of PER O-GlcNAcylation sites indicates that O-GlcNAcylation at PER(S942) reduces interactions between PER and CLOCK (CLK), the key transcriptional activator of clock-controlled genes. Since we observe a correlation between clock-controlled daytime feeding activity and higher level of PER O-GlcNAcylation, we propose that PER(S942) O-GlcNAcylation during the day functions to prevent premature initiation of circadian repression phase. This is consistent with the period-shortening behavioral phenotype of per(S942A) flies. Taken together, our results support that clock-controlled feeding activity provides metabolic signals to reinforce light entrainment to regulate circadian physiology at the post-translational level. The interplay between O-GlcNAcylation and other PTMs to regulate circadian physiology is expected to be complex and extensive, and reach far beyond the molecular oscillator. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236826 VL - 15 ER - TY - JOUR A1 - del Olmo Toledo, Valentina A1 - Puccinelli, Robert A1 - Fordyce, Polly M. A1 - Pérez, J. Christian T1 - Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi JF - PLoS Genetics N2 - The Sterol Regulatory Element Binding Proteins (SREBPs) are basic-helix-loop-helix transcription regulators that control the expression of sterol biosynthesis genes in higher eukaryotes and some fungi. Surprisingly, SREBPs do not regulate sterol biosynthesis in the ascomycete yeasts (Saccharomycotina) as this role was handed off to an unrelated transcription regulator in this clade. The SREBPs, nonetheless, expanded in fungi such as the ascomycete yeasts Candida spp., raising questions about their role and evolution in these organisms. Here we report that the fungal SREBPs diversified their DNA binding preferences concomitantly with an expansion in function. We establish that several branches of fungal SREBPs preferentially bind non-palindromic DNA sequences, in contrast to the palindromic DNA motifs recognized by most basic-helix-loop-helix proteins (including SREBPs) in higher eukaryotes. Reconstruction and biochemical characterization of the likely ancestor protein suggest that an intrinsic DNA binding promiscuity in the family was resolved by alternative mechanisms in different branches of fungal SREBPs. Furthermore, we show that two SREBPs in the human commensal yeast Candida albicans drive a transcriptional cascade that inhibits a morphological switch under anaerobic conditions. Preventing this morphological transition enhances C. albicans colonization of the mammalian intestine, the fungus’ natural niche. Thus, our results illustrate how diversification in DNA binding preferences enabled the functional expansion of a family of eukaryotic transcription regulators. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228983 VL - 14 ER - TY - JOUR A1 - Lu, Yuan A1 - Boswell, Mikki A1 - Boswell, William A1 - Kneitz, Susanne A1 - Klotz, Barbara A1 - Savage, Markita A1 - Salinas, Raquel A1 - Marks, Rebacca A1 - Regneri, Janine A1 - Postlethwait, John A1 - Warren, Wesley C. A1 - Schartl, Manfred A1 - Walter, Ronald T1 - Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model JF - PLoS Genetics N2 - Understanding the genetic mechanisms underlying segregation of phenotypic variation through successive generations is important for understanding physiological changes and disease risk. Tracing the etiology of variation in gene expression enables identification of genetic interactions, and may uncover molecular mechanisms leading to the phenotypic expression of a trait, especially when utilizing model organisms that have well-defined genetic lineages. There are a plethora of studies that describe relationships between gene expression and genotype, however, the idea that global variations in gene expression are also controlled by genotype remains novel. Despite the identification of loci that control gene expression variation, the global understanding of how genome constitution affects trait variability is unknown. To study this question, we utilized Xiphophorus fish of different, but tractable genetic backgrounds (inbred, F1 interspecies hybrids, and backcross hybrid progeny), and measured each individual’s gene expression concurrent with the degrees of inter-individual expression variation. We found, (a) F1 interspecies hybrids exhibited less variability than inbred animals, indicting gene expression variation is not affected by the fraction of heterozygous loci within an individual genome, and (b), that mixing genotypes in backcross populations led to higher levels of gene expression variability, supporting the idea that expression variability is caused by heterogeneity of genotypes of cis or trans loci. In conclusion, heterogeneity of genotype, introduced by inheritance of different alleles, accounts for the largest effects on global phenotypical variability. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237318 VL - 14 ER - TY - JOUR A1 - El Mouali, Youssef A1 - Gaviria-Cantin, Tania A1 - Sánchez-Romero, María Antonia A1 - Gibert, Marta A1 - Westermann, Alexander J. A1 - Vogel, Jörg A1 - Balsalobre, Carlos T1 - CRP-cAMP mediates silencing of Salmonella virulence at the post-transcriptional level JF - PLoS Genetics N2 - Invasion of epithelial cells by Salmonella enterica requires expression of genes located in the pathogenicity island I (SPI-1). The expression of SPI-1 genes is very tightly regulated and activated only under specific conditions. Most studies have focused on the regulatory pathways that induce SPI-1 expression. Here, we describe a new regulatory circuit involving CRP-cAMP, a widely established metabolic regulator, in silencing of SPI-1 genes under non-permissive conditions. In CRP-cAMP-deficient strains we detected a strong upregulation of SPI-1 genes in the mid-logarithmic growth phase. Genetic analyses revealed that CRP-cAMP modulates the level of HilD, the master regulator of Salmonella invasion. This regulation occurs at the post-transcriptional level and requires the presence of a newly identified regulatory motif within the hilD 3’UTR. We further demonstrate that in Salmonella the Hfq-dependent sRNA Spot 42 is under the transcriptional repression of CRP-cAMP and, when this transcriptional repression is relieved, Spot 42 exerts a positive effect on hilD expression. In vivo and in vitro assays indicate that Spot 42 targets, through its unstructured region III, the 3’UTR of the hilD transcript. Together, our results highlight the biological relevance of the hilD 3’UTR as a hub for post-transcriptional control of Salmonella invasion gene expression. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226614 VL - 14 ER - TY - JOUR A1 - Wheeler, Nicole E. A1 - Gardner, Paul P. A1 - Barquist, Lars T1 - Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica JF - PLoS Genetics N2 - Emerging pathogens are a major threat to public health, however understanding how pathogens adapt to new niches remains a challenge. New methods are urgently required to provide functional insights into pathogens from the massive genomic data sets now being generated from routine pathogen surveillance for epidemiological purposes. Here, we measure the burden of atypical mutations in protein coding genes across independently evolved Salmonella enterica lineages, and use these as input to train a random forest classifier to identify strains associated with extraintestinal disease. Members of the species fall along a continuum, from pathovars which cause gastrointestinal infection and low mortality, associated with a broad host-range, to those that cause invasive infection and high mortality, associated with a narrowed host range. Our random forest classifier learned to perfectly discriminate long-established gastrointestinal and invasive serovars of Salmonella. Additionally, it was able to discriminate recently emerged Salmonella Enteritidis and Typhimurium lineages associated with invasive disease in immunocompromised populations in sub-Saharan Africa, and within-host adaptation to invasive infection. We dissect the architecture of the model to identify the genes that were most informative of phenotype, revealing a common theme of degradation of metabolic pathways in extraintestinal lineages. This approach accurately identifies patterns of gene degradation and diversifying selection specific to invasive serovars that have been captured by more labour-intensive investigations, but can be readily scaled to larger analyses. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233662 VL - 14 ER - TY - JOUR A1 - Breitenbach, Tim A1 - Liang, Chunguang A1 - Beyersdorf, Niklas A1 - Dandekar, Thomas T1 - Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks JF - PLoS Computational Biology N2 - Once biological systems are modeled by regulatory networks, the next step is to include external stimuli, which model the experimental possibilities to affect the activity level of certain network’s nodes, in a mathematical framework. Then, this framework can be interpreted as a mathematical optimal control framework such that optimization algorithms can be used to determine external stimuli which cause a desired switch from an initial state of the network to another final state. These external stimuli are the intervention points for the corresponding biological experiment to obtain the desired outcome of the considered experiment. In this work, the model of regulatory networks is extended to controlled regulatory networks. For this purpose, external stimuli are considered which can affect the activity of the network’s nodes by activation or inhibition. A method is presented how to calculate a selection of external stimuli which causes a switch between two different steady states of a regulatory network. A software solution based on Jimena and Mathworks Matlab is provided. Furthermore, numerical examples are presented to demonstrate application and scope of the software on networks of 4 nodes, 11 nodes and 36 nodes. Moreover, we analyze the aggregation of platelets and the behavior of a basic T-helper cell protein-protein interaction network and its maturation towards Th0, Th1, Th2, Th17 and Treg cells in accordance with experimental data. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220385 VL - 15 ER - TY - JOUR A1 - Steimle, Alex A1 - Menz, Sarah A1 - Bender, Annika A1 - Ball, Brianna A1 - Weber, Alexander N. R. A1 - Hagemann, Thomas A1 - Lange, Anna A1 - Maerz, Jan K. A1 - Perusel, Raphael A1 - Michaelis, Lena A1 - Schäfer, Andrea A1 - Yao, Hans A1 - Löw, Hanna-Christine A1 - Beier, Sina A1 - Mebrhatu, Mehari Tesfazgi A1 - Gronbach, Kerstin A1 - Wagner, Samuel A1 - Voehringer, David A1 - Schaller, Martin A1 - Fehrenbacher, Birgit A1 - Autenrieth, Ingo B. A1 - Oelschlaeger, Tobias A. A1 - Frick, Julia-Stefanie T1 - Flagellin hypervariable region determinessymbiotic properties of commensalEscherichia coli strains JF - PLoS Biology N2 - Escherichia coli represents a classical intestinal gram-negative commensal. Despite this commensalism, different E. coli strains can mediate disparate immunogenic properties in a given host. Symbiotic E. coli strains such as E. coli Nissle 1917 (EcN) are attributed beneficial properties, e.g., promotion of intestinal homeostasis. Therefore, we aimed to identify molecular features derived from symbiotic bacteria that might help to develop innovative therapeutic alternatives for the treatment of intestinal immune disorders. This study was performed using the dextran sodium sulphate (DSS)-induced colitis mouse model, which is routinely used to evaluate potential therapeutics for the treatment of Inflammatory Bowel Diseases (IBDs). We focused on the analysis of flagellin structures of different E. coli strains. EcN flagellin was found to harbor a substantially longer hypervariable region (HVR) compared to other commensal E. coli strains, and this longer HVR mediated symbiotic properties through stronger activation of Toll-like receptor (TLR)5, thereby resulting in interleukin (IL)-22–mediated protection of mice against DSS-induced colitis. Furthermore, using bone-marrow–chimeric mice (BMCM), CD11c+ cells of the colonic lamina propria (LP) were identified as the main mediators of these flagellin-induced symbiotic effects. We propose flagellin from symbiotic E. coli strains as a potential therapeutic to restore intestinal immune homeostasis, e.g., for the treatment of IBD patients. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239501 VL - 17 ER - TY - JOUR A1 - Herpin, Amaury A1 - Schmidt, Cornelia A1 - Kneitz, Susanne A1 - Gobé, Clara A1 - Regensburger, Martina A1 - Le Cam, Aurélie A1 - Montfort, Jérome A1 - Adolfi, Mateus C. A1 - Lillesaar, Christina A1 - Wilhelm, Dagmar A1 - Kraeussling, Michael A1 - Mourot, Brigitte A1 - Porcon, Béatrice A1 - Pannetier, Maëlle A1 - Pailhoux, Eric A1 - Ettwiller, Laurence A1 - Dolle, Dirk A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - A novel evolutionary conserved mechanism of RNA stability regulates synexpression of primordial germ cell-specific genes prior to the sex-determination stage in medaka JF - PLoS Biology N2 - Dmrt1 is a highly conserved transcription factor, which is critically involved in regulation of gonad development of vertebrates. In medaka, a duplicate of dmrt1—acting as master sex-determining gene—has a tightly timely and spatially controlled gonadal expression pattern. In addition to transcriptional regulation, a sequence motif in the 3′ UTR (D3U-box) mediates transcript stability of dmrt1 mRNAs from medaka and other vertebrates. We show here that in medaka, two RNA-binding proteins with antagonizing properties target this D3U-box, promoting either RNA stabilization in germ cells or degradation in the soma. The D3U-box is also conserved in other germ-cell transcripts, making them responsive to the same RNA binding proteins. The evolutionary conservation of the D3U-box motif within dmrt1 genes of metazoans—together with preserved expression patterns of the targeting RNA binding proteins in subsets of germ cells—suggest that this new mechanism for controlling RNA stability is not restricted to fishes but might also apply to other vertebrates. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320011 VL - 17 ER - TY - JOUR A1 - Toepfer, Franziska A1 - Wolf, Reinhard A1 - Heisenberg, Martin T1 - Multi-stability with ambiguous visual stimuli in Drosophila orientation behavior JF - PLoS Biology N2 - It is widely accepted for humans and higher animals that vision is an active process in which the organism interprets the stimulus. To find out whether this also holds for lower animals, we designed an ambiguous motion stimulus, which serves as something like a multi-stable perception paradigm in Drosophila behavior. Confronted with a uniform panoramic texture in a closed-loop situation in stationary flight, the flies adjust their yaw torque to stabilize their virtual self-rotation. To make the visual input ambiguous, we added a second texture. Both textures got a rotatory bias to move into opposite directions at a constant relative angular velocity. The results indicate that the fly now had three possible frames of reference for self-rotation: either of the two motion components as well as the integrated motion vector of the two. In this ambiguous stimulus situation, the flies generated a continuous sequence of behaviors, each one adjusted to one or another of the three references. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228976 VL - 16 ER - TY - JOUR A1 - Nägele, Virginie A1 - Zugmaier, Gerhard A1 - Goebeler, Maria-Elisabeth A1 - Viardot, Andreas A1 - Bargou, Ralf A1 - Kufer, Peter A1 - Klinger, Matthias T1 - Relationship of T- and B-cell kinetics to clinical response in patients with relapsed/refractory non-Hodgkin lymphoma treated with blinatumomab JF - Experimental Hematology N2 - Blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE®) immune-oncology platform, which redirects CD3+ T cells to kill CD19+ target cells. The objective of this analysis was to describe the correlation between B- and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently investigated in a phase 1 dose-escalation and expansion trial (NCT00274742) wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5–90 μg/m2/day). B-Cell depletion and expansion of CD3+, CD4+, and CD8+ T cells was analyzed in patients stratified per clinical response (complete response [CR], n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity or PD. B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a complete response (PR, SD, or PD). T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR. T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4+ and CD8+ T cells compared with patients without CR. Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3+, CD4+, and CD8+ T cells than patients who did not achieve a CR. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371526 VL - 100 ER - TY - JOUR A1 - Nabeebaccus, Adam A A1 - Verma, Sharwari A1 - Zoccarato, Anna A1 - Emanuelli, Giulia A1 - Santos, Celio XC. A1 - Streckfuss-Bömeke, Katrin A1 - Shah, Ajay M. T1 - Cardiomyocyte protein O-GlcNAcylation is regulated by GFAT1 not GFAT2 JF - Biochemical and Biophysical Research Communications N2 - In response to cardiac injury, increased activity of the hexosamine biosynthesis pathway (HBP) is linked with cytoprotective as well as adverse effects depending on the type and duration of injury. Glutamine-fructose amidotransferase (GFAT; gene name gfpt) is the rate-limiting enzyme that controls flux through HBP. Two protein isoforms exist in the heart called GFAT1 and GFAT2. There are conflicting data on the relative importance of GFAT1 and GFAT2 during stress-induced HBP responses in the heart. Using neonatal rat cardiac cell preparations, targeted knockdown of GFPT1 and GFPT2 were performed and HBP activity measured. Immunostaining with specific GFAT1 and GFAT2 antibodies was undertaken in neonatal rat cardiac preparations and murine cardiac tissues to characterise cell-specific expression. Publicly available human heart single cell sequencing data was interrogated to determine cell-type expression. Western blots for GFAT isoform protein expression were performed in human cardiomyocytes derived from induced pluripotent stem cells (iPSCs). GFPT1 but not GFPT2 knockdown resulted in a loss of stress-induced protein O-GlcNAcylation in neonatal cardiac cell preparations indicating reduced HBP activity. In rodent cells and tissue, immunostaining for GFAT1 identified expression in both cardiac myocytes and fibroblasts whereas immunostaining for GFAT2 was only identified in fibroblasts. Further corroboration of findings in human heart cells identified an enrichment of GFPT2 gene expression in cardiac fibroblasts but not ventricular myocytes whereas GFPT1 was expressed in both myocytes and fibroblasts. In human iPSC-derived cardiomyocytes, only GFAT1 protein was expressed with an absence of GFAT2. In conclusion, these results indicate that GFAT1 is the primary cardiomyocyte isoform and GFAT2 is only present in cardiac fibroblasts. Cell-specific isoform expression may have differing effects on cell function and should be considered when studying HBP and GFAT functions in the heart. KW - hexosamine biosynthesis pathway KW - GFPT1 KW - GFPT2 KW - GFAT1 KW - GFAT2 KW - O-GlcNAc Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371510 VL - 583 ER - TY - JOUR A1 - Muzerelle, Aude A1 - Soiza-Reilly, Mariano A1 - Hainer, Cornelia A1 - Ruet, Pierre-Louis A1 - Lesch, Klaus-Peter A1 - Bader, Michael A1 - Alenina, Natalia A1 - Scotto-Lomassese, Sophie A1 - Gaspar, Patricia T1 - Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival JF - Scientific Reports N2 - Proper maternal care is an essential factor of reproductive success in mammals, involving a repertoire of behaviors oriented toward the feeding and care of the offspring. Among the neurotransmitters involved in the initiation of these behaviors, serotonin (5-HT) seems to play an important role. Here we compared pup-oriented maternal behaviors in mice with constitutive 5-HT depletion, the tryptophan hydroxylase 2-knock-out (Tph2-KO) and the Pet1-KO mice. We report that the only common pup-oriented defect in these 2 hyposerotoninergic models is a defective nursing in parturient mice and altered nursing-like (crouching) behavior in virgin mice, while pup retrieval defects are only present in Tph2-KO. Despite a normal mammary gland development and milk production, the defect in appropriate nursing is responsible for severe growth retardation and early lethality of pups born to hyposerotonergic dams. This nursing defect is due to acute rather constitutive 5-HT depletion, as it is reproduced by adult knockdown of Tph2 in the dorsal raphe nucleus in mothers with a prior normal maternal experience. We conclude that 5-HT innervation from the dorsal raphe is required for both the initiation and maintenance of a normal nursing behavior. Our findings may be related to observations of reduced maternal/infant interactions in human depression. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371501 VL - 11 ER - TY - JOUR A1 - Muysers, Christoph A1 - Messina, Fabrizio A1 - Keil, Thomas A1 - Roll, Stephanie T1 - A novel concept of screening for subgrouping factors for the association between socioeconomic status and respiratory allergies JF - Journal of Exposure Science & Environmental Epidemiology N2 - Background The new subgroup screening tool “subscreen” aims to understand the unclear and complex association between socioeconomic status (SES) and childhood allergy. This software R package has been successfully used in clinical trials but not in large population-based studies. Objective To screen and identify subgrouping factors explaining their impact on the association between SES and respiratory allergies in childhood and youth. Methods Using the national German childhood and youth survey dataset (KiGGS Wave 2), we included 56 suspected subgrouping factors to investigate the association between SES (low vs. high) and allergic rhinitis and/or asthma in an exploratory manner. The package enabled a comprehensive overview of odds ratios when considering the SES impact per subgroup and analogously all disease proportions per subgroup. Result Among the 56 candidate factors, striking subgrouping factors were identified; e.g., if mothers were younger and in the low SES group, their children had a higher risk of asthma. In addition children of the teen’s age were associated with increased risks in the low SES group. For the crude proportions, factors such as (parental) smoking or having had no “contact with farm animals” were identified as strong risk factors for rhinitis. Significance The “subscreen” package enabled the detection of notable subgroups for further investigations exemplarily for similar epidemiological research questions. KW - “Subscreen” R package KW - epidemiology survey KW - asthma KW - rhinitis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371490 VL - 32 ER - TY - JOUR A1 - Muszynska, Aleksandra A1 - Guendel, Andre A1 - Melzer, Michael A1 - Moya, Yudelsy Antonia Tandron A1 - Röder, Marion S. A1 - Rolletschek, Hardy A1 - Rutten, Twan A1 - Munz, Eberhard A1 - Melz, Gilbert A1 - Ortleb, Stefan A1 - Borisjuk, Ljudmilla A1 - Börner, Andreas T1 - A mechanistic view on lodging resistance in rye and wheat: a multiscale comparative study JF - Plant Biotechnology Journal N2 - The development of crop varieties that are resistant to lodging is a top priority for breeding programmes. Herein, we characterize the rye mutant ´Stabilstroh’ (‘stable straw’) possessing an exceptional combination of high lodging resistance, tall posture and high biomass production. Nuclear magnetic resonance imaging displayed the 3-dimensional assembly of vascular bundles in stem. A higher number of vascular bundles and a higher degree of their incline were the features of lodging-resistant versus lodging-prone lines. Histology and electron microscopy revealed that stems are fortified by a higher proportion of sclerenchyma and thickened cell walls, as well as some epidermal invaginations. Biochemical analysis using Fourier-transform infrared spectroscopy and inductively coupled plasma-optical emission spectrometry further identified elevated levels of lignin, xylan, zinc and silicon as features associated with high lodging resistance. Combined effects of above features caused superior culm stability. A simplistic mathematical model showed how mechanical forces distribute within the stem under stress. Main traits of the lodging-resistant parental line were heritable and could be traced back to the genetic structure of the mutant. Evaluation of lodging-resistant wheat ‘Babax’ (‘Baviacora’) versus contrasting, lodging-prone, genotype ´Pastor´ agreed with above findings on rye. Our findings on mechanical stability and extraordinary culm properties may be important for breeders for the improvement of lodging resistance of tall posture cereal crops. KW - cell wall KW - scanning electron microscopy KW - Fourier-transform infrared spectroscopy KW - lodging resistance; KW - nuclear magnetic resonance imaging KW - QTL mapping Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371478 VL - 19 ER - TY - JOUR A1 - Musto, Pellegrino A1 - Engelhardt, Monika A1 - Caers, Jo A1 - Bolli, Niccolo' A1 - Kaiser, Martin A1 - van de Donk, Niels A1 - Terpos, Evangelos A1 - Broijl, Annemiek A1 - de Larrea, Carlos Fernández A1 - Gay, Francesca A1 - Goldschmidt, Hartmut A1 - Hajek, Roman A1 - Vangsted, Annette Juul A1 - Zamagni, Elena A1 - Zweegman, Sonja A1 - Cavo, Michele A1 - Dimopoulos, Meletios A1 - Einsele, Hermann A1 - Ludwig, Heinz A1 - Barosi, Giovanni A1 - Boccadoro, Mario A1 - Mateos, Maria-Victoria A1 - Sonneveld, Pieter A1 - San Miguel, Jesus T1 - 2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde JF - Haematologica N2 - According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of “monoclonal gammopathy of undetermined significance-like”, in which patients never progress during their lifetimes, to “early multiple myeloma”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371372 VL - 106 ER - TY - JOUR A1 - Murali, Supriya A1 - Händel, Barbara T1 - The latency of spontaneous eye blinks marks relevant visual and auditory information processing JF - Journal of Vision N2 - Eye blinks are influenced by external sensory and internal cognitive factors, as mainly shown in the visual domain. In previous studies, these factors corresponded to the time period of task-relevant sensory information and were often linked to a motor response. Our aim was to dissociate the influence of overall sensory input duration, task-relevant information duration, and the motor response to further understand how the temporal modulation of blinks compares among sensory modalities. Using a visual and an auditory temporal judgment task, we found that blinks were suppressed during stimulus presentation in both domains and that the overall input length had a significant positive relationship with the length of this suppression (i.e., with the latency of the first blink after stimulus onset). Importantly, excluding the influence of the overall sensory input duration we could show that the duration of task-relevant input had an additional influence on blink latency in the visual and the auditory domain. Our findings further suggest that this influence was not based on sensory input but on top–down processes. We could exclude task difficulty and the timing of the motor response as driving factors in the blink modulation. Our results suggest a sensory domain–independent modulation of blink latencies, introduced by changes in the length of the task-relevant, attended period. Therefore, not only do blinks mark the timing of sensory input or the preparation of the motor output, but they can also act as precise indicators of periods of cognitive processing. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371361 VL - 21 ER - TY - JOUR A1 - Müller-Nordhorn, Jacqueline A1 - Neumann, Konrad A1 - Keil, Thomas A1 - Willich, Stefan N. A1 - Binting, Sylvia T1 - State-level trends in sudden unexpected infant death and immunization in the United States: an ecological study JF - BMC Pediatrics N2 - Background Sudden unexpected infant death (SUID) continues to be a major contributor to infant mortality in the United States. The objective was to analyze time trends in SUID and their association with immunization coverage. Methods The number of deaths and live births per year and per state (1992–2015) was obtained from the Centers for Disease Control and Prevention (CDC). We calculated infant mortality rates (i.e., deaths below one year of age) per 1000 live births for SUID. We obtained data on immunization in children aged 19–35 months with three doses or more of diphtheria-tetanus-pertussis (3+ DTP), polio (3+ Polio), and Haemophilus influenzae type b (3+ Hib) as well as four doses or more of DTP (4+ DTP) from the National Immunization Survey, and data on infant sleep position from the Pregnancy Risk Assessment Monitoring System (PRAMS) Study. Data on poverty and race were derived from the Current Population and American Community Surveys of the U.S. Census Bureau. We calculated mean SUID mortality rates with 95% confidence interval (CI) as well as the annual percentage change using breakpoint analysis. We used Poisson regression with random effects to examine the dependence of SUID rates on immunization coverage, adjusting for sleep position and poverty (1996–2015). In a second model, we additionally adjusted for race (2000–2015). Results Overall, SUID mortality decreased in the United States. The mean annual percent change was − 9.6 (95% CI = − 10.5, − 8.6) between 1992 and 1996, and − 0.3 (95% CI = − 0.4, − 0.1) from 1996 onwards. The adjusted rate ratios for SUID mortality were 0.91 (95% CI = 0.80, 1.03) per 10% increase for 3+ DTP, 0.88 (95% CI = 0.83, 0.95) for 4+ DTP, 1.00 (95% CI = 0.90, 1.10) for 3+ polio, and 0.95 (95% CI = 0.89, 1.02) for 3+ Hib. After additionally adjusting for race, the rate ratios were 0.76 (95% CI = 0.67, 0.85) for 3+ DTP, 0.83 (95% CI = 0.78, 0.89) for 4+ DTP, 0.81 (95% CI = 0.73, 0.90) for 3+ polio, and 0.94 (95% CI = 0.88, 1.00) for 3+ Hib. Conclusions SUID mortality is decreasing, and inversely related to immunization coverage. However, since 1996, the decline has slowed down. KW - sudden unexpected infant death KW - vaccination coverage KW - time trends Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371356 VL - 21 ER - TY - JOUR A1 - Müller-Edenborn, Björn A1 - Moreno-Weidmann, Zoraida A1 - Venier, Sandrine A1 - Defaye, Pascale A1 - Park, Chan-il A1 - Guerra, José A1 - Alonso-Martín, Concepcion A1 - Bazan, Victor A1 - Vinolas, Xavier A1 - Rodriguez-Font, Enrique A1 - Campos Garcia, Bieito A1 - Boveda, Serge A1 - Combes, Stéphane A1 - Albenque, Jean-Paul A1 - Guy-Moyat, Benoit A1 - Trenk, Dietmar A1 - Eichenlaub, Martin A1 - Chen, Juan A1 - Lehrmann, Heiko A1 - Neumann, Franz-Josef A1 - Arentz, Thomas A1 - Jadidi, Amir T1 - Determinants of fibrotic atrial cardiomyopathy in atrial fibrillation. A multicenter observational study of the RETAC (reseau européen de traîtement d’arrhythmies cardiaques)-group JF - Clinical Research in Cardiology N2 - Aims Despite advances in interventional treatment strategies, atrial fibrillation (AF) remains associated with significant morbidity and mortality. Fibrotic atrial myopathy (FAM) is a main factor for adverse outcomes of AF-ablation, but complex to diagnose using current methods. We aimed to derive a scoring system based entirely on easily available clinical parameters to predict FAM and ablation-success in everyday care. Methods In this multicenter, prospective study, a new risk stratification model termed AF-SCORE was derived in 220 patients undergoing high-density left-atrial(LA) voltage-mapping to quantify FAM. AF-SCORE was validated for FAM in an external mapping-validation cohort (n = 220) and for success following pulmonary vein isolation (PVI)-only (without adjunctive left- or right atrial ablations) in an external outcome-validation cohort (n = 518). Results FAM was rare in patients < 60 years (5.4%), but increased with ageing and affected 40.4% (59/146) of patients ≥ 60 years. Sex and AF-phenotype had additional predictive value in older patients and remained associated with FAM in multivariate models (odds ratio [OR] 6.194, p < 0.0001 for ≥ 60 years; OR 2.863, p < 0.0001 for female sex; OR 41.309, p < 0.0001 for AF-persistency). Additional clinical or diagnostic variables did not improve the model. AF-SCORE (+ 1 point for age ≥ 60 years and additional points for female sex [+ 1] and AF-persistency [+ 2]) showed good discrimination to detect FAM (c-statistic 0.792) and predicted arrhythmia-freedom following PVI (74.3%, 54.7% and 45.5% for AF-SCORE ≤ 2, 3 and 4, respectively, and hazard ratio [HR] 1.994 for AF-SCORE = 3 and HR 2.866 for AF-SCORE = 4, p < 0.001). Conclusions Age, sex and AF-phenotype are the main determinants for the development of FAM. A low AF-SCORE ≤ 2 is found in paroxysmal AF-patients of any age and younger patients with persistent AF irrespective of sex, and associated with favorable outcomes of PVI-only. Freedom from arrhythmia remains unsatisfactory with AF-SCORE ≥ 3 as found in older patients, particularly females, with persistent AF, and future studies investigating adjunctive atrial ablations to PVI-only should focus on these groups of patients. KW - atrial fibrillation KW - risk stratification KW - pulmonary vein isolation KW - fibrotic atrial myopathy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371312 VL - 111 ER - TY - JOUR A1 - Mueller, Jonathan Wolf A1 - Vogg, Nora A1 - Lightning, Thomas Alec A1 - Weigand, Isabel A1 - Ronchi, Cristina L A1 - Foster, Paul A A1 - Kroiss, Matthias T1 - Steroid Sulfation in Adrenal Tumors JF - Journal of Clinical Endocrinology & Metabolism N2 - Context The adrenal cortex produces specific steroid hormones including steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid hormone in the human circulation. Steroid sulfation involves a multistep enzyme machinery that may be impaired by inborn errors of steroid metabolism. Emerging data suggest a role of steroid sulfates in the pathophysiology of adrenal tumors and as potential biomarkers. Evidence Acquisition Selective literature search using “steroid,” “sulfat*,” “adrenal,” “transport,” “mass spectrometry” and related terms in different combinations. Evidence Synthesis A recent study highlighted the tissue abundance of estrogen sulfates to be of prognostic impact in adrenocortical carcinoma tissue samples using matrix-assisted laser desorption ionization mass spectrometry imaging. General mechanisms of sulfate uptake, activation, and transfer to substrate steroids are reasonably well understood. Key aspects of this pathway, however, have not been investigated in detail in the adrenal; these include the regulation of substrate specificity and the secretion of sulfated steroids. Both for the adrenal and targeted peripheral tissues, steroid sulfates may have relevant biological actions beyond their cognate nuclear receptors after desulfation. Impaired steroid sulfation such as low DHEAS in Cushing adenomas is of diagnostic utility, but more comprehensive studies are lacking. In bioanalytics, the requirement of deconjugation for gas-chromatography/mass-spectrometry has precluded the study of steroid sulfates for a long time. This limitation may be overcome by liquid chromatography/tandem mass spectrometry. Conclusions A role of steroid sulfation in the pathophysiology of adrenal tumors has been suggested and a diagnostic utility of steroid sulfates as biomarkers is likely. Recent analytical developments may target sulfated steroids specifically. KW - androgens KW - estrogens KW - sex hormones KW - DHEAS KW - DHEA-S KW - steroid disulfate KW - bis-sulfate KW - sulfation KW - sulfurylation KW - sulfonation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371305 VL - 106 ER - TY - JOUR A1 - Müller, Frank A1 - Kleinert, Evelyn A1 - Hillermann, Nele A1 - Simmenroth, Anne A1 - Hummers, Eva A1 - Zychlinsky Scharff, Anna A1 - Dopfer, Christian A1 - Happle, Christine A1 - Jablonka, Alexandra T1 - Disease burden in a large cohort of asylum seekers and refugees in Germany JF - Journal of Global Health N2 - Background: Currently, health care systems worldwide are challenged with providing care to an increasing number of migrants, refugees, and displaced persons. In this article, we report on disease burden and drug prescription patterns in a large refugee cohort in Germany. Methods: We conducted a cross-sectional study of anonymized medical records including demographic data, diagnoses, and drug prescriptions in two refugee reception centres between 2015 and 2019. Refugees and migrants received medical assistance exclusively through the on-site clinics. Thus, this study represents all medical visits of the housed residents. Results: In total, n = 15531 diagnoses from n = 4858 patients in a cohort of n = 10431 accommodated refugees were recorded. N = 11898 medications were prescribed. Overall, 29.8% of all refugees sought medical attention. Half of the patients were female (49.6%), the average age was 23.8 years (SD [standard deviation] 17.0, min 0, max 81), and 41.5% were minors (<18 years). Most patients had Middle Eastern or Northern African origin (63.9%). The largest proportion of diagnoses belonged to the ICD (International Statistical Classification of Diseases and Related Health Problems) category "R" (miscellaneous, 33.5%), followed by diseases of the respiratory system (category "J", 16.5%), or the musculoskeletal system (category "M", 7.1%). Non-steroidal anti-inflammatory drugs were most frequently prescribed. Conclusions: This analysis in two large refugee centres in Germany shows that about one third of refugees seek medical attention upon initial arrival. Complaints are manifold, with a high prevalence of respiratory infections. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371228 VL - 11 ER - TY - JOUR A1 - Müller, Daniel A1 - Schmitz, Patrick W. T1 - The right to quit work: An efficiency rationale for restricting the freedom of contract JF - Journal of Economic Behavior and Organization N2 - A principal hires an agent to provide a verifiable service. Initially, the agent can exert unobservable effort to reduce his disutility from providing the service. If the agent is free to waive his right to quit, he may voluntarily sign a contract specifying an inefficiently large service level, while there are insufficient incentives to exert effort. If the agent’s right to quit is inalienable, the underprovision of effort may be further aggravated, but the service level is ex post efficient. Overall, it turns out that the total surplus can be larger when agents are not permitted to contractually waive their right to quit work. Yet, we also study an extension of our model in which even the agent can be strictly better off when the parties have the contractual freedom to waive the agent’s right to quit. KW - moral hazard KW - incentive theory KW - labor contracts KW - efficiency wages KW - law and economics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371218 VL - 184 ER - TY - JOUR A1 - Müller, Christina A1 - Hassel, Holger T1 - Cooperative planning in childcare centers to improve physical activity: a qualitative investigation of directors’ perspectives JF - Health Promotion International N2 - Interventions to promote physical activity (PA) in childcare centers have been shown to increase children’s PA levels; moreover, a growing number of evidence-based best practice guidelines exist for this setting. However, there is a lack of knowledge on the facilitators of and barriers to the successful implementation of PA guidelines and interventions. We used Cooperative Planning to improve capabilities for PA in childcare centers. This qualitative study aimed to explore childcare center directors’ views on the Cooperative Planning process and identify the facilitators of and barriers to its implementation. We conducted guided semi-structured interviews with the directors of nine childcare centers after completion of the 12-month Cooperative Planning process. The interviews were recorded, transcribed and analyzed using qualitative content analysis with inductive category development. Facilitators and barriers were systematized according to the Consolidated Framework for Implementation Research (CFIR). Cooperative Planning was regarded as being helpful for structuring the process and involving all team members. Several facilitators within the CFIR domains inner setting (structural characteristics, networks and communications, implementation climate), outer setting (support from parents and provider), characteristics of individuals (intrinsic motivation of the staff) and process (individual drivers) were identified. The reported barriers included structural characteristics (e.g. lack of time), networks and communications (e.g. team conflicts) and characteristics of individuals (e.g. lack of willingness to accept change). Several contextual and interpersonal factors seem to influence the extent to which a Cooperative Planning process can be implemented by a childcare center’s team. Future research is needed to evaluate the strategies needed to overcome the identified barriers. KW - childcare KW - cooperative planning KW - physical activity KW - qualitative research methods Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371207 VL - 36(S2) ER - TY - JOUR A1 - Mossink, Britt A1 - van Rhijn, Jon-Ruben A1 - Wang, Shan A1 - Linda, Katrin A1 - Vitale, Maria R. A1 - Zöller, Johanna E. M A1 - van Hugte, Eline J. H. A1 - Bak, Jitske A1 - Verboven, Anouk H. A. A1 - Selten, Martijn A1 - Negwer, Moritz A1 - Latour, Brooke L. A1 - van der Werf, Ilse A1 - Keller, Jason M. A1 - Klein Gunnewiek, Teun M. A1 - Schoenmaker, Chantal A1 - Oudakker, Astrid A1 - Anania, Alessia A1 - Jansen, Sophie A1 - Lesch, Klaus-Peter A1 - Frega, Monica A1 - van Bokhoven, Hans A1 - Schubert, Dirk A1 - Kasri, Nael Nadif T1 - Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks JF - Molecular Psychiatry N2 - Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance. Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371170 VL - 27 ER - TY - JOUR A1 - Morgenstern, Marcel A1 - Peikert, Christian D. A1 - Lübbert, Philipp A1 - Suppanz, Ida A1 - Klemm, Cinzia A1 - Alka, Oliver A1 - Steiert, Conny A1 - Naumenko, Nataliia A1 - Schendzielorz, Alexander A1 - Melchionda, Laura A1 - Mühlhäuser, Wignand W. D. A1 - Knapp, Bettina A1 - Busch, Jakob D. A1 - Stiller, Sebastian B. A1 - Dannenmaier, Stefan A1 - Lindau, Caroline A1 - Licheva, Mariya A1 - Eickhorst, Christopher A1 - Galbusera, Riccardo A1 - Zerbes, Ralf M. A1 - Ryan, Michael T. A1 - Kraft, Claudine A1 - Kozjak-Pavlovic, Vera A1 - Drepper, Friedel A1 - Dennerlein, Sven A1 - Oeljeklaus, Silke A1 - Pfanner, Nikolaus A1 - Wiedemann, Nils A1 - Warscheid, Bettina T1 - Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context JF - Cell Metabolism N2 - Mitochondria are key organelles for cellular energetics, metabolism, signaling, and quality control and have been linked to various diseases. Different views exist on the composition of the human mitochondrial proteome. We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). We identified interactors of translocases, respiratory chain, and ATP synthase assembly factors. The abundance of MitoCoP proteins covers six orders of magnitude and amounts to 7% of the cellular proteome with the chaperones HSP60-HSP10 being the most abundant mitochondrial proteins. MitoCoP dynamics spans three orders of magnitudes, with half-lives from hours to months, and suggests a rapid regulation of biosynthesis and assembly processes. 460 MitoCoP genes are linked to human diseases with a strong prevalence for the central nervous system and metabolism. MitoCoP will provide a high-confidence resource for placing dynamics, functions, and dysfunctions of mitochondria into the cellular context. KW - mitochondria KW - human cells KW - high-confidence proteome KW - smORFs KW - copy numbers KW - half-lives KW - disease KW - complexome KW - protein translocation KW - respiratory chain Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371114 VL - 33 ER - TY - JOUR A1 - Moreno-Yruela, Carlos A1 - Bæk, Michael A1 - Vrsanova, Adela-Eugenie A1 - Schulte, Clemens A1 - Maric, Hans M. A1 - Olsen, Christian A. T1 - Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases JF - Nature Communications N2 - Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone–reader interactions, but not the transient interactions of Zn2+-dependent histone deacetylase (HDAC) eraser enzymes. Here, we synthesize hydroxamic acid-modified histone peptides and use them in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. Follow-up functional assays in solution provide insights into their suitability to discover HDAC substrates and inhibitors with nanomolar potency and activity in cellular assays. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme-selective HDAC inhibitors and probes. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371052 VL - 12 ER - TY - JOUR A1 - Moreno-Velásquez, Sergio D. A1 - Pérez, J. Christian T1 - Imaging and Quantification of mRNA Molecules at Single-Cell Resolution in the Human Fungal Pathogen Candida albicans JF - mSphere N2 - The study of gene expression in fungi has typically relied on measuring transcripts in populations of cells. A major disadvantage of this approach is that the transcripts’ spatial distribution and stochastic variation among individual cells within a clonal population is lost. Traditional fluorescence in situ hybridization techniques have been of limited use in fungi due to poor specificity and high background signal. Here, we report that in situ hybridization chain reaction (HCR), a method that employs split-initiator probes to trigger signal amplification upon mRNA-probe hybridization, is ideally suited for the imaging and quantification of low-abundance transcripts at single-cell resolution in the fungus Candida albicans. We show that HCR allows the absolute quantification of transcripts within a cell by microscopy as well as their relative quantification by flow cytometry. mRNA imaging also revealed the subcellular localization of specific transcripts. Furthermore, we establish that HCR is amenable to multiplexing by visualizing different transcripts in the same cell. Finally, we combine HCR with immunostaining to image specific mRNAs and proteins simultaneously within a single C. albicans cell. The fungus is a major pathogen in humans where it can colonize and invade mucosal surfaces and most internal organs. The technical development that we introduce, therefore, paves the way to study the patterns of expression of pathogenesis-associated C. albicans genes in infected organs at single-cell resolution. KW - hybridization chain reaction KW - FISH KW - Candida albicans KW - mRNA KW - single-cell analysis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370999 VL - 6 ER - TY - JOUR A1 - Moreaux, Céline A1 - Meireles, Desirée A. L. A1 - Sonne, Jesper A1 - Badano, Ernesto I. A1 - Classen, Alice A1 - González-Chaves, Adrian A1 - Hipólito, Juliana A1 - Klein, Alexandra-Maria A1 - Maruyama, Pietro K. A1 - Metzger, Jean Paul A1 - Philpott, Stacy M. A1 - Rahbek, Carsten A1 - Saturni, Fernanda T. A1 - Sritongchuay, Tuanjit A1 - Tscharntke, Teja A1 - Uno, Shinsuke A1 - Vergara, Carlos H. A1 - Viana, Blandina F. A1 - Strange, Niels A1 - Dalsgaard, Bo T1 - The value of biotic pollination and dense forest for fruit set of Arabica coffee: A global assessment JF - Agriculture, Ecosystems & Environment N2 - Animal pollinators are globally threatened by anthropogenic land use change and agricultural intensification. The yield of many food crops is therefore negatively impacted because they benefit from biotic pollination. This is especially the case in the tropics. For instance, fruit set of Coffea arabica has been shown to increase by 10–30% in plantations with a high richness of bee species, possibly influenced by the availability of surrounding forest habitat. Here, we performed a global literature review to (1) assess how much animal pollination enhances coffee fruit set, and to (2) examine the importance of the amount of forest cover, distance to nearby forest and forest canopy density for bee species richness and coffee fruit set. Using a systematic literature review, we identified eleven case studies with a total of 182 samples where fruit set of C. arabica was assessed. We subsequently gathered forest data for all study sites from satellite imagery. We modelled the effects of open (all forest with a canopy density of ≥25%), closed (≥50%) and dense (≥75%) forests on pollinator richness and fruit set of coffee. Overall, we found that animal pollination increases coffee fruit set by ~18% on average. In only one of the case studies, regression results indicate a positive effect of dense forest on coffee fruit set, which increased with higher forest cover and shorter distance to the forest. Against expectations, forest cover and distance to open forest were not related to bee species richness and fruit set. In summary, we provide strong empirical support for the notion that animal pollinators increase coffee fruit set. Forest proximity had little overall influence on bee richness and coffee fruit set, except when farms were surrounded by dense tropical forests, potentially because these may provide high-quality habitats for bees pollinating coffee. We, therefore, advocate that more research is done to understand the biodiversity value of dense forest for pollinators, notably assessing the mechanisms underlying the importance of forest for pollinators and their pollination services. KW - bee richness KW - coffee KW - forest KW - pollination KW - remote sensing KW - systematic literature review Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370982 VL - 323 ER - TY - JOUR A1 - Möhnle, Patrick A1 - Humpe, Andreas A1 - Boeck, Markus A1 - Gruetzner, Stefanie A1 - Hackstein, Holger A1 - Offner, Robert A1 - Hildebrandt, Martin T1 - Emergency Use of Convalescent Plasma: Perception of the Regulatory Framework from a Clinical Perspective JF - Transfusion Medicine and Hemotherapy N2 - The pandemic spread of an infectious disease poses a plethora of challenges to society, clinicians, health care providers and regulating authorities. In order to mount a rapid response and to provide hope in a potentially catastrophic situation as the current COVID-19 pandemic, emergency plans, regulations and funding strategies have to be developed on regional, national and international levels. The speed needed to establish rapid response programs is challenged by the dynamics of the spread of the disease, the concurrent and competing development of different and potentially more effective treatment options, and not the least by regulatory uncertainty. Convalescent plasma, that is plasma collected from patients who have recovered from COVID-19 infections, has emerged as one of the first potential treatment options in the absence of drugs or vaccines with proven efficacy against SARS-CoV-2. The societal aspects of convalescent plasma and the public awareness gave an additional boost to the rapid employment of convalescent plasma donation platforms immediately after the SARS-CoV-2 outbreak. At the same time, uncertainty remains as to the efficacy of convalescent plasma. With evidence mostly limited to empirical reports, convalescent plasma has been used for decades for the prophylaxis and treatment of various infectious diseases. Clinical trials have addressed different infectious agents, stages of disease, target groups of patients and yielded sometimes inconclusive results. The aim of this short review is to delineate the regulatory background for the emergency use of convalescent plasma in the USA, in the European Union and in Germany, and the transition to the setting of clinical trials. In addition, we describe observations made in the process of collecting COVID-19 convalescent plasma (herein referred to as CCP), and formulate proposals to further improve the framework for rapid responses in future emergency situations. KW - convalescent plasma KW - regulation KW - pandemic KW - clinical use Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311314 VL - 49 ER - TY - JOUR A1 - Möller, Hans-Jürgen A1 - Volz, Hans-Peter A1 - Seifritz, Erich A1 - Müller, Heiko A1 - Kenntner-Mabiala, Ramona A1 - Kaussner, Yvonne A1 - Schoch, Stefanie A1 - Kasper, Siegfried T1 - Silexan does not affect driving performance after single and multiple dose applications: Results from a double-blind, placebo and reference-controlled study in healthy volunteers JF - Journal of Psychiatric Research N2 - Anxiolytic drugs often have sedative effects that impair the ability to drive. Our double-blind, randomized crossover trial investigated the effect of Silexan, a non-sedating, anxiolytic herbal medicinal product, on driving performance in healthy volunteers. Part 1 aimed at demonstrating equivalence between 80 mg/d Silexan and placebo. Part 2 was performed to demonstrate superiority of 160 and 320 mg Silexan over 1 mg lorazepam and included a placebo arm for assay sensitivity. Driving performance was assessed in a validated, alcohol-calibrated simulator test. The primary outcome was the standard deviation of the lane position (SDLP). Secondary outcomes included driving errors and sleepiness. Fifty and 25 subjects were randomized in Parts 1 and 2, respectively. In Part 1, Silexan 80 mg was confirmed to be equivalent to placebo after single administration (equivalence range: δ = ±2 cm). The 95% confidence interval (CI) for the SDLP marginal mean value difference Silexan–placebo for single administration was −1.43; +1.38 and thus similar to the 95% CI of −1.45; +0.79 cm for 7 days’ multiple dosing. In Part 2, 95% CIs for SDLP marginal mean value differences to lorazepam were −8.58; −5.42 cm for Silexan 160 mg and −8.65; −5.45 cm for 320 mg (p < 0.001). Confirmatory results were supported by secondary outcomes, where results for Silexan were comparable to placebo and more favorable than for lorazepam. The study demonstrates that single doses of up to 320 mg Silexan and multiple doses of 80 mg/d have no adverse effect on driving performance. KW - Silexan KW - anxiolytic drug driving performance KW - sedation KW - clinical trial Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370908 VL - 136 ER - TY - JOUR A1 - Miyazaki, Mitsuhiko A1 - Kamiya, Tairiku A1 - Wohlgemuth, Matthias A1 - Chatterjee, Kuntal A1 - Mitrić, Roland A1 - Dopfer, Otto A1 - Fujii, Masaaki T1 - Real-time observation of photoionization-induced water migration dynamics in 4-methylformanilide–water by picosecond time-resolved infrared spectroscopy and ab initio molecular dynamics simulations JF - Physical Chemistry Chemical Physics N2 - A novel time-resolved pump–probe spectroscopic approach that enables to keep high resolution in both the time and energy domain, nanosecond excitation–picosecond ionization–picosecond infrared probe (ns–ps–ps TRIR) spectroscopy, has been applied to the trans-4-methylformanilide–water (4MetFA–W) cluster. Water migration dynamics from the CO to the NH binding site in a peptide linkage triggered by photoionization of 4MetFA–W is directly monitored by the ps time evolution of IR spectra, and the presence of an intermediate state is revealed. The time evolution is analyzed by rate equations based on a four-state model of the migration dynamics. Time constants for the initial to the intermediate and hot product and to the final product are obtained. The acceleration of the dynamics by methyl substitution and the strong contribution of intracluster vibrational energy redistribution in the termination of the solvation dynamics is suggested. This picture is well confirmed by the ab initio on-the-fly molecular dynamics simulations. Vibrational assignments of 4MetFA and 4MetFA–W in the neutral (S0 and S1) and ionic (D0) electronic states measured by ns IR dip and electron-impact IR photodissociation spectroscopy are also discussed prior to the results of time-resolved spectroscopy. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370868 VL - 24 ER - TY - JOUR A1 - Ming, Damien K. A1 - Myall, Ashleigh C. A1 - Hernandez, Bernard A1 - Weiße, Andrea Y. A1 - Peach, Robert L. A1 - Barahona, Mauricio A1 - Rawson, Timothy M. A1 - Holmes, Alison H. T1 - Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin JF - BMC Infectious Diseases N2 - Background To characterise the longitudinal dynamics of C-reactive protein (CRP) and Procalcitonin (PCT) in a cohort of hospitalised patients with COVID-19 and support antimicrobial decision-making. Methods Longitudinal CRP and PCT concentrations and trajectories of 237 hospitalised patients with COVID-19 were modelled. The dataset comprised of 2,021 data points for CRP and 284 points for PCT. Pairwise comparisons were performed between: (i) those with or without significant bacterial growth from cultures, and (ii) those who survived or died in hospital. Results CRP concentrations were higher over time in COVID-19 patients with positive microbiology (day 9: 236 vs 123 mg/L, p < 0.0001) and in those who died (day 8: 226 vs 152 mg/L, p < 0.0001) but only after day 7 of COVID-related symptom onset. Failure for CRP to reduce in the first week of hospital admission was associated with significantly higher odds of death. PCT concentrations were higher in patients with COVID-19 and positive microbiology or in those who died, although these differences were not statistically significant. Conclusions Both the absolute CRP concentration and the trajectory during the first week of hospital admission are important factors predicting microbiology culture positivity and outcome in patients hospitalised with COVID-19. Further work is needed to describe the role of PCT for co-infection. Understanding relationships of these biomarkers can support development of risk models and inform optimal antimicrobial strategies. KW - bacterial co-infection KW - COVID-19 KW - biomarkers KW - antimicrobial stewardship KW - risk stratification KW - clinical decision-support Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370797 VL - 21 ER - TY - JOUR A1 - Milić, Mirta A1 - Ceppi, Marcello A1 - Bruzzone, Marco A1 - Azqueta, Amaya A1 - Brunborg, Gunnar A1 - Godschalk, Roger A1 - Koppen, Gudrun A1 - Langie, Sabine A1 - Møller, Peter A1 - Teixeira, João Paulo A1 - Alija, Avdulla A1 - Anderson, Diana A1 - Andrade, Vanessa A1 - Andreoli, Cristina A1 - Asllani, Fisnik A1 - Bangkoglu, Ezgi Eyluel A1 - Barančoková, Magdalena A1 - Basaran, Nursen A1 - Boutet-Robinet, Elisa A1 - Buschini, Annamaria A1 - Cavallo, Delia A1 - Costa Pereira, Cristiana A1 - Costa, Carla A1 - Costa, Solange A1 - Da Silva, Juliana A1 - Del Boˊ, Cristian A1 - Dimitrijević Srećković, Vesna A1 - Djelić, Ninoslav A1 - Dobrzyńska, Malgorzata A1 - Duračková, Zdenka A1 - Dvořáková, Monika A1 - Gajski, Goran A1 - Galati, Serena A1 - García Lima, Omar A1 - Giovannelli, Lisa A1 - Goroshinskaya, Irina A. A1 - Grindel, Annemarie A1 - Gutzkow, Kristine B. A1 - Hernández, Alba A1 - Hernández, Carlos A1 - Holven, Kirsten B. A1 - Ibero-Baraibar, Idoia A1 - Ottestad, Inger A1 - Kadioglu, Ela A1 - Kažimirová, Alena A1 - Kuznetsova, Elena A1 - Ladeira, Carina A1 - Laffon, Blanca A1 - Lamonaca, Palma A1 - Lebailly, Pierre A1 - Louro, Henriqueta A1 - Mandina Cardoso, Tania A1 - Marcon, Francesca A1 - Marcos, Ricard A1 - Moretti, Massimo A1 - Moretti, Silvia A1 - Najafzadeh, Mojgan A1 - Nemeth, Zsuzsanna A1 - Neri, Monica A1 - Novotna, Bozena A1 - Orlow, Irene A1 - Paduchova, Zuzana A1 - Pastor, Susana A1 - Perdry, Hervé A1 - Spremo-Potparević, Biljana A1 - Ramadhani, Dwi A1 - Riso, Patrizia A1 - Rohr, Paula A1 - Rojas, Emilio A1 - Rossner, Pavel A1 - Safar, Anna A1 - Sardas, Semra A1 - Silva, Maria João A1 - Sirota, Nikolay A1 - Smolkova, Bozena A1 - Staruchova, Marta A1 - Stetina, Rudolf A1 - Stopper, Helga A1 - Surikova, Ekaterina I. A1 - Ulven, Stine M. A1 - Ursini, Cinzia Lucia A1 - Valdiglesias, Vanessa A1 - Valverde, Mahara A1 - Vodicka, Pavel A1 - Volkovova, Katarina A1 - Wagner, Karl-Heinz A1 - Živković, Lada A1 - Dušinská, Maria A1 - Collins, Andrew R. A1 - Bonassi, Stefano T1 - The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders JF - Mutation Research/Reviews in Mutation Research N2 - The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations. KW - comet assay KW - DNA damage KW - pooled analysis KW - human biomonitoring KW - biomarkers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371614 VL - 787 ER - TY - JOUR A1 - Michelen, Melina A1 - Manoharan, Lakshmi A1 - Elkheir, Natalie A1 - Cheng, Vincent A1 - Dagens, Andrew A1 - Hastie, Claire A1 - O'Hara, Margaret A1 - Suett, Jake A1 - Dahmash, Dania A1 - Bugaeva, Polina A1 - Rigby, Ishmeala A1 - Munblit, Daniel A1 - Harriss, Eli A1 - Burls, Amanda A1 - Foote, Carole A1 - Scott, Janet A1 - Carson, Gail A1 - Olliaro, Piero A1 - Sigfrid, Louise A1 - Stavropoulou, Charitini T1 - Characterising long COVID: a living systematic review JF - BMJ Global Health N2 - Background While it is now apparent clinical sequelae (long COVID) may persist after acute COVID-19, their nature, frequency and aetiology are poorly characterised. This study aims to regularly synthesise evidence on long COVID characteristics, to help inform clinical management, rehabilitation strategies and interventional studies to improve long-term outcomes. Methods A living systematic review. Medline, CINAHL (EBSCO), Global Health (Ovid), WHO Global Research on COVID-19 database, LitCovid and Google Scholar were searched till 17 March 2021. Studies including at least 100 people with confirmed or clinically suspected COVID-19 at 12 weeks or more post onset were included. Risk of bias was assessed using the tool produced by Hoy et al. Results were analysed using descriptive statistics and meta-analyses to estimate prevalence. Results A total of 39 studies were included: 32 cohort, 6 cross-sectional and 1 case–control. Most showed high or moderate risk of bias. None were set in low-income countries and few included children. Studies reported on 10 951 people (48% female) in 12 countries. Most included previously hospitalised people (78%, 8520/10 951). The longest mean follow-up time was 221.7 (SD: 10.9) days post COVID-19 onset. Over 60 physical and psychological signs and symptoms with wide prevalence were reported, most commonly weakness (41%; 95% CI 25% to 59%), general malaise (33%; 95% CI 15% to 57%), fatigue (31%; 95% CI 24% to 39%), concentration impairment (26%; 95% CI 21% to 32%) and breathlessness (25%; 95% CI 18% to 34%). 37% (95% CI 18% to 60%) of patients reported reduced quality of life; 26% (10/39) of studies presented evidence of reduced pulmonary function. Conclusion Long COVID is a complex condition with prolonged heterogeneous symptoms. The nature of studies precludes a precise case definition or risk evaluation. There is an urgent need for prospective, robust, standardised, controlled studies into aetiology, risk factors and biomarkers to characterise long COVID in different at-risk populations and settings. PROSPERO registration number CRD42020211131. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370762 VL - 6 ER - TY - JOUR A1 - Meyer, Axel A1 - Schloissnig, Siegfried A1 - Franchini, Paolo A1 - Du, Kang A1 - Woltering, Joost M. A1 - Irisarri, Iker A1 - Wong, Wai Yee A1 - Nowoshilow, Sergej A1 - Kneitz, Susanne A1 - Kawaguchi, Akane A1 - Fabrizius, Andrej A1 - Xiong, Peiwen A1 - Dechaud, Corentin A1 - Spaink, Herman P. A1 - Volff, Jean-Nicolas A1 - Simakov, Oleg A1 - Burmester, Thorsten A1 - Tanaka, Elly M. A1 - Schartl, Manfred T1 - Giant lungfish genome elucidates the conquest of land by vertebrates JF - Nature N2 - Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, ‘conquered’ the land and ultimately gave rise to all land vertebrates, including humans1,2,3. Here we determine the chromosome-quality genome of the Australian lungfish (Neoceratodus forsteri), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14× larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods4,5, underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370750 VL - 590 ER - TY - JOUR A1 - Mertens, Griet A1 - Hofkens, Anouk A1 - Van de Heyning, Paul A1 - Van Rompaey, Vincent A1 - Boudewyns, An A1 - Di Gregorio, Maria Fernanda A1 - Eikelboom, Robert H. A1 - Marino, Roberta A1 - Kurz, Anja A1 - Kühn, Heike A1 - Shehata-Dieler, Wafaa A1 - Lorens, Artur A1 - Pulibalathingal, Sasidharan A1 - Rajeswaran, Ranjith A1 - Tavora-Vieira, Dayse A1 - Bellekom, Sandra R. A1 - Topsakal, Vedat T1 - Minimal outcome measurements in pediatric cochlear implant users: a consensus paper JF - B-ENT N2 - The benefits of cochlear implantation in children with severe hearing impairments are widely known; however, there is no consensus regarding which minimal outcome measurements (MOMs) should be used to determine outcomes in this population with pediatric cochlear implant (CI). Therefore, the authors aim to propose a MOM test battery for pediatric CI recipients that can facilitate international multi-center research and collaboration. A pediatric MOM test battery was developed and agreed-upon by members of the HEARRING group across 30 expert clinics in the field of hearing implantation. The MOM test battery was chosen based on a literature search that focused on outcome measurements applied in clinical trials involving children with a hearing implant. Members of the HEARRING group were then asked to evaluate each of the pediatric MOM tests used. The final pediatric MOM test battery was defined for different chronological age categories (six weeks–18 years) at different suggested test intervals. The test battery includes objective hearing measurements, aided and unaided audiometry, speech perception tests in quiet and in noise, subjective hearing assessments, assessment of language development, and mental and motor development. This study presents a consensus on a MOM test battery for pediatric CI recipients that was agreed upon by members of the HEARRING group. This test battery should allow for international multi-center research to be able to extend and share evidence that will guide future clinical practice and research efforts in pediatric populations with CI. KW - paediatric cochlear implant recipients KW - cochlear implantation KW - minimal outcomes measurements KW - testing framework KW - standardization Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370700 VL - 17 ER - TY - JOUR A1 - Melfsen, Siebke A1 - Romanos, Marcel A1 - Jans, Thomas A1 - Walitza, Susanne T1 - Betrayed by the nervous system: a comparison group study to investigate the ‘unsafe world’ model of selective mutism JF - Journal of Neural Transmission N2 - The study presented in the following verifies some assumptions of the novel ‘unsafe world’ model of selective mutism (SM). According to this model, SM is a stress reaction to situations erroneously experienced via cognition without awareness as ‘unsafe’. It assumes a high sensitivity to unsafety, whereby the nervous system triggers dissociation or freeze mode at relatively low thresholds. We examine whether there is a correlation between SM, sensory-processing sensitivity and dissociation. We compared a sample of 28 children and adolescents with SM (mean age 12.66 years; 18 females) to 33 controls without SM (mean age 12.45 years; 21 females). Both groups were compared using a medical history sheet, the ‘Selective Mutism Questionnaire’ (SMQ), a ‘Checklist for Speaking Behaviour’ (CheckS), the ‘Highly Sensitive Person Scale’ (HSPS), the ‘Child Dissociative Checklist’ (CDC), the ‘Adolescent Dissociative Experience Scale’ (A-DES) and the ‘Social Phobia and Anxiety Inventory for Children’ (SPAIK). Appropriate parametric and non-parametric tests were conducted to examine differences between groups. The results indicate that sensory-processing sensitivity was significantly higher in the group of children and adolescents with SM [X2(1) = 7.224, p = 0.0007; d = 1.092]. Furthermore, dissociative symptoms were more common in children and adolescents with SM than in controls [F(1, 33) = 13.004, p = 0.001; d = 0.986]. The results indicate that sensory-processing sensitivity and dissociation are important factors of SM that may hold important implications for the treatment. KW - selective mutism KW - aetiology KW - high sensory-processing sensitivity KW - dissociation KW - anxiety KW - schoolchildren Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370681 VL - 128 ER - TY - JOUR T1 - Search for heavy long-lived multicharged particles in proton-proton collisions at √\(s\)=13 TeV using the ATLAS detector JF - Physical Review D N2 - A search for heavy long-lived multicharged particles is performed using the ATLAS detector at the LHC. Data with an integrated luminosity of 36.1 fb(-1) collected in 2015 and 2016 from proton-proton collisions at root s = 13 TeV are examined. Particles producing anomalously high ionization, consistent with long-lived massive particles with electric charges from vertical bar q vertical bar = 2e to vertical bar q vertical bar = 7e, are searched for. No events are observed, and 95% confidence level cross-section upper limits are interpreted as lower mass limits for a Drell-Yan production model. Multicharged particles with masses between 50 and 980-1220 GeV (depending on their electric charge) are excluded. KW - Symmetry KW - Matter KW - Extensions of fermion sector Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-314061 VL - 99 IS - 5 ER - TY - JOUR A1 - Mansour, Ahmed M. A1 - Soliman, Fatma A. A1 - Shehab, Ola R. A1 - Abdel-Ghani, Nour T. T1 - Photodegradation of sulfadiazine catalyzed by p-benzoquinones and picric acid: application to charge transfer complexes JF - RSC Advances N2 - As the treatment of effluents containing the antibiotic drug sulfadiazine (SZ) is one of the challenging problems in the field of environmental chemistry, it is essential to determine the concentration of SZ by a rapid and accurate method and then find a suitable method to degrade the assayed products into harmless chemicals. The color of the charge transfer (CT) complexes developed from the reaction of SZ with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), chloranilic acid (CHL) and picric acid (PA) was used to determine the concentration of SZ at 528, 510 and 410 nm, respectively. The Lambert–Beer's law is obeyed in the ranges of 6.80–68.06, 13.61–136.12 and 6.80–27.22 μg mL\(^{−1}\) for DDQ, CHL and PA complexes. The photolysis of SZ → DDQ in presence of sodium nitrite at 256 nm leads to faster degradation of SZ compared with the control experiments. This was simply spectrophotometrically followed by a decrease in the intensity of the CT band. The effect of some additives such as oxalic acid, and hematite nano particles was studied. For comparison, other π-acceptor reagents such as CHL and PA were used. About 80% of SZ is degraded in 45 min upon the illumination of SZ → DDQ at 256 nm, whereas 90 min is required in the case of CHL and PA to attain the same degradation limit. KW - antibiotic drug sulfadiazine (SZ) KW - environmental chemistry KW - effluents Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181507 VL - 7 IS - 63 ER - TY - JOUR A1 - Sharma, Piyush A1 - Khairnar, Vishal A1 - Madunic, Ivana Vrhovac A1 - Singh, Yogesh A1 - Pandyra, Aleksandra A1 - Salker, Madhuri S. A1 - Koepsell, Hermann A1 - Sabolic, Ivan A1 - Lang, Florian A1 - Lang, Pilipp A. A1 - Lang, Karl S. T1 - SGLT1 deficiency turns listeria infection into a lethal disease in mice JF - Cellular Physiology and Biochemistry N2 - Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na\(^+\)-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose oncentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x10\(^4\) CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1\(^{–/–}\) mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection. KW - glucose uptake KW - Na+-coupled glucose transport KW - Listeria infection KW - TNF-α and IL-12a KW - survival KW - liver KW - spleen KW - kidney KW - lung KW - bacterial clearance Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181496 VL - 42 IS - 4 ER - TY - JOUR A1 - Ma, Jie A1 - Gulbins, Erich A1 - Edwards, Michael J. A1 - Caldwell, Charles C. A1 - Fraunholz, Martin A1 - Becker, Katrin Anne T1 - Staphylococcus aureus α-toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides JF - Cellular Physiology and Biochemistry N2 - Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines. KW - Staphylococcus aureus KW - sphingomyelinase KW - ceramide KW - toxins KW - macrophages KW - cytokines Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181481 VL - 43 IS - 6 ER - TY - JOUR A1 - Wang, Yiwen A1 - Zhang, Zhen A1 - Bai, Liying A1 - Lin, Chongde A1 - Osinsky, Roman A1 - Hewig, Johannes T1 - Ingroup/outgroup membership modulates fairness consideration: neural signatures from ERPs and EEG oscillations JF - Scientific Reports N2 - Previous studies have shown that ingroup/outgroup membership influences individual’s fairness considerations. However, it is not clear yet how group membership influences brain activity when a recipient evaluates the fairness of asset distribution. In this study, subjects participated as recipients in an Ultimatum Game with alleged members of both an experimentally induced ingroup and outgroup. They either received extremely unequal, moderately unequal, or equal offers from proposers while electroencephalogram was recorded. Behavioral results showed that the acceptance rates for unequal offers were higher when interacting with ingroup partners than with outgroup partners. Analyses of event related potentials revealed that proposers’ group membership modulated offer evaluation at earlier processing stages. Feedback-related negativity was more negative for extremely and moderately unequal offers compared to equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Analyses of event related oscillations revealed that the theta power (4–6 Hz) was larger for moderately unequal offers than equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Thus, early mechanisms of fairness evaluation are strongly modulated by the ingroup/outgroup membership of the interaction partner. KW - psychology KW - group membership KW - brain activity KW - asset distribution Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181461 VL - 7 ER - TY - JOUR A1 - Scheunert, Gunther A1 - Cohen, Sidney R. A1 - Kullock, René A1 - McCarron, Ryan A1 - Rechev, Katya A1 - Kaplan-Ashiri, Ifat A1 - Bitton, Ora A1 - Dawson, Paul A1 - Hecht, Bert A1 - Oron, Dan T1 - Grazing-incidence optical magnetic recording with super-resolution JF - Beilstein Journal of Nanotechnology N2 - Heat-assisted magnetic recording (HAMR) is often considered the next major step in the storage industry: it is predicted to increase the storage capacity, the read/write speed and the data lifetime of future hard disk drives. However, despite more than a decade of development work, the reliability is still a prime concern. Featuring an inherently fragile surface-plasmon resonator as a highly localized heat source, as part of a near-field transducer (NFT), the current industry concepts still fail to deliver drives with sufficient lifetime. This study presents a method to aid conventional NFT-designs by additional grazing-incidence laser illumination, which may open an alternative route to high-durability HAMR. Magnetic switching is demonstrated on consumer-grade CoCrPt perpendicular magnetic recording media using a green and a near-infrared diode laser. Sub-500 nm magnetic features are written in the absence of a NFT in a moderate bias field of only μ0H = 0.3 T with individual laser pulses of 40 mW power and 50 ns duration with a laser spot size of 3 μm (short axis) at the sample surface – six times larger than the magnetic features. Herein, the presence of a nanoscopic object, i.e., the tip of an atomic force microscope in the focus of the laser at the sample surface, has no impact on the recorded magnetic features – thus suggesting full compatibility with NFT-HAMR. KW - laser absorption KW - laser heating KW - thermally assisted magnetic recording Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181457 VL - 8 ER - TY - JOUR A1 - Szklarczyk, Damian A1 - Morris, John H. A1 - Cook, Helen A1 - Kuhn, Michael A1 - Wyder, Stefan A1 - Simonovic, Milan A1 - Santos, Aalberto A1 - Doncheva, Nadezhda T. A1 - Roth, Alexander A1 - Bork, Peer A1 - Jensen, Lars J. A1 - von Mering, Christian T1 - The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible JF - Nucleic Acids Research N2 - A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein–protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein–protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/. KW - string database KW - quality control KW - proteins KW - cellular function Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181445 VL - 45 IS - D1 ER - TY - JOUR A1 - Rhee, Jae-Sung A1 - Choi, Beom-Soon A1 - Kim, Jaebum A1 - Kim, Bo-Mi A1 - Lee, Young-Mi A1 - Kim, Il-Chan A1 - Kanamori, Akira A1 - Choi, Ik-Young A1 - Schartl, Manfred A1 - Lee, Jae-Seong T1 - Diversity, distribution, and significance of transposable elements in the genome of the only selfing hermaphroditic vertebrate Kryptolebias marmoratus JF - Scientific Reports N2 - The Kryptolebias marmoratus is unique because it is the only selffertilizing hermaphroditic vertebrate, known to date. It primarily reproduces by internal self-fertilization in a mixed ovary/testis gonad. Here, we report on a high-quality genome assembly for the K. marmoratus South Korea (SK) strain highlighting the diversity and distribution of transposable elements (TEs). We find that K. marmoratus genome maintains number and composition of TEs. This can be an important genomic attribute promoting genome recombination in this selfing fish, while, in addition to a mixed mating strategy, it may also represent a mechanism contributing to the evolutionary adaptation to ecological pressure of the species. Future work should help clarify this point further once genomic information is gathered for other taxa of the family Rivulidae that do not self-fertilize. We provide a valuable genome resource that highlights the potential impact of TEs on the genome evolution of a fish species with an uncommon life cycle. KW - ecological genetics KW - evolutionary genetics KW - ichthyology KW - Kryptolebias marmoratus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181329 VL - 7 ER - TY - THES A1 - Reichelt, Niklas T1 - Exploring the natural variation of heat-dependent metabolic rearrangements in \(Arabidopsis\) \(thaliana\) to identify genes involved in thermotolerance T1 - Untersuchung der natürlichen Variation des hitzeregulierten Metaboloms in \(Arabidopsis\) \(thaliana\), um Gene der pflanzlichen Thermotoleranz zu identifizieren N2 - Climate change and associated extreme weather events are a threat not only for agricultural yields but the plant kingdom in general. Therefore, there is a great necessity to better understand the plants' intrinsic mechanisms to combat heat stress. The plant heat stress response already has been investigated in many studies, including the role of HSFA1 transcription factors as the central regulators. Other aspects such as the initial perception of heat and the role of heat-induced changes in plant metabolism are rather unknown. In this thesis, the natural variation of 250 different accessions of Arabidopsis thaliana was investigated regarding the temperature-dependent accumulation of raffinose and triacylglycerols. A connection between these phenotypes and respective genotypes was established using genome-wide association studies. As a result, the candidate gene TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1), was identified. Enzymatic TPS1 is responsible for the synthesis of trehalose 6-phosphate (T6P), which serves as an indicator and regulator of sucrose homeostasis. Subsequent analyses using tps1 tilling mutants demonstrated a link between T6P metabolism and an increased accumulation of various soluble carbohydrates and starch, including raffinose both under control conditions and during heat exposure. Furthermore, the mutant lines displayed enhanced thermotolerance and survival rates following long-term heat stress. Transcriptome analyses, however, did not show any difference in the regulation of canonical heat stress-associated genes. Instead, genes related to photosynthesis were overrepresented among the differentially upregulated genes in tps1 tilling lines during heat exposure. In this work, a direct connection of T6P signaling, sucrose homeostasis, and thermotolerance is shown for the first time. In a second project, two Arabidopsis thaliana accessions (Oberursel-0, accession ID: 7276; Nieps-0, accession ID: 7268) showing distinct capacities to acquire short-term thermotolerance were compared to identify the putative causative regulators or mechanisms that lead to the different levels of thermotolerance. An examination of the transcriptomes of 7268 and 7276 showed that several hundreds of genes were already differentially regulated within 10 minutes of exposure to 32 °C or 34 °C. Among these, several genes associated with sulfur metabolism were more highly induced in the more thermotolerant accession 7268. However, experimental as well as genetic manipulation of sulfur availability and metabolism did not result in altered thermotolerance. In addition to sulfur-related genes, most of the canonical heat stress-associated genes were more highly expressed in 7268 than in 7276. While we could not identify a causative regulator or mechanism of differential thermotolerances, the data strongly suggests that 7268 either has a higher overall sensitivity, i.e., the heat stress response is initiated at lower temperatures, or stronger overall heat stress response when exposed to a certain elevated temperature. N2 - Der Klimawandel und die damit einhergehenden extremen Wetterereignisse stellen eine große Bedrohung für den Ertrag der Landwirtschaft aber auch das Reich der Pflanzen im Allgemeinen dar. Es ist daher von großer Notwendigkeit, die der Pflanzen intrinsischen Mechanismen zur Bekämpfung von Hitzestress besser zu verstehen. Die hierbei zugrundeliegende Hitzestressantwort der Pflanzen ist bereits durch viele Studien untersucht worden, unter anderem die Rolle von HSFA1 Transkriptionsfaktoren als zentrale Regulatoren. Andere Aspekte wie die initiale Wahrnehmung von Hitze sowie die Rolle von hitzeinduzierten Veränderungen des Pflanzenmetabolismus sind eher unbekannt. In dieser Thesis wurde die natürliche Variation von 250 Populationen von Arabidopsis thaliana hinsichtlich der temperatur-abhängigen Akkumulation von Raffinose und Triacylglycerolen untersucht. Ein statistischer Zusammenhang dieser Phänotypen sowie zugrundeliegender Genotypen wurde mittels Genomweiter Assoziationsstudien erstellt. Als Ergebnis konnte das Kandidatengen Trehalose-6-Phosphate Synthase 1 (TPS1) identifiziert werden. Das Enzym TPS1 ist verantwortlich für die Synthese von T6P, welches als Indikator sowie Regulator der Homöostase von Saccharose fungiert. Folgestudien an tps1 tilling lines konnten sowohl unter Kontrollbedingungen als auch bei Hitzestress einen Zusammenhang zwischen dem T6P Metabolismus und einer erhöhten Akkumulation von Raffinose, weiterer löslicher Zucker, sowie Stärke nachweisen. Des Weiteren zeigten die tps1 tilling lines eine erhöhte Thermotoleranz und Überlebensrate gegenüber Langzeit-Hitzestress. Eine Analyse der Transkriptome zeigte keinen Unterschied in der Regulation klassischer Hitzestress-assoziierter Gene. In beiden tps1 tilling lines war in Folge von Hitzestress eine Überrepräsentation von signifikant hochregulierten Genen vorzufinden, welche mit der Photosynthese der Pflanze assoziiert sind. In dieser Arbeit konnte erstmalig ein direkter Zusammenhang von T6P Signaling, Zucker-Homöostase und Thermotoleranz gezeigt werden. In einem zweiten Projekt wurden zwei Arabidopsis thaliana Populationen (Oberursel-0, Populations-ID: 7276; Nieps-0, Populations-ID: 7268) verglichen, welche deutliche Unterschiede in ihrer Fähigkeit der kurzzeitig akquirierten Thermotoleranz aufweisen. Ziel war hierbei die Identifikation etwaiger kausaler Regulatoren oder Mechanismen, welche zu den unterschiedlich ausgeprägten Thermotoleranzen führen. Eine Untersuchung der Transkriptome von 7268 und 7276 konnte zeigen, dass bereits nach 10 Minuten einer 32 °C oder auch 37 °C Hitzebehandlung hunderte von Genen differentiell reguliert sind. Hierbei waren in der hitzetoleranteren Population 7268 mehrere Gene, welche mit dem Schwefel-Metabolismus assoziiert sind, im Vergleich zu 7276 höher exprimiert. Jedoch hatten sowohl die experimentelle Schwefelverfügbarkeit als auch die genetische Manipulation des Schwefelmetabolismus keinen Effekt auf die Thermotoleranz. Neben den Schwefel-assoziierten Genen waren auch die meisten der klassischen Hitzestress-assoziierten Gene in 7268 höher exprimiert als in 7276. Zwar konnte kein kausaler Regulator oder Mechanismus für die unterschiedlichen Thermotoleranzen identifiziert werden, jedoch weisen die generierten Daten auf eine allgemein stärkere Hitzestressantwort oder aber eine höhere Hitzesensitivität von 7268 gegenüber 7276 hin. KW - Schmalwand KW - Hitzestress KW - Stärke KW - Raffinose KW - Genomweite-Assoziationsstudien KW - Genome-wide association studies KW - RNA-Seq KW - Natürliche Variation KW - Natural Variation KW - Trehalose-6-Phosphate Synthase 1 (TPS1) KW - Triacylglycerole Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371324 ER - TY - JOUR A1 - Megy, Karyn A1 - Downes, Kate A1 - Morel-Kopp, Marie-Christine A1 - Bastida, José M. A1 - Brooks, Shannon A1 - Bury, Loredana A1 - Leinoe, Eva A1 - Gomez, Keith A1 - Morgan, Neil V. A1 - Othman, Maha A1 - Ouwehand, Willem H. A1 - Perez Botero, Juliana A1 - Rivera, José A1 - Schulze, Harald A1 - Trégouët, David-Alexandre A1 - Freson, Kathleen T1 - GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis JF - Journal of Thrombosis and Haemostasis N2 - The implementation of high‐throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease‐causing variants associated with specific genes, but for BTPD, such well‐curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap‐based interface, aimed at the community, to submit curated genetic variants for diagnostic‐grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open‐access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar. KW - blood KW - genes KW - hemorrhage KW - mutation KW - platelets KW - thrombosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370602 VL - 19 ER - TY - JOUR A1 - Maynard, Stephanie A A1 - Rostaing, Philippe A1 - Schaefer, Natascha A1 - Gemin, Olivier A1 - Candat, Adrien A1 - Dumoulin, Andréa A1 - Villmann, Carmen A1 - Triller, Antoine A1 - Specht, Christian G T1 - Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses JF - eLife N2 - Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370504 VL - 10 ER - TY - JOUR A1 - Maulana, Tengku Ibrahim A1 - Kromidas, Elena A1 - Wallstabe, Lars A1 - Cipriano, Madalena A1 - Alb, Miriam A1 - Zaupa, Cécile A1 - Hudecek, Michael A1 - Fogal, Birgit A1 - Loskill, Peter T1 - Immunocompetent cancer-on-chip models to assess immuno-oncology therapy JF - Advanced Drug Delivery Reviews N2 - The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines. KW - tumor-on-chip KW - microphysiological systems KW - immunotherapy KW - in vitro models KW - adoptive cell therapy KW - immune checkpoint inhibitor KW - cytokine therapy KW - oncolytic viruses KW - cancer vaccine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370493 VL - 173 ER - TY - JOUR A1 - Mateos, Maria-Victoria A1 - Dimopoulos, Meletios A. A1 - Cavo, Michele A1 - Suzuki, Kenshi A1 - Knop, Stefan A1 - Doyen, Chantal A1 - Lucio, Paulo A1 - Nagy, Zsolt A1 - Pour, Ludek A1 - Grosicki, Sebastian A1 - Crepaldi, Andre A1 - Liberati, Anna Marina A1 - Campbell, Philip A1 - Yoon, Sung-Soo A1 - Iosava, Genadi A1 - Fujisaki, Tomoaki A1 - Garg, Mamta A1 - Iida, Shinsuke A1 - Bladé, Joan A1 - Ukropec, Jon A1 - Pei, Huiling A1 - Van Rampelbergh, Rian A1 - Kudva, Anupa A1 - Qi, Ming A1 - San-Miguel, Jesus T1 - Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Background In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients. Results Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). Conclusion Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status. KW - CD38 KW - clinical study KW - efficacy KW - frail KW - monoclonal antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370456 VL - 21 ER - TY - JOUR A1 - Matarranz, Beatriz A1 - Ghosh, Goutam A1 - Kandanelli, Ramesh A1 - Sampedro, Angel A1 - Kartha, Kalathil K. A1 - Fernández, Gustavo T1 - Understanding the role of conjugation length on the self-assembly behaviour of oligophenyleneethynylenes JF - Chemical Communications N2 - Oligophenyleneethynylenes (OPEs) are prominent building blocks with exciting optical and supramolecular properties. However, their generally small spectroscopic changes upon aggregation make the analysis of their self-assembly challenging, especially in the absence of additional hydrogen bonds. Herein, by investigating a series of OPEs of increasing size, we have unravelled the role of the conjugation length on the self-assembly properties of OPEs. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370444 VL - 57 ER - TY - JOUR A1 - Masias, J. A1 - Cerna-Velazco, N. A1 - Jones-Pérez, J. A1 - Porod, W. T1 - Resolving a challenging supersymmetric low-scale seesaw scenario at the ILC JF - Physical Review D N2 - We investigate a scenario inspired by natural supersymmetry, where neutrino data is explained within a low-scale seesaw scenario. For this the minimal supersymmetric Standard Model is extended by adding light right-handed neutrinos and their superpartners, the R-sneutrinos. Moreover, we consider the lightest neutralinos to be Higgsino-like. We first update a previous analysis and assess to which extent does existing LHC data constrain the allowed slepton masses. Here we find scenarios where sleptons with masses as low as 175 GeV are consistent with existing data. However, we also show that the upcoming run will either discover or rule out sleptons with masses of 300 GeV, even for these challenging scenarios. We then take a scenario which is on the borderline of observability of the upcoming LHC run assuming a luminosity of 300 fb(-1). We demonstrate that a prospective international e(+)e(-) linear collider with a center of mass energy of 1 TeV will be able to discover sleptons in scenarios which are difficult for the LHC. Moreover, we also show that a measurement of the spectrum will be possible within 1-3 percent accuracy. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370328 VL - 103 ER - TY - JOUR A1 - Martinez, Simon A1 - Lenz, Jürgen A1 - Schindler, Hans A1 - Wendler, Willi A1 - Rues, Stefan A1 - Schweizerhof, Karl A1 - Terebesi, Sophia A1 - Giannakopoulos, Nikolaos Nikitas A1 - Schmitter, Marc T1 - Clinical Data-Driven Finite Element Analysis of the Kinetics of Chewing Cycles in Order to Optimize Occlusal Reconstructions JF - Computer Modeling in Engineering & Sciences N2 - The occlusal design plays a decisive role in the fabrication of dental restorations. Dentists and dental technicians depend on mechanical simulations of mandibular movement that are as accurate as possible, in particular, to produce interference-free yet chewing-efficient dental restorations. For this, kinetic data must be available, i.e., movements and deformations under the influence of forces and stresses. In the present study, so-called functional data were collected from healthy volunteers to provide consistent information for proper kinetics. For the latter purpose, biting and chewing forces, electrical muscle activity and jaw movements were registered synchronously, and individual magnetic resonance tomograms (MRI) were prepared. The acquired data were then added to a large complex finite element model of the complete masticatory system using the functional information obtained and individual anatomical geometries so that the kinetics of the chewing process and teeth grinding could be realistically simulated. This allows developing algorithms that optimize computer-aided manufacturing of dental prostheses close to occlusion. In this way, a failure-free function of the dental prosthesis can be guaranteed and its damage during usage can be reduced or prevented even including endosseous implants. KW - occlusal design KW - mechanical simulations of mandibular movement KW - finite element model of the complete masticatory system KW - simulation of chewing process and teeth grinding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370318 VL - 129 ER - TY - JOUR A1 - Maron, Roman C. A1 - Haggenmüller, Sarah A1 - von Kalle, Christof A1 - Utikal, Jochen S. A1 - Meier, Friedegund A1 - Gellrich, Frank F. A1 - Hauschild, Axel A1 - French, Lars E. A1 - Schlaak, Max A1 - Ghoreschi, Kamran A1 - Kutzner, Heinz A1 - Heppt, Markus V. A1 - Haferkamp, Sebastian A1 - Sondermann, Wiebke A1 - Schadendorf, Dirk A1 - Schilling, Bastian A1 - Hekler, Achim A1 - Krieghoff-Henning, Eva A1 - Kather, Jakob N. A1 - Fröhling, Stefan A1 - Lipka, Daniel B. A1 - Brinker, Titus J. T1 - Robustness of convolutional neural networks in recognition of pigmented skin lesions JF - European Journal of Cancer N2 - Background A basic requirement for artificial intelligence (AI)–based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems. Objective To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)–mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing). Methods We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes (‘brittleness’) was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions. Results All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor. Conclusions Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic. KW - artificial intelligence KW - machine learning KW - deep learning KW - neural networks KW - dermatology KW - skin neoplasms KW - melanoma KW - nevus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370245 VL - 145 ER - TY - JOUR A1 - Marcu, Ana A1 - Schlosser, Andreas A1 - Keupp, Anne A1 - Trautwein, Nico A1 - Johann, Pascal A1 - Wölfl, Matthias A1 - Lager, Johanna A1 - Monoranu, Camelia Maria A1 - Walz, Juliane S A1 - Henkel, Lisa M A1 - Krauß, Jürgen A1 - Ebinger, Martin A1 - Schuhmann, Martin A1 - Thomale, Ulrich Wilhelm A1 - Pietsch, Torsten A1 - Klinker, Erdwine A1 - Schlegel, Paul G A1 - Oyen, Florian A1 - Reisner, Yair A1 - Rammensee, Hans-Georg A1 - Eyrich, Matthias T1 - Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors JF - Journal for ImmunoTherapy of Cancer N2 - Background Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. Methods Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. Results Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. Conclusions These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370214 VL - 9 ER - TY - JOUR A1 - Marcu, Ana A1 - Bichmann, Leon A1 - Kuchenbecker, Leon A1 - Kowalewski, Daniel Johannes A1 - Freudenmann, Lena Katharina A1 - Backert, Linus A1 - Mühlenbruch, Lena A1 - Szolek, András A1 - Lübke, Maren A1 - Wagner, Philipp A1 - Engler, Tobias A1 - Matovina, Sabine A1 - Wang, Jian A1 - Hauri-Hohl, Mathias A1 - Martin, Roland A1 - Kapolou, Konstantina A1 - Walz, Juliane Sarah A1 - Velz, Julia A1 - Moch, Holger A1 - Regli, Luca A1 - Silginer, Manuela A1 - Weller, Michael A1 - Löffler, Markus W. A1 - Erhard, Florian A1 - Schlosser, Andreas A1 - Kohlbacher, Oliver A1 - Stevanović, Stefan A1 - Rammensee, Hans-Georg A1 - Neidert, Marian Christoph T1 - HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org . Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370160 VL - 9 ER - TY - JOUR A1 - Mannucci, Ilaria A1 - Dang, Nghi D. P. A1 - Huber, Hannes A1 - Murry, Jaclyn B. A1 - Abramson, Jeff A1 - Althoff, Thorsten A1 - Banka, Siddharth A1 - Baynam, Gareth A1 - Bearden, David A1 - Beleza-Meireles, Ana A1 - Benke, Paul J. A1 - Berland, Siren A1 - Bierhals, Tatjana A1 - Bilan, Frederic A1 - Bindoff, Laurence A. A1 - Braathen, Geir Julius A1 - Busk, Øyvind L. A1 - Chenbhanich, Jirat A1 - Denecke, Jonas A1 - Escobar, Luis F. A1 - Estes, Caroline A1 - Fleischer, Julie A1 - Groepper, Daniel A1 - Haaxma, Charlotte A. A1 - Hempel, Maja A1 - Holler-Managan, Yolanda A1 - Houge, Gunnar A1 - Jackson, Adam A1 - Kellogg, Laura A1 - Keren, Boris A1 - Kiraly-Borri, Catherine A1 - Kraus, Cornelia A1 - Kubisch, Christian A1 - Le Guyader, Gwenael A1 - Ljungblad, Ulf W. A1 - Brenman, Leslie Manace A1 - Martinez-Agosto, Julian A. A1 - Might, Matthew A1 - Miller, David T. A1 - Minks, Kelly Q. A1 - Moghaddam, Billur A1 - Nava, Caroline A1 - Nelson, Stanley F. A1 - Parant, John M. A1 - Prescott, Trine A1 - Rajabi, Farrah A1 - Randrianaivo, Hanitra A1 - Reiter, Simone F. A1 - Schuurs-Hoeijmakers, Janneke A1 - Shieh, Perry B. A1 - Slavotinek, Anne A1 - Smithson, Sarah A1 - Stegmann, Alexander P. A. A1 - Tomczak, Kinga A1 - Tveten, Kristian A1 - Wang, Jun A1 - Whitlock, Jordan H. A1 - Zweier, Christiane A1 - McWalter, Kirsty A1 - Juusola, Jane A1 - Quintero-Rivera, Fabiola A1 - Fischer, Utz A1 - Yeo, Nan Cher A1 - Kreienkamp, Hans-Jürgen A1 - Lessel, Davor T1 - Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders JF - Genome Medicine N2 - Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306477 VL - 13 ER - TY - JOUR A1 - Maksimova, Varvara A1 - Shalginskikh, Natalya A1 - Vlasova, Olga A1 - Usalka, Olga A1 - Beizer, Anastasia A1 - Bugaeva, Polina A1 - Fedorov, Dmitry A1 - Lizogub, Olga A1 - Lesovaya, Ekaterina A1 - Katz, Richard A1 - Belitsky, Gennady A1 - Kirsanov, Kirill A1 - Yakubovskaya, Marianna T1 - HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes JF - PLoS ONE N2 - Chemicals reactivating epigenetically silenced genes target diverse classes of enzymes, including DNMTs, HDACs, HMTs and BET protein family members. They can strongly influence the expression of genes and endogenous retroviral elements with concomitant dsRNA synthesis and massive transcription of LTRs. Chemicals reactivating gene expression may cause both beneficial effects in cancer cells and may be hazardous by promoting carcinogenesis. Among chemicals used in medicine and commerce, only a small fraction has been studied with respect to their influence on epigenetic silencing. Screening of chemicals reactivating silent genes requires adequate systems mimicking whole-genome processes. We used a HeLa TSA-inducible cell population (HeLa TI cells) obtained by retroviral infection of a GFP-containing vector followed by several rounds of cell sorting for screening purposes. Previously, the details of GFP epigenetic silencing in HeLa TI cells were thoroughly described. Herein, we show that the epigenetically repressed gene GFP is reactivated by 15 agents, including HDAC inhibitors–vorinostat, sodium butyrate, valproic acid, depsipeptide, pomiferin, and entinostat; DNMT inhibitors–decitabine, 5-azacytidine, RG108; HMT inhibitors–UNC0638, BIX01294, DZNep; a chromatin remodeler–curaxin CBL0137; and BET inhibitors–JQ-1 and JQ-35. We demonstrate that combinations of epigenetic modulators caused a significant increase in cell number with reactivated GFP compared to the individual effects of each agent. HeLa TI cells are competent to metabolize xenobiotics and possess constitutively expressed and inducible cytochrome P450 mono-oxygenases involved in xenobiotic biotransformation. Thus, HeLa TI cells may be used as an adequate test system for the extensive screening of chemicals, including those that must be metabolically activated. Studying the additional metabolic activation of xenobiotics, we surprisingly found that the rat liver S9 fraction, which has been widely used for xenobiotic activation in genotoxicity tests, reactivated epigenetically silenced genes. Applying the HeLa TI system, we show that N-nitrosodiphenylamine and N-nitrosodimethylamine reactivate epigenetically silenced genes, probably by affecting DNA methylation. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370152 VL - 16 ER - TY - JOUR A1 - Maistrenko, Oleksii A1 - Scharf, Benedikt A1 - Manske, Dirk A1 - Hankiewicz, Ewelina M. T1 - Planar Josephson Hall effect in topological Josephson junctions JF - Physical Review B N2 - Josephson junctions based on three-dimensional topological insulators offer intriguing possibilities to realize unconventional 𝑝-wave pairing and Majorana modes. Here, we provide a detailed study of the effect of a uniform magnetization in the normal region: We show how the interplay between the spin-momentum locking of the topological insulator and an in-plane magnetization parallel to the direction of phase bias leads to an asymmetry of the Andreev spectrum with respect to transverse momenta. If sufficiently large, this asymmetry induces a transition from a regime of gapless, counterpropagating Majorana modes to a regime with unprotected modes that are unidirectional at small transverse momenta. Intriguingly, the magnetization-induced asymmetry of the Andreev spectrum also gives rise to a Josephson Hall effect, that is, the appearance of a transverse Josephson current. The amplitude and current phase relation of the Josephson Hall current are studied in detail. In particular, we show how magnetic control and gating of the normal region can enable sizable Josephson Hall currents compared to the longitudinal Josephson current. Finally, we also propose in-plane magnetic fields as an alternative to the magnetization in the normal region and discuss how the planar Josephson Hall effect could be observed in experiments. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370139 VL - 103 ER - TY - JOUR A1 - Maina, Ezio A1 - Pelliccioli, Giovanni T1 - Polarized Z bosons from the decay of a Higgs boson produced in association with two jets at the LHC JF - The European Physical Journal C N2 - Investigating the polarization of weak bosons provides an important probe of the scalar and gauge sector of the Standard Model. This can be done in the Higgs decay to four leptons, whose Standard-Model leading-order amplitude enables to generate polarized observables from unpolarized ones via a fully-differential reweighting method. We study the Z-boson polarization from the decay of a Higgs boson produced in association with two jets, both in the gluon-fusion and in the vector-boson fusion channel. We also address the possibility of extending the results of this work to higher orders in perturbation theory. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370126 VL - 81 ER - TY - JOUR A1 - Maier, Gerrit S. A1 - Weissenberger, Manuel A1 - Rudert, Maximilian A1 - Roth, Klaus E. A1 - Horas, Konstantin T1 - The role of vitamin D and vitamin D deficiency in orthopaedics and traumatology—a narrative overview of the literature JF - Annals of Translational Medicine N2 - Vitamin D is considered to play an important role in musculoskeletal health. It’s classical function is the regulation of calcium and phosphate homeostasis, thus ensuring a balanced bone metabolism that is characterised by an equal amount of bone resorption and bone formation. In the past decades, a plethora of pre-clinical and clinical studies reporting on potential health-beneficial properties of vitamin D have emerged. Moreover, there is an abundance of reports highlighting vitamin D deficiency and insufficiency in patients with almost innumerable diseases. Further, it is estimated that more than one billion people globally are affected by insufficient vitamin D levels. As such, research on vitamin D has been particularly popular over the past years. In orthopaedics and traumatology, most studies describe favourable effects of vitamin D in general. However, the relative importance of vitamin D is oftentimes debated. In this narrative review of the literature, we consider first, the properties of vitamin D and how vitamin D, vitamin D deficiency and the vitamin D receptor (VDR) impact on musculoskeletal health. Secondly, we provide an overview of studies reporting the prevalence of vitamin D deficiency in traumatology and diverse orthopaedic diseases including bone oncology. Lastly, we emphasise recent findings and touch on future perspectives in vitamin D research. KW - vitamin D KW - vitamin D deficiency (VDR) KW - orthopaedics KW - orthopedics KW - traumatology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370110 VL - 9 ER - TY - JOUR A1 - Magunia, Harry A1 - Lederer, Simone A1 - Verbuecheln, Raphael A1 - Gilot, Bryant Joseph A1 - Koeppen, Michael A1 - Haeberle, Helene A. A1 - Mirakaj, Valbona A1 - Hofmann, Pascal A1 - Marx, Gernot A1 - Bickenbach, Johannes A1 - Nohe, Boris A1 - Lay, Michael A1 - Spies, Claudia A1 - Edel, Andreas A1 - Schiefenhövel, Fridtjof A1 - Rahmel, Tim A1 - Putensen, Christian A1 - Sellmann, Timur A1 - Koch, Thea A1 - Brandenburger, Timo A1 - Kindgen-Milles, Detlef A1 - Brenner, Thorsten A1 - Berger, Marc A1 - Zacharowski, Kai A1 - Adam, Elisabeth A1 - Posch, Matthias A1 - Moerer, Onnen A1 - Scheer, Christian S. A1 - Sedding, Daniel A1 - Weigand, Markus A. A1 - Fichtner, Falk A1 - Nau, Carla A1 - Prätsch, Florian A1 - Wiesmann, Thomas A1 - Koch, Christian A1 - Schneider, Gerhard A1 - Lahmer, Tobias A1 - Straub, Andreas A1 - Meiser, Andreas A1 - Weiss, Manfred A1 - Jungwirth, Bettina A1 - Wappler, Frank A1 - Meybohm, Patrick A1 - Herrmann, Johannes A1 - Malek, Nisar A1 - Kohlbacher, Oliver A1 - Biergans, Stephanie A1 - Rosenberger, Peter T1 - Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort JF - Critical Care N2 - Background Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451. KW - COVID-19 KW - critical care KW - ARDS KW - outcome KW - prognostic models Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306766 VL - 25 ER - TY - THES A1 - Köhler, Jonas T1 - Predicting Future Snow Line Elevation Dynamics in the Alps - The Potential of Long Earth Observation Time Series T1 - Prognose zukünftiger Schneeliniendynamiken in den Alpen - Das Potential langer Zeitreihen aus Erdbeobachtungsdaten N2 - The seasonal snow cover in the European Alps plays a crucial role in the region's climate, ecology, and economy. It affects the local climate through its high albedo, protects permafrost, provides habitats, and acts as a water reservoir that feeds European rivers. However, these functions are threatened by climate change. Analyzing snow cover dynamics is essential to predict future developments and assess related ecological and economic impacts. This study explores the potential of long Earth Observation (EO) time series for modeling and predicting the snow line elevation (SLE) in the Alps. Based on approximately 15,000 Landsat satellite images, SLE time series were generated for the years 1985 to 2022. Various univariate forecasting models were evaluated, with the best results achieved by Random Forests, Telescope, and Seasonal ARIMA. A newly developed approach combines the best models into a robust ensemble, achieving an average Nash-Sutcliffe efficiency (NSE) of 0.8 in catchments with strong seasonal signals. Forecasts for 2030 indicate significant upward shifts in the SLE, particularly in the Western and Southern Alps. Given the variability in results, a multivariate modeling approach using climate variables is recommended to improve prediction accuracy. This study lays the groundwork for future models that could potentially project SLE dynamics through the end of the 21st century under various climate scenarios, which is highly relevant for climate policy in the Alpine region. N2 - Die saisonale Schneedecke in den europäischen Alpen spielt eine zentrale Rolle für das Klima, die Ökologie und die Wirtschaft der Region. Sie beeinflusst das lokale Klima durch ihre Albedo, beeinflusst den Permafrost, bildet Lebensräume und fungiert als Wasserspeicher, der große europäische Flüsse speist. Diese Funktionen sind jedoch durch den Klimawandel bedroht. Um zukünftige Entwicklungen der Schneedecke vorherzusagen und die damit verbundenen ökologischen und wirtschaftlichen Auswirkungen abzuschätzen, ist die Analyse vergangener und Prognose zukünftiger Schneedeckendynamiken essenziell. Diese Arbeit untersucht das Potenzial langer Zeitreihen aus der Satellitenfernerkundung (Earth Observation, EO) zur Modellierung und Vorhersage der Schneelinienhöhe (SLE) in den Alpen. Auf Basis von etwa 15.000 Landsat-Satellitenbildern wurden SLE-Zeitreihen für die Jahre 1985 bis 2022 erstellt. Verschiedene univariate Prognosemodelle wurden evaluiert, wobei die besten Ergebnisse mit Random Forests, Telescope und Seasonal ARIMA erzielt wurden. Ein neu entwickelter Ansatz kombiniert die besten Modelle zu einer Ensemble-Prognose und erreicht einen mittleren Nash-Sutcliffe-Effizienz-Wert (NSE) von 0,8 in Einzugsgebieten mit starkem saisonalem Signal. Die Prognosen bis 2030 zeigen signifikante Verschiebungen der SLE in höhere Lagen, besonders in den West- und Südalpen. Angesichts der Varianz in den Ergebnissen wird eine multivariate Modellierung mit Klimavariablen vorgeschlagen, um die Vorhersagegenauigkeit zu verbessern. Diese Ergebnisse legen den Grundstein für zukünftige Ansätze, die SLE-Dynamiken bis zum Ende des 21. Jahrhunderts unter verschiedenen Klimaszenarien auf Basis von EO-Daten projizieren können, was für die Klimapolitik im Alpenraum potenziell von hoher Relevanz ist. KW - Fernerkundung KW - Schnee KW - Prognose KW - Zeitreihe KW - Alps KW - remote sensing KW - snow KW - prediction KW - time series KW - Alpen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371392 ER - TY - THES A1 - Hesen, Nienke Aiyuan T1 - The importance of antibody isotype and idiotype in FcγR-dependent agonism induced by anti-CD40 antibodies T1 - Die Bedeutung des Antikörper-Isotyps und des Idiotyps beim FcγR-abhängigen Agonismus, der durch Anti-CD40-Antikörper induziert wird N2 - The TRAF-binding receptor CD40 belongs to the TNFR superfamily and is broadly expressed on healthy cells, mainly on antigen-presenting cells, but also on other immune cells and non-immune cells. CD40 is bound by its ligand CD40L, which is essential for a wide range of immunological responses by inducing or inhibiting different pathways that are essential for a variety of cellular processes, including immune activation and maturation. (1,2) Dysregulated CD40 signalling has been implicated in inflammatory diseases, such as hyper-IgM syndrome, psoriasis, and cancer. (3–6) Due to its broad expression across various tumour types, it can serve as a tumour-associated antigen and has therefore been proposed as a target for antibodies for cancer treatment. (2,7,8) Agonistic anti-CD40 antibodies have been demonstrated to induce anti-tumoural immune responses as well as therapeutic immunity. (2) Furthermore, prolonged stimulation of CD40 in tumour cells in vitro has been shown to decrease proliferation, increase expression of cytotoxic TNFSFLs and induce apoptosis. (9,10) Their effect on anti-tumoral responses has been well studied and anti-tumoral responses by DC maturation and suppression of malignant growth of B-cells have been confirmed and were found to induce cell death in tumours in vitro. (11–14) Many agonistic anti-CD40 antibodies specifically have been reported to require secondary crosslinking by binding to either activating or inhibitory FcγRs to be agonistic in vitro, while in vivo studies have indicated inhibitory FcƴR2B expression as critical factor. (15–17) However, FcƴR independent agonism has also been reported for anti-CD40 antibodies. (18,19) While agonistic anti-CD40 IgG1, IgG3 and IgG4 antibodies have been shown to display FcƴR dependent agonism, agonistic anti-CD40 IgG2 antibodies have shown to display FcƴR independent agonism. Conversion of anti-CD40 IgG1 antibodies into IgG2 has also been shown to convert the antibody’s agonism into FcƴR independent agonism. (20) To overcome FcƴR dependency, bispecific antibody fusion proteins containing a scFv as anchoring domain allowing for crosslink independent of FcƴR binding have been designed before. This approach has been found to display strong agonism for other antibody fusion proteins when bound to both targets, with response levels resembling that of FcƴR bound antibodies. (21,22) The relevance of antibody isotype and idiotype for FcƴR-dependent agonism as well as the relevance of valency and antibody oligomerization for FcƴR-independent agonism were investigated in this study on a panel of different anti-CD40 antibodies. Several clinically investigated anti-CD40 antibodies (ADC-1013(23), APX005M(24), ChiLob7.4(25) and CP-870,893(26)) and one preclinical antibody (G28.5(27,28)) were considered. Selected antibodies were then cloned onto an IgG1, IgG1(N297A), IgG2 and IgG4 backbone. The IgG1(N297A) isotype is an IgG1 antibody with a point mutation (N297A) that is known to strongly reduce binding to FcƴR1, while reducing the binding affinity to FcƴR2B to undetectable levels. (29,30) In this work it is demonstrated that the investigated anti-CD40 antibody variants across different isotypes activate both the classical and alternative NFκB pathway by stimulating U2OS cells in an FcƴR dependent manner. Stimulation in the presence of both human FcƴRs as well as murine FcƴRs resulted in CD40 stimulation. A difference in binding competition was observed for the various anti-CD40 IgG1 antibodies, but no indication of a CRD-dependent mechanism responsible for their agonistic activity was found. Moreover, this FcƴR dependency could be overcome by creation of tetravalent antibody fusion proteins. N2 - Zusammenfassung Der TRAF-bindende Rezeptor CD40 ist Teil der TNFR-Superfamilie. CD40 wird auf gesunden Zellen, vor allem auf Antigen-präsentierenden Zellen, aber auch auf anderen Immunzellen und Nicht-Immunzellen in großem Umfang exprimiert. Die Aktivierung von CD40 durch seinen Liganden CD40L ist für zahlreiche immunologische Reaktionen von entscheidender Bedeutung, da sie verschiedene Signalwege induziert oder hemmt, die für zahlreiche zelluläre Prozesse, einschließlich Immunaktivierung und -reifung, wichtig sind. (1,2) Defekte CD40-Signalwege werden mit Entzündungskrankheiten wie dem Hyper-IgM-Syndrom, Psoriasis und Krebs in Verbindung gebracht. (3–6) Da CD40 auf verschiedenen Tumorarten weit verbreitet ist, kann es als tumorassoziiertes Antigen verwendet werden, das dann von zytotoxischen Antikörpern angegriffen werden kann, und wurde als Ziel für Antikörper zur Krebsbehandlung vorgeschlagen. (2,7,8) Es hat sich gezeigt, dass agonistische Anti-CD40-Antikörper antitumorale Immunreaktionen und therapeutische Immunität auslösen können. (2) Es hat sich gezeigt, dass die kontinuierliche Stimulation von CD40 in Tumorzellen in vitro die Proliferation reduziert, die Expression zytotoxischer TNFSFLs hochreguliert und Apoptose induziert. (9,10) Ihre Wirkung auf antitumorale Reaktionen wurde gut untersucht, und antitumorale Reaktionen durch DCReifung und Unterdrückung des malignen Wachstums von B-Zellen wurden bestätigt und es wurde festgestellt, dass sie in vitro den Zelltod in Tumoren induzieren. (11–14) Viele agonistische Anti-CD40-Antikörper erfordern Berichten zufolge eine sekundäre Vernetzung durch Bindung an entweder aktivierende oder hemmende FcγRs, um in vitro agonistisch zu wirken, während In-vivo-Studien auf eine hemmende FcƴR2B-Expression als kritischen Faktor hinwiesen. (15–17) Allerdings wurde auch für Anti-CD40-Antikörper ein FcƴR-unabhängiger Agonismus festgestellt. (18,19) Während agonistische Anti-CD40-IgG1-, IgG3- und IgG4-Antikörper nachweislich einen FcƴR-abhängigen Agonismus aufweisen, haben agonistische Anti-CD40-IgG2-Antikörper einen FcƴR-unabhängigen Agonismus gezeigt. Die Umwandlung von Anti-CD40-IgG1-Antikörpern in IgG2-Antikörper hat ebenfalls gezeigt, dass der Agonismus des Antikörpers in einen FcƴR-unabhängigen Agonismus umgewandelt wird. (20) Um die FcƴR-Abhängigkeit zu überwinden, wurden bereits bispezifische AntikörperFusionsproteine entwickelt, die ein scFv als Verankerungsdomäne enthalten und eine von der FcƴR-Bindung unabhängige Vernetzung ermöglichen. Es hat sich gezeigt, dass dieser Ansatz einen starken Agonismus für andere Antikörper-Fusionsproteine aufweist, wenn sie an beide Zielmoleküle gebunden sind, wobei die Ansprechraten denen von FcƴRgebundenen Antikörpern ähneln. (21,22) Die Bedeutung des Antikörper-Isotyps und des Idiotyps für den FcƴR-abhängigen Agonismus sowie die Bedeutung der Valenz und der Antikörper-Oligomerisierung für den FcƴRunabhängigen Agonismus wurden in dieser Studie an einem Panel verschiedener Anti-CD40-Antikörper untersucht. Es wurden mehrere klinisch untersuchte Anti-CD40-Antikörper (ADC1013(23), APX005M(24), ChiLob7.4(25) und CP-870,893(26)) und ein präklinischer Antikörper (G28.5(27,28)) berücksichtigt. Die ausgewählten Antikörper wurden dann auf ein IgG1-, IgG1(N297A)-, IgG2- und IgG4-Backbone kloniert. Beim Isotyp gG1(N297A) handelt es sich um einen IgG1-Antikörper mit einer Punktmutation (N297A), von der bekannt ist, dass sie die Bindung an FcƴR1 stark reduziert, während sie die Bindungsaffinität zu FcƴR2B auf ein nicht nachweisbares Niveau verringert. (29,30)In dieser Arbeit wird gezeigt, dass die Anti-CD40-Antikörper-Varianten verschiedener Isotypen sowohl den klassischen als auch den alternativen NFκB-Signalweg aktivieren, indem sie U2OS-Zellen in einer FcƴR-abhängigen Weise stimulieren. Die Stimulierung in Anwesenheit sowohl von humanen FcƴRs als auch von murinen FcƴRs führte zu einer CD40-Stimulierung. Während für die verschiedenen Anti-CD40-IgG1-Antikörper ein Unterschied in der Bindungskonkurrenz beobachtet wurde, konnten die CRD-Bindungsprofile keine Erkenntnisse über die zugrunde liegenden Mechanismen liefern. Darüber hinaus konnte diese FcƴR-Abhängigkeit durch die Herstellung von tetravalenten AntikörperFusionsproteinen überwunden werden. KW - Antigen CD40 KW - FcƴR Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371872 ER - TY - THES A1 - Vialetto, Elena T1 - Outcomes of genome targeting with CRISPR-Cas systems in bacteria T1 - Folgen des Genom-Targeting mit CRISPR-Cas-Systemen in Bakterien N2 - CRISPR-Cas systems are a versatile tool in genetic engineering because they can be easily reprogrammed to cut a specific chromosomal region or RNA transcript. The choice of nuclease, gRNA design, and target region all influence targeting efficiency, so the appropriate CRISPR components should be chosen depending on the desired application. This thesis examines factors that influence targeting in both DNA- and RNA-targeting CRISPR systems. Chapter 1 discusses the importance of target RNA abundance in shaping the immunity of type VI CRISPR systems. In bacteria, the Cas13 nuclease is known to degrade RNA specifically and non-specifically, leading to cell growth arrest, also known as dormancy. In this chapter, the factors that determine dormancy are investigated by targeting genome- and plasmid-encoded transcripts in E. coli. The observations are extended to a gRNA library targeting the entire coding genome and gRNA design rules are extrapolated. Finally, the role of Cas13 in defense is investigated by testing how the system behaves during viral infection or plasmid transformation. Chapter 2 also looks at the factors that characterize targeting efficiency, but focuses on the Cas12a DNA-targeting system in K. pneumoniae. The ultimate goal is to develop CRISPR antimicrobials as alternatives to antibiotics to eliminate multidrug-resistant and hypervirulent bacteria. Several nucleases are tested for antimicrobial activity, the Cas12a nuclease is selected and the same gRNAs are used against different strains to understand the robustness of the method. Rules for gRNA design are also investigated by looking at secondary structure and testing a gRNA library across several genomic regions in two different strains. This information is used to develop a machine-learning algorithm to predict gRNA activity. In addition, the CRISPR-Cas systems are also packaged in a T7-like phage with engineered tail fibers and delivered to K. pneumoniae. While Chapter 2 uncovers various factors that improve targeting efficiency, Chapter 3 aims to reduce targeting by the Cas9 and Cas12a nucleases to favor homology-directed repair for genome editing in E. coli. Targeting is slowed down so that some copies of the chromosomes remain intact, allowing the bacterium to survive and integrate the desired edit. To reduce targeting, different gRNA formats or nuclease variations are used, gRNA expression is modulated, or gRNAs with attenuated targeting are designed. Attenuated gRNAs are tested to introduce point mutations as well as whole gene deletions and substitutions, and the method is extended to Klebsiella oxytoca and Klebsiella pneumoniae, where it is applied to block transcription of an antibiotic resistance gene in the genome, restoring sensitivity to ampicillin. Overall, this work discusses how changing the CRISPR components alters the outcome of targeting and highlights strategies to achieve efficient or attenuated targeting depending on the desired application. N2 - CRISPR-Cas-Systeme sind ein vielseitiges Werkzeug in der Gentechnik, da sie leicht umprogrammiert werden können, um eine bestimmte chromosomale Region oder ein RNA-Transkript zu schneiden. Die Wahl der Nuklease, das Design der gRNA und die Zielregion beeinflussen alle die Effizienz des Targetings, so dass die richtigen CRISPR-Komponenten je nach gewünschter Anwendung ausgewählt werden sollten. In dieser Arbeit werden die Faktoren untersucht, die das Targeting sowohl bei DNA-targeting als auch bei RNA-targeting CRISPR-Systemen beeinflussen. In Kapitel 1 wird erörtert, wie die Häufigkeit der Ziel-RNA die Immunität von Typ VI CRISPR-Systemen ausprägt. In Bakterien ist von der Cas13-Nuklease bekannt, dass sie RNA spezifisch und unspezifisch abbaut, was zu einem Stillstand des Zellwachstums führt, der auch als Dormanz bezeichnet wird. In diesem Kapitel werden die Faktoren untersucht, die Dormanz determinieren, indem genom- und plasmidkodierte Transkripte in E. coli ins Visier genommen werden. Die Beobachtungen werden auf eine gRNA-Bibliothek ausgeweitet, die auf das gesamte kodierende Genom abzielt, und es werden gRNA-Designregeln extrapoliert. Schließlich wird die Rolle von Cas13 bei der Verteidigung untersucht, indem getestet wird, wie sich das System während einer Virusinfektion oder Plasmidtransformation verhält. Kapitel 2 befasst sich ebenfalls mit den Faktoren, die die Targeteffizienz charakterisieren, konzentriert sich jedoch auf das Cas12a-DNA-Targeting-System in K. pneumoniae. Das Endziel ist die Entwicklung von CRISPR-Antimikroben als Alternative zu Antibiotika, um multiresistente und hypervirulente Bakterien zu eliminieren. Mehrere Nukleasen werden auf ihre antimikrobielle Aktivität getestet, die Cas12a-Nuklease wird ausgewählt und dieselben gRNAs werden gegen verschiedene Stämme eingesetzt, um die Robustheit der Methode zu verstehen. Außerdem werden die Regeln für das Design von gRNAs untersucht, indem die Sekundärstruktur betrachtet und eine gRNA-Bibliothek, die verschiedenen genomische Regionen in zwei verschiedenen Stämmen umfasst, getestet wird. Diese Informationen werden zur Entwicklung eines Algorithmus für maschinelles Lernen verwendet, um die gRNA-Aktivität vorherzusagen. Darüber hinaus werden die CRISPR-Cas-Systeme auch in einen T7-ähnlichen Phagen mit manipulierten Schwanzfasern verpackt und an K. pneumoniae übertragen. Während in Kapitel 2 verschiedene Faktoren aufgedeckt werden, die die Effizienz des Targetings verbessern, zielt Kapitel 3 darauf ab, das Targeting durch die Cas9- und Cas12a-Nukleasen zu reduzieren, um homology directed repair für Genom-Editierung in E. coli zu begünstigen. Das Targeting wird verlangsamt, so dass einige Kopien der Chromosomen intakt bleiben und das Bakterium überleben und die gewünschte Veränderung integrieren kann. Um das Targeting zu reduzieren, werden verschiedene gRNA-Formate oder Nuklease-Variationen verwendet, die gRNA-Expression wird moduliert, oder es werden gRNAs mit abgeschwächten Targeting entwickelt. Abgeschwächte gRNAs werden getestet, um Punktmutationen, Deletionen und Substitutionen ganzer Gene einzuführen, und die Methode wird auf Klebsiella oxytoca und Klebsiella pneumoniae ausgeweitet, wo sie zur Blockierung der Transkription eines Antibiotikaresistenzgens im Genom eingesetzt wird, um die Empfindlichkeit gegenüber Ampicillin wiederherzustellen. Insgesamt wird in dieser Arbeit erörtert, wie die Veränderung der CRISPR-Komponenten die Folgen des Targetings verändert und es werden Strategien hervorgehoben, um effizientes oder abgeschwächtes Targeting, je nach der gewünschten Anwendung, zu erreichen. KW - CRISPR/Cas-Methode KW - CRISPR KW - Genome editing KW - Antimicrobials KW - Cas13 KW - Cas12a Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371264 ER - TY - THES A1 - Seal, Rishav T1 - Selective inhibition of the transcription factor NFAT in mitigating GvHD with small molecule inhibitors T1 - Selektive Hemmung des Transkriptionsfaktors NFAT bei der Milderung von GvHD durch kleine Molekül-Inhibitoren N2 - Hematopoietic stem cell transplantation (HSCT) is a promising therapy for various malignancies and immune deficiency diseases, but it is often associated with graft versus host disease (GvHD), a life-threatening complication arising from immunological incompatibility between donor T cells and host tissues. Current standard therapies for GvHD involve the use of calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus (FK506), which effectively suppress T cell activation and proliferation. However, these drugs also impair the graft versus leukemia (GvL) effect, which is the advantageous ability of donor T cells to eliminate malignant cells. Our previous studies demonstrated that the selective deletion of one or two members of the nuclear factor of activated T cells (NFAT) transcription factor family in donor T cells effectively prevented harmful GvHD without compromising GvL activity. This finding highlighted the potential of NFAT as a therapeutic target for GvHD. In this study, we developed and evaluated novel treatment strategies that specifically target NFAT during allogeneic HSCT. We focused on the development of small molecules that mimic the PxIxIT motif of NFAT, thereby competitively inhibiting its binding to CN (CN) without affecting CN phosphatase activity. We identified two promising candidates, C17 and MRD37, and evaluated their efficacy in inhibiting NFAT and suppressing pro-inflammatory cytokine production. Among these molecules, MRD37 demonstrated the highest potency in selectively inhibiting NFAT at a sub-IC50 concentration without compromising the functional capacity of regulatory T cells (Tregs) in vitro. Furthermore, we demonstrated that MRD37 could effectively protect mice from major mismatch GvHD in vivo. This protection was initially predicted to be due to the enhanced presence of Tregs and Tr1-type cells but when pretreated T cells devoid of Tregs were transplanted it unraveled an additional increase of Th2-like cytokine release. Finally, our in vitro studies on human T cells confirmed that MRD37 could specifically inhibit NFAT while preserving the Treg population, suggesting its potential as a novel therapeutic strategy for GvHD. Our findings provide compelling evidence for the development of MRD37 as promising alternative to CNIs in mitigating GvHD. N2 - Die hämatopoetische Stammzelltransplantation (HSCT) ist eine vielversprechende Therapie für verschiedene bösartige Erkrankungen und Immunschwächekrankheiten, wird jedoch häufig mit der Graft versus Host Disease (GvHD) in Verbindung gebracht, einer lebensbe drohlichen Komplikation, die durch immunologische Inkompatibilität zwischen Spender T Zellen und Wirtsgewebe entsteht. Die derzeitigen Standardtherapien für die GvHD umfassen den Einsatz von Calcineurin Inhibitoren (CNI) wie Cyclosporin A (CsA) und Tacroli mus (FK506), die die Aktivierung und Vermehrung von T Zellen wirksam unterdrücken. Diese Medikamente beeinträchtigen jedoch auch den Transplantat gegen Leukämie Effekt (GvL), d. h. die vorteilhafte Fähigkeit von Spender T Zellen, bösartige Zellen zu elimin ieren. Unsere früheren Studien haben gezeigt, dass die selektive Deletion von einem oder zwei Mitgliedern der Transkriptionsfaktor Familie Nuclear Factor of Activated T Cells (NFAT) in Spender T Zellen die schädliche GvHD wirksam verhindert, ohne die GvL Aktivitä t zu beeinträchtigen. Dieses Ergebnis unterstreicht das Potenzial von NFAT als therapeutisches Ziel für GvHD. In dieser Studie haben wir neuartige Behandlungsstrategien entwickelt und evaluiert, die spezifisch auf NFAT bei allogener HSCT abzielen. Wir konzentrierten uns auf die Entwicklung kleiner Moleküle, die das PxIxIT Motiv von NFAT nachahmen und dadurch seine Bindung an Calcineurin (CN) kompetitiv hemmen, ohne die Phosphataseaktivität von CN zu beeinträchtigen. Wir haben zwei vielversprechende Kandidaten, C17 und MRD37, identifiziert und ihre Wirksamkeit bei der Hemmung von NFAT und der Unterdrückung der Produ ktion entzündungsfördernder Zytokine untersucht. Von diesen Molekülen zeigte MRD37 die höchste Wirksamkeit bei der selektiven Hemmung von NFAT in einer Konzentration unterhalb von IC50, ohne die Funktionsfähigkeit der regulatorischen T Zellen (Tregs) zu be einträchtigen. Darüber hinaus konnten wir zeigen, dass MRD37 Mäuse in vivo wirksam vor Major Mismatch GvHD schützen kann. Ursprünglich wurde angenommen, dass dieser Schutz auf das verstärkte Vorhandensein von Tregs und Zellen vom Tr1 Typ zurückzuführen ist , doch als vorbehandelte T Zellen ohne Tregs transplantiert wurden, zeigte sich darüberhinaus eine erhöhte Freisetzung von Th2 ähnlichen Zytokinen. Schließlich bestätigten unsere In vitro Studien an menschlichen T Zellen, dass MRD37 spezifisch NFAT hemmen kann, während die Treg 9 Population erhalten bleibt, was auf sein Potenzial als neuartige therapeutische Strategie für Population erhalten bleibt, was auf sein Potenzial als neuartige therapeutische Strategie für GvHD hindeutet.GvHD hindeutet. Unsere Ergebnisse liefern überzeugende Beweise für die Entwicklung von MRD37 als Unsere Ergebnisse liefern überzeugende Beweise für die Entwicklung von MRD37 als vielversprechende Alternative zu CNIs bei der Behandlung von GvHD.vielversprechende Alternative zu CNIs bei der Behandlung von GvHD. KW - GVHD KW - Transplantat-Wirt-Reaktion KW - Stammzelltransplantation KW - Graft versus host disease KW - NFAT inhibitor KW - Stem cell transplantation KW - CsA KW - T cell Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370537 ER - TY - JOUR A1 - Magnea, Lorenzo A1 - Pelliccioli, Giovanni A1 - Signorile-Signorile, Chiara A1 - Torrielli, Paolo A1 - Uccirati, Sandro T1 - Analytic integration of soft and collinear radiation in factorised QCD cross sections at NNLO JF - Journal of High Energy Physics N2 - Within the framework of local analytic sector subtraction, we present the full analytic integration of double-real and real-virtual local infrared counterterms that enter NNLO QCD computations with any number of massless final-state partons. We show that a careful choice of phase-space mappings leads to simple analytic results, including non-singular terms, that can be obtained with conventional integration techniques. KW - QCD Phenomenology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370064 VL - 2021 ER - TY - JOUR A1 - MacLeod, Lucy A1 - Suruliraj, Banuchitra A1 - Gall, Dominik A1 - Bessenyei, Kitti A1 - Hamm, Sara A1 - Romkey, Isaac A1 - Bagnell, Alexa A1 - Mattheisen, Manuel A1 - Muthukumaraswamy, Viswanath A1 - Orji, Rita A1 - Meier, Sandra T1 - A Mobile Sensing App to Monitor Youth Mental Health: Observational Pilot Study JF - JMIR mHealth and uHealth N2 - Background: Internalizing disorders are the most common psychiatric problems observed among youth in Canada. Sadly, youth with internalizing disorders often avoid seeking clinical help and rarely receive adequate treatment. Current methods of assessing internalizing disorders usually rely on subjective symptom ratings, but internalizing symptoms are frequently underreported, which creates a barrier to the accurate assessment of these symptoms in youth. Therefore, novel assessment tools that use objective data need to be developed to meet the highest standards of reliability, feasibility, scalability, and affordability. Mobile sensing technologies, which unobtrusively record aspects of youth behaviors in their daily lives with the potential to make inferences about their mental health states, offer a possible method of addressing this assessment barrier. Objective: This study aims to explore whether passively collected smartphone sensor data can be used to predict internalizing symptoms among youth in Canada. Methods: In this study, the youth participants (N=122) completed self-report assessments of symptoms of anxiety, depression, and attention-deficit hyperactivity disorder. Next, the participants installed an app, which passively collected data about their mobility, screen time, sleep, and social interactions over 2 weeks. Then, we tested whether these passive sensor data could be used to predict internalizing symptoms among these youth participants. Results: More severe depressive symptoms correlated with more time spent stationary (r=0.293; P=.003), less mobility (r=0.271; P=.006), higher light intensity during the night (r=0.227; P=.02), and fewer outgoing calls (r=−0.244; P=.03). In contrast, more severe anxiety symptoms correlated with less time spent stationary (r=−0.249; P=.01) and greater mobility (r=0.234; P=.02). In addition, youths with higher anxiety scores spent more time on the screen (r=0.203; P=.049). Finally, adding passively collected smartphone sensor data to the prediction models of internalizing symptoms significantly improved their fit. Conclusions: Passively collected smartphone sensor data provide a useful way to monitor internalizing symptoms among youth. Although the results replicated findings from adult populations, to ensure clinical utility, they still need to be replicated in larger samples of youth. The work also highlights intervention opportunities via mobile technology to reduce the burden of internalizing symptoms early on. KW - mobile sensing KW - youth KW - psychiatry KW - feasibility KW - mobile phone Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370054 VL - 9 ER - TY - JOUR A1 - Macchiaroli, Natalia A1 - Preza, Matías A1 - Gastón Pérez, Matías A1 - Kamenetzky, Laura A1 - Cucher, Marcela A1 - Koziol, Uriel A1 - Castillo, Estela A1 - Berriman, Matthew A1 - Brehm, Klaus A1 - Rosenzvit, Mara Cecilia T1 - Expression profiling of Echinococcus multilocularis miRNAs throughout metacestode development in vitro JF - PLOS Neglected Tropical Diseases N2 - The neglected zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode stage of the tapeworm parasite Echinococcus multilocularis. MicroRNAs (miRNAs) are small non-coding RNAs with a major role in regulating gene expression in key biological processes. We analyzed the expression profile of E. multilocularis miRNAs throughout metacestode development in vitro, determined the spatial expression of miR-71 in metacestodes cultured in vitro and predicted miRNA targets. Small cDNA libraries from different samples of E. multilocularis were sequenced. We confirmed the expression of 37 miRNAs in E. multilocularis being some of them absent in the host, such as miR-71. We found a few miRNAs highly expressed in all life cycle stages and conditions analyzed, whereas most miRNAs showed very low expression. The most expressed miRNAs were miR-71, miR-9, let-7, miR-10, miR-4989 and miR-1. The high expression of these miRNAs was conserved in other tapeworms, suggesting essential roles in development, survival, or host-parasite interaction. We found highly regulated miRNAs during the different transitions or cultured conditions analyzed, which might suggest a role in the regulation of developmental timing, host-parasite interaction, and/or in maintaining the unique developmental features of each developmental stage or condition. We determined that miR-71 is expressed in germinative cells and in other cell types of the germinal layer in E. multilocularis metacestodes cultured in vitro. MiRNA target prediction of the most highly expressed miRNAs and in silico functional analysis suggested conserved and essential roles for these miRNAs in parasite biology. We found relevant targets potentially involved in development, cell growth and death, lifespan regulation, transcription, signal transduction and cell motility. The evolutionary conservation and expression analyses of E. multilocularis miRNAs throughout metacestode development along with the in silico functional analyses of their predicted targets might help to identify selective therapeutic targets for treatment and control of AE. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370046 VL - 15 ER - TY - JOUR A1 - Maas, Bea A1 - Brandl, Manuela A1 - Hussain, Raja Imran A1 - Frank, Thomas A1 - Zulka, Klaus Peter A1 - Rabl, Dominik A1 - Walcher, Ronnie A1 - Moser, Dietmar T1 - Functional traits driving pollinator and predator responses to newly established grassland strips in agricultural landscapes JF - Journal of Applied Ecology N2 - Agricultural biodiversity and associated ecosystem functions are declining at alarming rates due to widespread land use intensification. They can only be maintained through targeted landscape management that supports species with different habitat preferences, dispersal capacities and other functional traits that determine their survival. However, we need better understanding whether short-term measures can already improve functional diversity in European agroecosystems. We investigated spatio-temporal responses of bees (solitary bees, bumblebees and honey bees), hoverflies, carabid beetles and spiders to newly established grassland strips in Lower Austria over 3 years, and along a distance gradient to old grasslands. Specifically, we asked if new grasslands, compared to old grasslands and cereal fields, serve as temporal dispersal habitat or corridor, and how species-specific traits affect dispersal patterns. Using a trait-based functional diversity approach, we investigated year and distance effects for nine selected key traits per taxon (e.g. body size, feeding guild and habitat preferences). Our results show that the functional diversity of predators and pollinators (i.e. functional richness and evenness), as well as community-weighted means of selected key traits in new grasslands significantly differed from adjacent cereal fields, but only slowly adjusted to adjacent old grasslands. These effects significantly decreased with increasing distance to old grasslands for carabids and spiders, but not for mobile bees and hoverflies. Synthesis and applications. Over 3 years, newly established grassland strips supported larger sized and actively foraging/hunting species in the agricultural landscape. Adjacent crops likely benefit from such measures through enhanced functional diversity and related ecosystem services. However, our results also suggest that 3-year period is too short to enhance the occurrence of pollinators and epigeic predators in new grasslands. Agri-environment measures need to be complemented by the conservation of permanent habitats to effectively maintain species and functional diversity. Our findings should be acknowledged by European policy and agricultural decision makers for the design of more effective agri-environment schemes, taking into account trait-dependent species responses to land use change. KW - agri-environment schemes KW - Common Agricultural Policy KW - ecosystem services; KW - Europe KW - functional diversity analysis; KW - pollination KW - predation KW - trait-based management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369992 VL - 58 ER - TY - JOUR A1 - Lux, Michael P. A1 - Schneeweiss, Andreas A1 - Hartkopf, Andreas D. A1 - Müller, Volkmar A1 - Janni, Wolfgang A1 - Belleville, Erik A1 - Stickeler, Elmar A1 - Thill, Marc A1 - Fasching, Peter A. A1 - Kolberg, Hans-Christian A1 - Untch, Michael A1 - Harbeck, Nadia A1 - Wöckel, Achim A1 - Thomssen, Christoph A1 - Schulmeyer, Carla E. A1 - Welslau, Manfred A1 - Overkamp, Friedrich A1 - Schütz, Florian A1 - Lüftner, Diana A1 - Ditsch, Nina T1 - Update Breast Cancer 2020 Part 5 – Moving Therapies From Advanced to Early Breast Cancer Patients JF - Geburtshilfe und Frauenheilkunde N2 - In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2−/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020. KW - early breast cancer KW - therapy KW - prognosis KW - immune therapy KW - digital medicine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369989 VL - 81 ER - TY - JOUR A1 - Luu, Maik A1 - Riester, Zeno A1 - Baldrich, Adrian A1 - Reichardt, Nicole A1 - Yuille, Samantha A1 - Busetti, Alessandro A1 - Klein, Matthias A1 - Wempe, Anne A1 - Leister, Hanna A1 - Raifer, Hartmann A1 - Picard, Felix A1 - Muhammad, Khalid A1 - Ohl, Kim A1 - Romero, Rossana A1 - Fischer, Florence A1 - Bauer, Christian A. A1 - Huber, Magdalena A1 - Gress, Thomas M. A1 - Lauth, Matthias A1 - Danhof, Sophia A1 - Bopp, Tobias A1 - Nerreter, Thomas A1 - Mulder, Imke E. A1 - Steinhoff, Ulrich A1 - Hudecek, Michael A1 - Visekruna, Alexander T1 - Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer JF - Nature Communications N2 - Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy. KW - tumour immunology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309332 VL - 12 ER - TY - JOUR A1 - Luo, Yueming A1 - Ling, Chuanren A1 - Liu, Yangchen A1 - Deng, Chong A1 - Waaga-Gasser, Ana Maria A1 - Chen, Minggui A1 - He, Zehui A1 - Chen, Erhui A1 - Wei, Lin A1 - Luo, Shimiao A1 - Gong, Xiaozhen A1 - Ye, Hong A1 - Zhu, Jing A1 - Song, Shan A1 - Wang, Qiuting A1 - Li, Shunmin A1 - Gasser, Martin A1 - Lin, Meizhen T1 - The Beneficial Role of Auricular Point Pressure in Insomnia and Anxiety in Isolated COVID-19 Patients JF - Evidence-Based Complementary and Alternative Medicine N2 - Background Coronavirus disease 2019 (COVID-19) causes psychological distress and can have a negative impact on the general mental health and rehabilitation in affected patients under currently implemented isolation guidelines. Auricular point pressure (APP) as well-established technique in traditional Chinese medicine may help to relieve sleep disturbance and anxiety in COVID-19 patients. Methods During the early phase of the epidemic/pandemic, patients were enrolled in this study (02/2020 until 03/2020 n = 84). They were strictly isolated on specific wards at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei. The retrospective cohort study design included two groups. Group A patients were treated with an auricular point pressure (APP) in addition to standard intensive care medicine while Group B participants (No-APP) received routine nursing measures alone. Treatment outcome was measured using the St. Mary’s Hospital Sleep Questionnaire (SMH) Score and the 7-Item Generalized Anxiety Disorder Scale (GAD-7). Both scores were measured in each patient at baseline and on the discharge day. Results The SMH score and sleep status changed in APP patients at the end of the treatment period when compared with No-APP patients (P < 0.01). APP-treated patients demonstrated lower GAD-7 scores than No-APP controls (P < 0.01). Further, no significant differences in safety or adverse events between the APP and No-APP groups were observed. Conclusion The results from our snapshot study during the early phase of the SARS-CoV-2 epidemic/pandemic suggest that auricular point pressure could be a simple and effective tool to relieve insomnia and situational anxiety in hospitalized patients suffering from COVID-19 and kept under disconcerting conditions of isolation. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369658 VL - 2021 ER - TY - JOUR A1 - Luijten, Linda W G A1 - Leonhard, Sonja E A1 - van der Eijk, Annemiek A A1 - Doets, Alex Y A1 - Appeltshauser, Luise A1 - Arends, Samuel A1 - Attarian, Shahram A1 - Benedetti, Luana A1 - Briani, Chiara A1 - Casasnovas, Carlos A1 - Castellani, Francesca A1 - Dardiotis, Efthimios A1 - Echaniz-Laguna, Andoni A1 - Garssen, Marcel P J A1 - Harbo, Thomas A1 - Huizinga, Ruth A1 - Humm, Andrea M A1 - Jellema, Korné A1 - van der Kooi, Anneke J A1 - Kuitwaard, Krista A1 - Kuntzer, Thierry A1 - Kusunoki, Susumu A1 - Lascano, Agustina M A1 - Martinez-Hernandez, Eugenia A1 - Rinaldi, Simon A1 - Samijn, Johnny P A A1 - Scheidegger, Olivier A1 - Tsouni, Pinelopi A1 - Vicino, Alex A1 - Visser, Leo H A1 - Walgaard, Christa A1 - Wang, Yuzhong A1 - Wirtz, Paul W A1 - Ripellino, Paolo A1 - Jacobs, Bart C T1 - Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study JF - Brain N2 - In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12–22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not. KW - Guillain-Barré syndrome KW - COVID-19 KW - SARS-CoV-2 KW - preceding infections KW - clinical phenotype Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371609 VL - 144 ER - TY - JOUR A1 - Lüders, Carolin A1 - Pukrop, Matthias A1 - Rozas, Elena A1 - Schneider, Christian A1 - Höfling, Sven A1 - Sperling, Jan A1 - Schumacher, Stefan A1 - Aßmann, Marc T1 - Quantifying Quantum Coherence in Polariton Condensates JF - PRX Quantum N2 - We theoretically and experimentally investigate quantum features of an interacting light-matter system from a multidisciplinary perspective, combining approaches from semiconductor physics, quantum optics, and quantum-information science. To this end, we quantify the amount of quantum coherence that results from the quantum superposition of Fock states, constituting a measure of the resourcefulness of the produced state for modern quantum protocols. This notion of quantum coherence from quantum-information theory is distinct from other quantifiers of nonclassicality that have previously been applied to condensed-matter systems. As an archetypal example of a hybrid light-matter interface, we study a polariton condensate and implement a numerical model to predict its properties. Our simulation is confirmed by our proof-of-concept experiment in which we measure and analyze the phase-space distributions of the emitted light. Specifically, we drive a polariton microcavity across the condensation threshold and observe the transition from an incoherent thermal state to a coherent state in the emission, thus confirming the buildup of quantum coherence in the condensate itself. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369644 VL - 2 ER - TY - JOUR A1 - Ludwig, Jonas A1 - Dignath, David A1 - Lukas, Sarah T1 - Positive and negative action-effects improve task-switching performance JF - Acta Psychologica N2 - Anticipation of one's own actions' effects drives goal-directed behavior. In multitasking environments, the learning of stable action-effect associations seems particularly important, because establishing reliable response-effect associations for multiple competing tasks may help to differentiate between these tasks and thereby improve task-switching performance. Action-effects not only have cognitive, but also motivational aspects and often the consequences of our actions are hedonically marked. Thus, the anticipated hedonic quality of action-effects may also become part of the task representation, and positive and negative affect may distinctly modulate task-switching performance. We report a pre-registered experiment (N = 120) designed to examine how positive, negative, and neutral valence of action-effects impact performance in a cued task-switching paradigm. Pictures from the IAPS database were used to manipulate the action-effects' valence. Affective valence determined reaction times: participants who learned positive or negative action-effects responded faster than participants in the control condition. In particular, task-switch trials were faster in both conditions than in the control condition, while task-repetition trials were comparable across valence conditions. Our results further suggest that performance improvements in the positive and negative valence conditions occurred for different reasons. Negative action-effects expedited responses specifically for the task that produced the unpleasant outcome, while positive affect more generally promoted performance of both tasks. These findings point toward distinct roles of positive and negative valence of action-effects in regulating multitasking performance. KW - action control KW - multitasking KW - task-switching KW - action-effects KW - affective valence Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369638 VL - 221 ER - TY - JOUR A1 - Lu, Yuan A1 - Bierbach, David A1 - Ormanns, Jenny A1 - Warren, Wesley C. A1 - Walter, Ronald B. A1 - Schartl, Manfred T1 - Fixation of allelic gene expression landscapes and expression bias pattern shape the transcriptome of the clonal Amazon molly JF - Genome Research N2 - The Amazon molly is a unique clonal fish species that originated from an interspecies hybrid between Poecilia species P. mexicana and P. latipinna. It reproduces by gynogenesis, which eliminates paternal genomic contribution to offspring. An earlier study showed that Amazon molly shows biallelic expression for a large portion of the genome, leading to two main questions: (1) Are the allelic expression patterns from the initial hybridization event stabilized or changed during establishment of the asexual species and its further evolution? (2) Is allelic expression biased toward one parental allele a stochastic or adaptive process? To answer these questions, the allelic expression of P. formosa siblings was assessed to investigate intra- and inter-cohort allelic expression variability. For comparison, interspecies hybrids between P. mexicana and P. latipinna were produced in the laboratory to represent the P. formosa ancestor. We have identified inter-cohort and intra-cohort variation in parental allelic expression. The existence of inter-cohort divergence suggests functional P. formosa allelic expression patterns do not simply reflect the atavistic situation of the first interspecies hybrid but potentially result from long-term selection of transcriptional fitness. In addition, clonal fish show a transcriptional trend representing minimal intra-clonal variability in allelic expression patterns compared to the corresponding hybrids. The intra-clonal similarity in gene expression translates to sophisticated genetic functional regulation at the individuum level. These findings suggest the parental alleles inherited by P. formosa form tightly regulated genetic networks that lead to a stable transcriptomic landscape within clonal individuals. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369578 VL - 31 ER - TY - JOUR A1 - Loza-Valdes, Angel A1 - Mayer, Alexander E A1 - Kassouf, Toufic A1 - Trujillo-Viera, Jonathan A1 - Schmitz, Werner A1 - Dziaczkowski, Filip A1 - Leitges, Michael A1 - Schlosser, Andreas A1 - Sumara, Grzegorz T1 - A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism JF - Life Science Alliance N2 - Members of the protein kinase D (PKD) family (PKD1, 2, and 3) integrate hormonal and nutritional inputs to regulate complex cellular metabolism. Despite the fact that a number of functions have been annotated to particular PKDs, their molecular targets are relatively poorly explored. PKD3 promotes insulin sensitivity and suppresses lipogenesis in the liver of animals fed a high-fat diet. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified more than 300 putative targets of PKD3. Furthermore, biochemical analysis revealed that PKD3 regulates cAMP-dependent PKA activity, a master regulator of the hepatic response to glucagon and fasting. PKA regulates glucose, lipid, and amino acid metabolism in the liver, by targeting key enzymes in the respective processes. Among them the PKA targets phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Consistently, we showed that PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Therefore, our data indicate that PKD3 might play a role in the hepatic response to glucagon. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369560 VL - 4 ER - TY - JOUR A1 - Lotan, Yair A1 - Gakis, Georgios A1 - Manfredi, Matteo A1 - Morote, Juan A1 - Mostafid, Hugh A1 - Porpiglia, Francesco A1 - Poyet, Cedric A1 - Roupret, Morgan A1 - Schulman, Claude A1 - Shariat, Shahrokh F. A1 - Witjes, Johannes Alfred T1 - Alternating Cystoscopy with Bladder EpiCheck® in the Surveillance of Low-Grade Intermediate-Risk NMIBC: A Cost Comparison Model JF - Bladder Cancer N2 - Background: Bladder cancer surveillance is invasive, intensive and costly. Patients with low grade intermediate risk non-muscle invasive bladder cancer (NMIBC) are at high risk of recurrence. Objective: The objective of this model is to compare the cost of a strategy to alternate surveillance with cystoscopy and a urine marker, Bladder EpiCheck, to standard surveillance. Methods: A decision tree model was built using TreeAge Pro Healthcare to compare standard surveillance (Standard) with a modified surveillance incorporating Bladder EpiCheck. The model was based on 2 years of surveillance. Outcomes were obtained from literature. Costs were obtained from US and 9 European countries. Sensitivity analyses were performed. Results: The efficacy of the model was equivalent in terms of recurrence for each arm with median recurrence rate of 22%. When setting marker price at 200 local currency, the marker arm was less expensive in the USA, Netherlands, Switzerland, Belgium, Italy, Austria and UK by 154€ to 329£ per patient, for a 2-year period. Cost was higher in France, Spain, and Germany by 33–103€. Cost parity was achieved with marker price between 148€ and $421. Marker cost and specificity have the greatest impact on the overall model cost. Conclusions: A strategy alternating the urine marker Bladder EpiCheck with cystoscopy in the surveillance of patients with low grade intermediate risk bladder cancer is cost equivalent in the US and European countries when the marker is priced 148€ –$421, as a result of the marker’s high specificity (86%). Prospective studies will be necessary to validate these findings. KW - bladder cancer KW - urinary markers KW - NMIBC surveillance KW - cost model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369512 VL - 7 ER - TY - JOUR A1 - Loscher, Georg A1 - Löhlein, Lukas A1 - Lenz, Hansrudi T1 - Dual Roles and Blurred Identities: A Framing Contest between Professional Associations in a Local Strategic Action Field JF - European Accounting Review N2 - This paper examines professional associations’ local responses to global demands of accounting standardisation. Our longitudinal study from 1998 to 2018 analyses how professional associations of the German audit profession engaged in an intense framing contest over the adoption of external quality controls. Drawing on the concept of strategic action field and the literature on framing, we unpack how the gap between large audit firms and small audit firms increasingly undermined the capacity of the professional associations to fulfil their dual role of governance and representation. We unveil how their failed attempt to maintain the image of an unified profession ultimately led to the creation of a new professional association representing the ‘small auditor’ professional, which successfully, albeit temporarily, took control over the field of German auditing. Our findings suggest that the passivity of small audit firms in the process of translating global regulatory regimes should not be presumed. Rather, we provide insight into how small audit firms can rebuild their own identity by actively responding to waves of global regulation. Doing so, and contrary to prior research, our case highlights that governance units within strategic action fields are not necessarily aligned with the interests of the most powerful field actors. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369504 VL - 30 ER - TY - JOUR A1 - Löw, Johannes A1 - Ullmann, Tobias A1 - Conrad, Christopher T1 - The Impact of Phenological Developments on Interferometric and Polarimetric Crop Signatures Derived from Sentinel-1: Examples from the DEMMIN Study Site (Germany) JF - Remote Sensing N2 - This study explores the potential of Sentinel-1 Synthetic Aperture Radar (SAR) to identify phenological phases of wheat, sugar beet, and canola. Breakpoint and extreme value analyses were applied to a dense time series of interferometric (InSAR) and polarimetric (PolSAR) features recorded during the growing season of 2017 at the JECAM site DEMMIN (Germany). The analyses of breakpoints and extrema allowed for the distinction of vegetative and reproductive stages for wheat and canola. Certain phenological stages, measured in situ using the BBCH-scale, such as leaf development and rosette growth of sugar beet or stem elongation and ripening of wheat, were detectable by a combination of InSAR coherence, polarimetric Alpha and Entropy, and backscatter (VV/VH). Except for some fringe cases, the temporal difference between in situ observations and breakpoints or extrema ranged from zero to five days. Backscatter produced the signature that generated the most breakpoints and extrema. However, certain micro stadia, such as leaf development of BBCH 10 of sugar beet or flowering BBCH 69 of wheat, were only identifiable by the InSAR coherence and Alpha. Hence, it is concluded that combining PolSAR and InSAR features increases the number of detectable phenological events in the phenological cycles of crops. KW - PolSAR KW - InSAR KW - Kennaugh matrix KW - time series KW - Sentinel-1 KW - crop phenology KW - DEMMIN Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369452 VL - 13 ER - TY - JOUR A1 - Löblein, Jochen A1 - Lorson, Thomas A1 - Komma, Miriam A1 - Kielholz, Tobias A1 - Windbergs, Maike A1 - Dalton, Paul D. A1 - Luxenhofer, Robert T1 - An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone) JF - Beilstein Journal of Organic Chemistry N2 - Additive manufacturing or 3D printing as an umbrella term for various materials processing methods has distinct advantages over many other processing methods, including the ability to generate highly complex shapes and designs. However, the performance of any produced part not only depends on the material used and its shape, but is also critically dependent on its surface properties. Important features, such as wetting or fouling, critically depend mainly on the immediate surface energy. To gain control over the surface chemistry post-processing modifications are generally necessary, since it′s not a feature of additive manufacturing. Here, we report on the use of initiator and catalyst-free photografting and photopolymerization for the hydrophilic modification of microfiber scaffolds obtained from hydrophobic medical-grade poly(ε-caprolactone) via melt-electrowriting. Contact angle measurements and Raman spectroscopy confirms the formation of a more hydrophilic coating of poly(2-hydroxyethyl methacrylate). Apart from surface modification, we also observe bulk polymerization, which is expected for this method, and currently limits the controllability of this procedure. KW - additive manufacturing KW - light-induced polymerization KW - self-initiated photografting and photopolymerization KW - surface-initiated polymerization KW - surface modification Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369433 VL - 17 ER - TY - JOUR A1 - Lock, Johan F A1 - Reimer, Stanislaus A1 - Pietryga, Sebastian A1 - Jakubietz, Rafael A1 - Flemming, Sven A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Seyfried, Florian T1 - Managing esophagocutaneous fistula after secondary gastric pull-up: A case report JF - World Journal of Gastroenterology N2 - Background Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure. Case summary A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events. Conclusion A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition. KW - esophageal fistula KW - gastric fistula KW - esophageal stenosis KW - esophageal perforation KW - endoscopic vacuum therapy KW - free-jejunal graft KW - autogenous jejunum transplantation KW - case report Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369417 VL - 27 ER - TY - JOUR A1 - Ljubojević-Holzer, Senka A1 - Kraler, Simon A1 - Djalinac, Nataša A1 - Abdellatif, Mahmoud A1 - Voglhuber, Julia A1 - Schipke, Julia A1 - Schmidt, Marlene A1 - Kling, Katharina-Maria A1 - Franke, Greta Therese A1 - Herbst, Viktoria A1 - Zirlik, Andreas A1 - von Lewinski, Dirk A1 - Scherr, Daniel A1 - Rainer, Peter P A1 - Kohlhaas, Michael A1 - Nickel, Alexander A1 - Mühlfeld, Christian A1 - Maack, Christoph A1 - Sedej, Simon T1 - Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling JF - Cardiovascular Research N2 - Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve. KW - cardiomyocytes KW - calcium KW - mitochondria KW - autophagy KW - beta-adrenergic signalling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369345 VL - 118 ER - TY - JOUR A1 - Linz, Christian A1 - Brands, Roman C. A1 - Kertels, Olivia A1 - Dierks, Alexander A1 - Brumberg, Joachim A1 - Gerhard-Hartmann, Elena A1 - Hartmann, Stefan A1 - Schirbel, Andreas A1 - Serfling, Sebastian A1 - Zhi, Yingjun A1 - Buck, Andreas K. A1 - Kübler, Alexander A1 - Hohm, Julian A1 - Lapa, Constantin A1 - Kircher, Malte T1 - Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [18F]FDG PET/CT and MRI JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose While [18F]-fluorodeoxyglucose ([18F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [18F]FDG and [68Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUVmax) and peak (SUVpeak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [18F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([18F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [18F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted. KW - molecular imaging KW - fibroblast activation protein KW - head and neck cancer KW - PET Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369331 VL - 48 ER - TY - JOUR A1 - Linz, Christian A1 - Brands, Roman C. A1 - Herterich, Theresia A1 - Hartmann, Stefan A1 - Müller-Richter, Urs A1 - Kübler, Alexander C. A1 - Haug, Lukas A1 - Kertels, Olivia A1 - Bley, Thorsten A. A1 - Dierks, Alexander A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Brumberg, Joachim T1 - Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity JF - JAMA Network Open N2 - Importance Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis. Objective To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases. Design, Setting, and Participants This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients’ tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled. Exposures All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection. Main Outcomes and Measures The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference. Results Of the 150 patients enrolled, 135 patients (74 [54.8%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3% sensitivity (95% CI, 71.2%-95.5%) and 84.8% specificity (95% CI, 77.8%-91.9%) and had a negative predictive value of 93.3% (95% CI, 88.2%-98.5%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0%; 95% CI, 57.4%-76.7%; P < .01) and cervical magnetic resonance imaging (62.6%; 95% CI, 52.7%-72.6%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6% sensitivity (95% CI, 63.4%-93.8%) and 83.1% specificity (95% CI, 75.1%-91.2%), and contralateral metastatic involvement was detected with 66.7% sensitivity (95% CI, 28.9%-100.0%) and 98.6% specificity (95% CI, 95.9%-100.0%). No distant metastases were observed. Conclusions and Relevance In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369313 VL - 4 ER - TY - JOUR A1 - Linz, Benedikt A1 - Hohl, Mathias A1 - Lang, Lisa A1 - Wong, Dickson W. L. A1 - Nickel, Alexander G. A1 - De La Torre, Carolina A1 - Sticht, Carsten A1 - Wirth, Klaus A1 - Boor, Peter A1 - Maack, Christoph A1 - Speer, Thimoteus A1 - Jespersen, Thomas A1 - Schotten, Ulrich A1 - Sanders, Prashanthan A1 - Böhm, Michael A1 - Linz, Dominik T1 - Repeated exposure to transient obstructive sleep apnea–related conditions causes an atrial fibrillation substrate in a chronic rat model JF - Heart Rhythm N2 - Background High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. Objective We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate. Methods INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). Results INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). Conclusion Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development. KW - atrial fibrillation KW - night-to-night variability KW - obstructive sleep apnea KW - rats KW - substrate Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369298 VL - 18 ER - TY - JOUR A1 - Linhoff, Lena A1 - Sandrock, Alexander A1 - Kadler, Matthias A1 - Elsässer, Dominik A1 - Rhode, Wolfgang T1 - Excluding possible sites of high-energy emission in 3C 84 JF - Monthly Notices of the Royal Astronomical Society N2 - The FR-I galaxy 3C 84, that is identified with the misaligned blazar NGC 1275, is well known as one of the very few radio galaxies emitting gamma-rays in the TeV range. Yet, the gamma-ray emission region cannot be pinpointed and the responsible mechanisms are still unclear. We calculate the optical absorption depth of high-energy photons in the broad-line region of 3C 84 depending on their energy and distance to the central black hole. Based on these calculations, a lower limit on the distance of the emission region from the central black hole can be derived. These lower limits are estimated for two broad-line region geometries (shell and ring) and two states of the source, the low state in 2016 October–December and a flare state in 2017 January. For the shell geometry, we can place the emission region outside the Ly α radius. For the ring geometry and the low flux activity, the minimal distance between the black hole, and the gamma-ray emission region is close to the Ly α radius. In the case of the flaring state (ring geometry), the results are not conclusive. Our results exclude the region near the central black hole as the origin of the gamma-rays detected by Fermi–LAT and Major Atmospheric Gamma-Ray Imaging Cherenkov. With these findings, we can constrain the theoretical models of acceleration mechanisms and compare the possible emission region to the source’s morphology resolved by radio images from the Very Long Baseline Array. KW - acceleration of particles KW - astroparticle physics KW - galaxies: individual: NGC 1275 KW - galaxies: jets KW - gamma-rays: galaxies KW - radio continuum: galaxies Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369287 VL - 500 ER - TY - JOUR A1 - Liebers, Nora A1 - Duell, Johannes A1 - Fitzgerald, Donnacha A1 - Kerkhoff, Andrea A1 - Noerenberg, Daniel A1 - Kaebisch, Eva A1 - Acker, Fabian A1 - Fuhrmann, Stephan A1 - Leng, Corinna A1 - Welslau, Manfred A1 - Chemnitz, Jens A1 - Middeke, Jan-Moritz A1 - Weber, Thomas A1 - Holtick, Udo A1 - Trappe, Ralf A1 - Pfannes, Roald A1 - Liersch, Ruediger A1 - Spoer, Christian A1 - Fuxius, Stefan A1 - Gebauer, Niklas A1 - Caillé, Léandra A1 - Geer, Thomas A1 - Koenecke, Christian A1 - Keller, Ulrich A1 - Claus, Rainer A1 - Mougiakakos, Dimitrios A1 - Mayer, Stephanie A1 - Huettmann, Andreas A1 - Pott, Christiane A1 - Trummer, Arne A1 - Wulf, Gerald A1 - Brunnberg, Uta A1 - Bullinger, Lars A1 - Hess, Georg A1 - Mueller-Tidow, Carsten A1 - Glass, Bertram A1 - Lenz, Georg A1 - Dreger, Peter A1 - Dietrich, Sascha T1 - Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas JF - Blood Advances N2 - The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369173 VL - 5 ER - TY - JOUR A1 - Liang, Huan-Chang A1 - Costanza, Mariantonia A1 - Prutsch, Nicole A1 - Zimmerman, Mark W. A1 - Gurnhofer, Elisabeth A1 - Montes-Mojarro, Ivonne A. A1 - Abraham, Brian J. A1 - Prokoph, Nina A1 - Stoiber, Stefan A1 - Tangermann, Simone A1 - Lobello, Cosimo A1 - Oppelt, Jan A1 - Anagnostopoulos, Ioannis A1 - Hielscher, Thomas A1 - Pervez, Shahid A1 - Klapper, Wolfram A1 - Zammarchi, Francesca A1 - Silva, Daniel-Adriano A1 - Garcia, K. Christopher A1 - Baker, David A1 - Janz, Martin A1 - Schleussner, Nikolai A1 - Fend, Falko A1 - Pospíšilová, Šárka A1 - Janiková, Andrea A1 - Wallwitz, Jacqueline A1 - Stoiber, Dagmar A1 - Simonitsch-Klupp, Ingrid A1 - Cerroni, Lorenzo A1 - Pileri, Stefano A1 - de Leval, Laurence A1 - Sibon, David A1 - Fataccioli, Virginie A1 - Gaulard, Philippe A1 - Assaf, Chalid A1 - Knörr, Fabian A1 - Damm-Welk, Christine A1 - Woessmann, Wilhelm A1 - Turner, Suzanne D. A1 - Look, A. Thomas A1 - Mathas, Stephan A1 - Kenner, Lukas A1 - Merkel, Olaf T1 - Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma JF - Nature Communications N2 - Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL. KW - CRISPR-Cas9 genome editing KW - high-throughput screening KW - mechanisms of disease KW - T-cell lymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371581 VL - 12 ER - TY - JOUR A1 - Li, Yuanyue A1 - Kuhn, Michael A1 - Zukowska-Kasprzyk, Joanna A1 - Hennrich, Marco L. A1 - Kastritis, Panagiotis L. A1 - O'Reilly, Francis J. A1 - Phapale, Prasad A1 - Beck, Martin A1 - Gavin, Anne-Claude A1 - Bork, Peer T1 - Coupling proteomics and metabolomics for the unsupervised identification of protein–metabolite interactions in Chaetomium thermophilum JF - PLOS ONE N2 - Protein–metabolite interactions play an important role in the cell’s metabolism and many methods have been developed to screen them in vitro. However, few methods can be applied at a large scale and not alter biological state. Here we describe a proteometabolomic approach, using chromatography to generate cell fractions which are then analyzed with mass spectrometry for both protein and metabolite identification. Integrating the proteomic and metabolomic analyses makes it possible to identify protein-bound metabolites. Applying the concept to the thermophilic fungus Chaetomium thermophilum, we predict 461 likely protein-metabolite interactions, most of them novel. As a proof of principle, we experimentally validate a predicted interaction between the ribosome and isopentenyl adenine. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364299 VL - 16 ER - TY - JOUR A1 - Li, Wenhong A1 - Sancho, Ana A1 - Chung, Wen-Lu A1 - Vinik, Yaron A1 - Groll, Jürgen A1 - Zick, Yehiel A1 - Medalia, Ohad A1 - Bershadsky, Alexander D. A1 - Benjamin, Geiger T1 - Differential cellular responses to adhesive interactions with galectin-8- and fibronectin-coated substrates JF - Journal of Cell Science N2 - The mechanisms underlying the cellular response to extracellular matrices (ECMs) that consist of multiple adhesive ligands are still poorly understood. Here, we address this topic by monitoring specific cellular responses to two different extracellular adhesion molecules – the main integrin ligand fibronectin and galectin-8, a lectin that binds β-galactoside residues − as well as to mixtures of the two proteins. Compared with cell spreading on fibronectin, cell spreading on galectin-8-coated substrates resulted in increased projected cell area, more-pronounced extension of filopodia and, yet, the inability to form focal adhesions and stress fibers. These differences can be partially reversed by experimental manipulations of small G-proteins of the Rho family and their downstream targets, such as formins, the Arp2/3 complex and Rho kinase. We also show that the physical adhesion of cells to galectin-8 was stronger than adhesion to fibronectin. Notably, galectin-8 and fibronectin differently regulate cell spreading and focal adhesion formation, yet act synergistically to upregulate the number and length of filopodia. The physiological significance of the coherent cellular response to a molecularly complex matrix is discussed. This article has an associated First Person interview with the first author of the paper. KW - extracellular matrix KW - focal adhesions KW - filopodia KW - lamellipodia KW - myosin-II KW - Rho GTPases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364286 VL - 134 ER - TY - JOUR A1 - Li, Shushan A1 - Stöckl, Sabine A1 - Lukas, Christoph A1 - Herrmann, Marietta A1 - Brochhausen, Christoph A1 - König, Matthias A. A1 - Johnstone, Brian A1 - Grässel, Susanne T1 - Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1β-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p JF - Stem Cell Research & Therapy N2 - Background Curcumin has anti-inflammatory effects and qualifies as a potential candidate for the treatment of osteoarthritis (OA). However, curcumin has limited bioavailability. Extracellular vesicles (EVs) are released by multiple cell types and act as molecule carrier during intercellular communication. We assume that EVs can maintain bioavailability and stability of curcumin after encapsulation. Here, we evaluated modulatory effects of curcumin-primed human (h)BMSC-derived EVs (Cur-EVs) on IL-1β stimulated human osteoarthritic chondrocytes (OA-CH). Methods CellTiter-Blue Viability- (CTB), Caspase 3/7-, and live/dead assays were used to determine range of cytotoxic curcumin concentrations for hBMSC and OA-CH. Cur-EVs and control EVs were harvested from cell culture supernatants of hBMSC by ultracentrifugation. Western blotting (WB), transmission electron microscopy, and nanoparticle tracking analysis were performed to characterize the EVs. The intracellular incorporation of EVs derived from PHK26 labeled and curcumin-primed or control hBMSC was tested by adding the labeled EVs to OA-CH cultures. OA-CH were pre-stimulated with IL-1β, followed by Cur-EV and control EV treatment for 24 h and subsequent analysis of viability, apoptosis, and migration (scratch assay). Relative expression of selected anabolic and catabolic genes was assessed with qRT-PCR. Furthermore, WB was performed to evaluate phosphorylation of Erk1/2, PI3K/Akt, and p38MAPK in OA-CH. The effect of hsa-miR-126-3p expression on IL-1β-induced OA-CH was determined using CTB-, Caspase 3/7-, live/dead assays, and WB. Results Cur-EVs promoted viability and reduced apoptosis of IL-1β-stimulated OA-CH and attenuated IL-1β-induced inhibition of migration. Furthermore, Cur-EVs increased gene expression of BCL2, ACAN, SOX9, and COL2A1 and decreased gene expression of IL1B, IL6, MMP13, and COL10A1 in IL-1β-stimulated OA-CH. In addition, phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK, induced by IL-1β, is prevented by Cur-EVs. Cur-EVs increased IL-1β-reduced expression of hsa-miR-126-3p and hsa-miR-126-3p mimic reversed the effects of IL-1β. Conclusion Cur-EVs alleviated IL-1β-induced catabolic effects on OA-CH by promoting viability and migration, reducing apoptosis and phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK thereby modulating pro-inflammatory signaling pathways. Treatment of OA-CH with Cur-EVs is followed by upregulation of expression of hsa-miR-126-3p which is involved in modulation of anabolic response of OA-CH. EVs may be considered as promising drug delivery vehicles of curcumin helping to alleviate OA. KW - BMSC KW - curcumin KW - extracellular vesicles KW - IL-1β KW - osteoarthritis KW - pro-inflammatory signaling pathways KW - chondrocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364237 VL - 12 ER - TY - JOUR A1 - Li, Ming A1 - Zhang, Rui A1 - Fan, Guangyi A1 - Xu, Wenteng A1 - Zhou, Qian A1 - Wang, Lei A1 - Li, Wensheng A1 - Pang, Zunfang A1 - Yu, Mengjun A1 - Liu, Qun A1 - Liu, Xin A1 - Schartl, Manfred A1 - Chen, Songlin T1 - Reconstruction of the Origin of a Neo-Y Sex Chromosome and Its Evolution in the Spotted Knifejaw, Oplegnathus punctatus JF - Molecular Biology and Evolution N2 - Sex chromosomes are a peculiar constituent of the genome because the evolutionary forces that fix the primary sex-determining gene cause genic degeneration and accumulation of junk DNA in the heterogametic partner. One of the most spectacular phenomena in sex chromosome evolution is the occurrence of neo-Y chromosomes, which lead to X1X2Y sex-determining systems. Such neo-sex chromosomes are critical for understanding the processes of sex chromosome evolution because they rejuvenate their total gene content. We assembled the male and female genomes at the chromosome level of the spotted knifejaw (Oplegnathus punctatus), which has a cytogenetically recognized neo-Y chromosome. The full assembly and annotation of all three sex chromosomes allowed us to reconstruct their evolutionary history. Contrary to other neo-Y chromosomes, the fusion to X2 is quite ancient, estimated at 48 Ma. Despite its old age and being even older in the X1 homologous region which carries a huge inversion that occurred as early as 55–48 Ma, genetic degeneration of the neo-Y appears to be only moderate. Transcriptomic analysis showed that sex chromosomes harbor 87 genes, which may serve important functions in the testis. The accumulation of such male-beneficial genes, a large inversion on the X1 homologous region and fusion to X2 appear to be the main drivers of neo-Y evolution in the spotted knifejaw. The availability of high-quality assemblies of the neo-Y and both X chromosomes make this fish an ideal model for a better understanding of the variability of sex determination mechanisms and of sex chromosome evolution. KW - neo-Y KW - evolution; KW - spotted knifejaw KW - genome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364215 VL - 38 ER - TY - JOUR A1 - Li, Jinlin A1 - Nagy, Noemi A1 - Liu, Jiangnan A1 - Gupta, Soham A1 - Frisan, Teresa A1 - Hennig, Thomas A1 - Cameron, Donald P. A1 - Baranello, Laura A1 - Masucci, Maria G. T1 - The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection JF - PLOS Pathogens N2 - Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOy-lated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363841 VL - 17 ER - TY - JOUR A1 - Li, Donghai A1 - Trovatello, Chiara A1 - Dal Conte, Stefano A1 - Nuß, Matthias A1 - Soavi, Giancarlo A1 - Wang, Gang A1 - Ferrari, Andrea C. A1 - Cerullo, Giulio A1 - Brixner, Tobias T1 - Exciton–phonon coupling strength in single-layer MoSe2 at room temperature JF - Nature Communications N2 - Single-layer transition metal dichalcogenides are at the center of an ever increasing research effort both in terms of fundamental physics and applications. Exciton–phonon coupling plays a key role in determining the (opto)electronic properties of these materials. However, the exciton–phonon coupling strength has not been measured at room temperature. Here, we use two-dimensional micro-spectroscopy to determine exciton–phonon coupling of single-layer MoSe2. We detect beating signals as a function of waiting time induced by the coupling between A excitons and A′1 optical phonons. Analysis of beating maps combined with simulations provides the exciton–phonon coupling. We get a Huang–Rhys factor ~1, larger than in most other inorganic semiconductor nanostructures. Our technique offers a unique tool to measure exciton–phonon coupling also in other heterogeneous semiconducting systems, with a spatial resolution ~260 nm, and provides design-relevant parameters for the development of optoelectronic devices. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363837 VL - 12 ER - TY - JOUR A1 - Lewis, Richard A1 - Habringer, Stefan A1 - Kircher, Malte A1 - Hefter, Maike A1 - Peuker, Caroline Anna A1 - Werner, Rudolf A1 - Ademaj-Kospiri, Valëza A1 - Gäble, Alexander A1 - Weber, Wolfgang A1 - Wester, Hans-Jürgen A1 - Buck, Andreas A1 - Herhaus, Peter A1 - Lapa, Constantin A1 - Keller, Ulrich T1 - Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients JF - EJNMMI Research N2 - Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities. KW - solid tumors KW - clinical studies KW - retrospective studies KW - molecular imaging KW - PET KW - CXCR4 KW - Pentixafor KW - spleen KW - uptake Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363820 VL - 11 ER - TY - JOUR A1 - Levitis, Elizabeth A1 - Gould van Praag, Cassandra D A1 - Gau, Rémi A1 - Heunis, Stephan A1 - DuPre, Elizabeth A1 - Kiar, Gregory A1 - Bottenhorn, Katherine L A1 - Glatard, Tristan A1 - Nikolaidis, Aki A1 - Whitaker, Kirstie Jane A1 - Mancini, Matteo A1 - Niso, Guiomar A1 - Afyouni, Soroosh A1 - Alonso-Ortiz, Eva A1 - Appelhoff, Stefan A1 - Arnatkeviciute, Aurina A1 - Atay, Selim Melvin A1 - Auer, Tibor A1 - Baracchini, Giulia A1 - Bayer, Johanna M M A1 - Beauvais, Michael J S A1 - Bijsterbosch, Janine D A1 - Bilgin, Isil P A1 - Bollmann, Saskia A1 - Bollmann, Steffen A1 - Botvinik-Nezer, Rotem A1 - Bright, Molly G A1 - Calhoun, Vince D A1 - Chen, Xiao A1 - Chopra, Sidhant A1 - Chuan-Peng, Hu A1 - Close, Thomas G A1 - Cookson, Savannah L A1 - Craddock, R Cameron A1 - De La Vega, Alejandro A1 - De Leener, Benjamin A1 - Demeter, Damion V A1 - Di Maio, Paola A1 - Dickie, Erin W A1 - Eickhoff, Simon B A1 - Esteban, Oscar A1 - Finc, Karolina A1 - Frigo, Matteo A1 - Ganesan, Saampras A1 - Ganz, Melanie A1 - Garner, Kelly G A1 - Garza-Villarreal, Eduardo A A1 - Gonzalez-Escamilla, Gabriel A1 - Goswami, Rohit A1 - Griffiths, John D A1 - Grootswagers, Tijl A1 - Guay, Samuel A1 - Guest, Olivia A1 - Handwerker, Daniel A A1 - Herholz, Peer A1 - Heuer, Katja A1 - Huijser, Dorien C A1 - Iacovella, Vittorio A1 - Joseph, Michael J E A1 - Karakuzu, Agah A1 - Keator, David B A1 - Kobeleva, Xenia A1 - Kumar, Manoj A1 - Laird, Angela R A1 - Larson-Prior, Linda J A1 - Lautarescu, Alexandra A1 - Lazari, Alberto A1 - Legarreta, Jon Haitz A1 - Li, Xue-Ying A1 - Lv, Jinglei A1 - Mansour L., Sina A1 - Meunier, David A1 - Moraczewski, Dustin A1 - Nandi, Tulika A1 - Nastase, Samuel A A1 - Nau, Matthias A1 - Noble, Stephanie A1 - Norgaard, Martin A1 - Obungoloch, Johnes A1 - Oostenveld, Robert A1 - Orchard, Edwina R A1 - Pinho, Ana Luísa A1 - Poldrack, Russell A A1 - Qiu, Anqi A1 - Raamana, Pradeep Reddy A1 - Rokem, Ariel A1 - Rutherford, Saige A1 - Sharan, Malvika A1 - Shaw, Thomas B A1 - Syeda, Warda T A1 - Testerman, Meghan M A1 - Toro, Roberto A1 - Valk, Sofie L A1 - Van Den Bossche, Sofie A1 - Varoquaux, Gaël A1 - Váša, František A1 - Veldsman, Michele A1 - Vohryzek, Jakub A1 - Wagner, Adina S A1 - Walsh, Reubs J A1 - White, Tonya A1 - Wong, Fu-Te A1 - Xie, Xihe A1 - Yan, Chao-Gan A1 - Yang, Yu-Fang A1 - Yee, Yohan A1 - Zanitti, Gaston E A1 - Van Gulick, Ana E A1 - Duff, Eugene A1 - Maumet, Camille T1 - Centering inclusivity in the design of online conferences—An OHBM–Open Science perspective JF - GigaScience N2 - As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume. KW - online conferences KW - diversity KW - inclusivity KW - open science KW - collaborative events Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371574 VL - 10 ER -