@article{ShaoMaPairaetal.2018, author = {Shao, Yi-Ming and Ma, Xiaohua and Paira, Priyankar and Tan, Aaron and Herr, Deron Raymond and Lim, Kah Leong and Ng, Chee Hoe and Venkatesan, Gopalakrishnan and Klotz, Karl-Norbert and Federico, Stephanie and Spalluto, Giampiero and Cheong, Siew Lee and Chen, Yu Zong and Pastorin, Giorgia}, title = {Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment}, series = {PLoS ONE}, volume = {13}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0188212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237766}, year = {2018}, abstract = {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).}, language = {en} } @article{FoersterKoziolSchaeferetal.2019, author = {F{\"o}rster, Sabine and Koziol, Uriel and Sch{\"a}fer, Tina and Duvoisin, Raphael and Cailliau, Katia and Vanderstraete, Mathieu and Dissous, Colette and Brehm, Klaus}, title = {The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction}, series = {PLoS Neglected Tropical Diseases}, volume = {13}, journal = {PLoS Neglected Tropical Diseases}, doi = {10.1371/journal.pntd.0006959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228190}, year = {2019}, abstract = {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.}, language = {en} } @article{NagyCusumanoAndreattaetal.2019, author = {Nagy, D{\´o}ra and Cusumano, Paola and Andreatta, Gabriele and Martin Anduaga, Ane and Hermann-Luibl, Christiane and Reinhard, Nils and Gesto, Jo{\~a}o and Wegener, Christian and Mazzotta, Gabriella and Rosato, Ezio and Kyriacou, Charalambos P. and Helfrich-F{\"o}rster, Charlotte and Costa, Rodolfo}, title = {Peptidergic signaling from clock neurons regulates reproductive dormancy in Drosophila melanogaster}, series = {PLoS Genetics}, volume = {15}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1008158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231681}, year = {2019}, abstract = {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.}, language = {en} } @article{LiLiuVanselowetal.2019, author = {Li, Ying H. and Liu, Xianhui and Vanselow, Jens T. and Zheng, Haiyan and Schlosser, Andreas and Chiu, Joanna C.}, title = {O-GlcNAcylation of PERIOD regulates its interaction with CLOCK and timing of circadian transcriptional repression}, series = {PLoS Genetics}, volume = {15}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007953}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236826}, year = {2019}, abstract = {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.}, language = {en} } @article{delOlmoToledoPuccinelliFordyceetal.2018, author = {del Olmo Toledo, Valentina and Puccinelli, Robert and Fordyce, Polly M. and P{\´e}rez, J. Christian}, title = {Diversification of DNA binding specificities enabled SREBP transcription regulators to expand the repertoire of cellular functions that they govern in fungi}, series = {PLoS Genetics}, volume = {14}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007884}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228983}, year = {2018}, abstract = {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.}, language = {en} } @article{LuBoswellBoswelletal.2018, author = {Lu, Yuan and Boswell, Mikki and Boswell, William and Kneitz, Susanne and Klotz, Barbara and Savage, Markita and Salinas, Raquel and Marks, Rebacca and Regneri, Janine and Postlethwait, John and Warren, Wesley C. and Schartl, Manfred and Walter, Ronald}, title = {Gene expression variation and parental allele inheritance in a Xiphophorus interspecies hybridization model}, series = {PLoS Genetics}, volume = {14}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007875}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237318}, year = {2018}, abstract = {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.}, language = {en} } @article{ElMoualiGaviriaCantinSanchezRomeroetal.2018, author = {El Mouali, Youssef and Gaviria-Cantin, Tania and S{\´a}nchez-Romero, Mar{\´i}a Antonia and Gibert, Marta and Westermann, Alexander J. and Vogel, J{\"o}rg and Balsalobre, Carlos}, title = {CRP-cAMP mediates silencing of Salmonella virulence at the post-transcriptional level}, series = {PLoS Genetics}, volume = {14}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007401}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226614}, year = {2018}, abstract = {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.}, language = {en} } @article{WheelerGardnerBarquist2018, author = {Wheeler, Nicole E. and Gardner, Paul P. and Barquist, Lars}, title = {Machine learning identifies signatures of host adaptation in the bacterial pathogen Salmonella enterica}, series = {PLoS Genetics}, volume = {14}, journal = {PLoS Genetics}, doi = {10.1371/journal.pgen.1007333}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233662}, year = {2018}, abstract = {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.}, language = {en} } @article{BreitenbachLiangBeyersdorfetal.2019, author = {Breitenbach, Tim and Liang, Chunguang and Beyersdorf, Niklas and Dandekar, Thomas}, title = {Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks}, series = {PLoS Computational Biology}, volume = {15}, journal = {PLoS Computational Biology}, doi = {10.1371/journal.pcbi.1007075}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220385}, year = {2019}, abstract = {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.}, language = {en} } @article{SteimleMenzBenderetal.2019, author = {Steimle, Alex and Menz, Sarah and Bender, Annika and Ball, Brianna and Weber, Alexander N. R. and Hagemann, Thomas and Lange, Anna and Maerz, Jan K. and Perusel, Raphael and Michaelis, Lena and Sch{\"a}fer, Andrea and Yao, Hans and L{\"o}w, Hanna-Christine and Beier, Sina and Mebrhatu, Mehari Tesfazgi and Gronbach, Kerstin and Wagner, Samuel and Voehringer, David and Schaller, Martin and Fehrenbacher, Birgit and Autenrieth, Ingo B. and Oelschlaeger, Tobias A. and Frick, Julia-Stefanie}, title = {Flagellin hypervariable region determinessymbiotic properties of commensalEscherichia coli strains}, series = {PLoS Biology}, volume = {17}, journal = {PLoS Biology}, doi = {10.1371/journal.pbio.3000334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239501}, year = {2019}, abstract = {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.}, language = {en} } @article{HerpinSchmidtKneitzetal.2019, author = {Herpin, Amaury and Schmidt, Cornelia and Kneitz, Susanne and Gob{\´e}, Clara and Regensburger, Martina and Le Cam, Aur{\´e}lie and Montfort, J{\´e}rome and Adolfi, Mateus C. and Lillesaar, Christina and Wilhelm, Dagmar and Kraeussling, Michael and Mourot, Brigitte and Porcon, B{\´e}atrice and Pannetier, Ma{\"e}lle and Pailhoux, Eric and Ettwiller, Laurence and Dolle, Dirk and Guiguen, Yann and Schartl, Manfred}, title = {A novel evolutionary conserved mechanism of RNA stability regulates synexpression of primordial germ cell-specific genes prior to the sex-determination stage in medaka}, series = {PLoS Biology}, volume = {17}, journal = {PLoS Biology}, doi = {10.1371/journal.pbio.3000185}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320011}, year = {2019}, abstract = {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.}, language = {en} } @article{ToepferWolfHeisenberg2018, author = {Toepfer, Franziska and Wolf, Reinhard and Heisenberg, Martin}, title = {Multi-stability with ambiguous visual stimuli in Drosophila orientation behavior}, series = {PLoS Biology}, volume = {16}, journal = {PLoS Biology}, doi = {10.1371/journal.pbio.2003113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228976}, year = {2018}, abstract = {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.}, language = {en} } @article{NaegeleZugmaierGoebeleretal.2021, author = {N{\"a}gele, Virginie and Zugmaier, Gerhard and Goebeler, Maria-Elisabeth and Viardot, Andreas and Bargou, Ralf and Kufer, Peter and Klinger, Matthias}, title = {Relationship of T- and B-cell kinetics to clinical response in patients with relapsed/refractory non-Hodgkin lymphoma treated with blinatumomab}, series = {Experimental Hematology}, volume = {100}, journal = {Experimental Hematology}, doi = {https://doi.org/10.1016/j.exphem.2021.06.005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371526}, pages = {32-36}, year = {2021}, abstract = {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.}, language = {en} } @article{NabeebaccusVermaZoccaratoetal.2021, author = {Nabeebaccus, Adam A and Verma, Sharwari and Zoccarato, Anna and Emanuelli, Giulia and Santos, Celio XC. and Streckfuss-B{\"o}meke, Katrin and Shah, Ajay M.}, title = {Cardiomyocyte protein O-GlcNAcylation is regulated by GFAT1 not GFAT2}, series = {Biochemical and Biophysical Research Communications}, volume = {583}, journal = {Biochemical and Biophysical Research Communications}, doi = {10.1016/j.bbrc.2021.10.056}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371510}, pages = {121-127}, year = {2021}, abstract = {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.}, language = {en} } @article{MuzerelleSoizaReillyHaineretal.2021, author = {Muzerelle, Aude and Soiza-Reilly, Mariano and Hainer, Cornelia and Ruet, Pierre-Louis and Lesch, Klaus-Peter and Bader, Michael and Alenina, Natalia and Scotto-Lomassese, Sophie and Gaspar, Patricia}, title = {Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, doi = {10.1038/s41598-021-84368-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371501}, year = {2021}, abstract = {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.}, language = {en} } @article{MuysersMessinaKeiletal.2022, author = {Muysers, Christoph and Messina, Fabrizio and Keil, Thomas and Roll, Stephanie}, title = {A novel concept of screening for subgrouping factors for the association between socioeconomic status and respiratory allergies}, series = {Journal of Exposure Science \& Environmental Epidemiology}, volume = {32}, journal = {Journal of Exposure Science \& Environmental Epidemiology}, doi = {10.1038/s41370-021-00365-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371490}, pages = {295-302}, year = {2022}, abstract = {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.}, language = {en} } @article{MuszynskaGuendelMelzeretal.2021, author = {Muszynska, Aleksandra and Guendel, Andre and Melzer, Michael and Moya, Yudelsy Antonia Tandron and R{\"o}der, Marion S. and Rolletschek, Hardy and Rutten, Twan and Munz, Eberhard and Melz, Gilbert and Ortleb, Stefan and Borisjuk, Ljudmilla and B{\"o}rner, Andreas}, title = {A mechanistic view on lodging resistance in rye and wheat: a multiscale comparative study}, series = {Plant Biotechnology Journal}, volume = {19}, journal = {Plant Biotechnology Journal}, doi = {10.1111/pbi.13689}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371478}, pages = {2646-2661}, year = {2021}, abstract = {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.}, language = {en} } @article{MustoEngelhardtCaersetal.2021, author = {Musto, Pellegrino and Engelhardt, Monika and Caers, Jo and Bolli, Niccolo' and Kaiser, Martin and van de Donk, Niels and Terpos, Evangelos and Broijl, Annemiek and de Larrea, Carlos Fern{\´a}ndez and Gay, Francesca and Goldschmidt, Hartmut and Hajek, Roman and Vangsted, Annette Juul and Zamagni, Elena and Zweegman, Sonja and Cavo, Michele and Dimopoulos, Meletios and Einsele, Hermann and Ludwig, Heinz and Barosi, Giovanni and Boccadoro, Mario and Mateos, Maria-Victoria and Sonneveld, Pieter and San Miguel, Jesus}, title = {2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde}, series = {Haematologica}, volume = {106}, journal = {Haematologica}, doi = {10.3324/haematol.2021.278519}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371372}, pages = {2799-2812}, year = {2021}, abstract = {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.}, language = {en} } @article{MuraliHaendel2021, author = {Murali, Supriya and H{\"a}ndel, Barbara}, title = {The latency of spontaneous eye blinks marks relevant visual and auditory information processing}, series = {Journal of Vision}, volume = {21}, journal = {Journal of Vision}, doi = {10.1167/jov.21.6.7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371361}, year = {2021}, abstract = {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.}, language = {en} } @article{MuellerNordhornNeumannKeiletal.2021, author = {M{\"u}ller-Nordhorn, Jacqueline and Neumann, Konrad and Keil, Thomas and Willich, Stefan N. and Binting, Sylvia}, title = {State-level trends in sudden unexpected infant death and immunization in the United States: an ecological study}, series = {BMC Pediatrics}, volume = {21}, journal = {BMC Pediatrics}, doi = {10.1186/s12887-021-02733-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371356}, year = {2021}, abstract = {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.}, language = {en} } @article{MuellerEdenbornMorenoWeidmannVenieretal.2022, author = {M{\"u}ller-Edenborn, Bj{\"o}rn and Moreno-Weidmann, Zoraida and Venier, Sandrine and Defaye, Pascale and Park, Chan-il and Guerra, Jos{\´e} and Alonso-Mart{\´i}n, Concepcion and Bazan, Victor and Vinolas, Xavier and Rodriguez-Font, Enrique and Campos Garcia, Bieito and Boveda, Serge and Combes, St{\´e}phane and Albenque, Jean-Paul and Guy-Moyat, Benoit and Trenk, Dietmar and Eichenlaub, Martin and Chen, Juan and Lehrmann, Heiko and Neumann, Franz-Josef and Arentz, Thomas and Jadidi, Amir}, title = {Determinants of fibrotic atrial cardiomyopathy in atrial fibrillation. A multicenter observational study of the RETAC (reseau europ{\´e}en de tra{\^i}tement d'arrhythmies cardiaques)-group}, series = {Clinical Research in Cardiology}, volume = {111}, journal = {Clinical Research in Cardiology}, doi = {10.1007/s00392-021-01973-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371312}, pages = {1018-1027}, year = {2022}, abstract = {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.}, language = {en} } @article{MuellerVoggLightningetal.2021, author = {Mueller, Jonathan Wolf and Vogg, Nora and Lightning, Thomas Alec and Weigand, Isabel and Ronchi, Cristina L and Foster, Paul A and Kroiss, Matthias}, title = {Steroid Sulfation in Adrenal Tumors}, series = {Journal of Clinical Endocrinology \& Metabolism}, volume = {106}, journal = {Journal of Clinical Endocrinology \& Metabolism}, doi = {10.1210/clinem/dgab182}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371305}, pages = {3385-3397}, year = {2021}, abstract = {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.}, language = {en} } @article{MuellerKleinertHillermannetal.2021, author = {M{\"u}ller, Frank and Kleinert, Evelyn and Hillermann, Nele and Simmenroth, Anne and Hummers, Eva and Zychlinsky Scharff, Anna and Dopfer, Christian and Happle, Christine and Jablonka, Alexandra}, title = {Disease burden in a large cohort of asylum seekers and refugees in Germany}, series = {Journal of Global Health}, volume = {11}, journal = {Journal of Global Health}, doi = {10.7189/jogh.11.04002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371228}, year = {2021}, abstract = {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.}, language = {en} } @article{MuellerSchmitz2021, author = {M{\"u}ller, Daniel and Schmitz, Patrick W.}, title = {The right to quit work: An efficiency rationale for restricting the freedom of contract}, series = {Journal of Economic Behavior and Organization}, volume = {184}, journal = {Journal of Economic Behavior and Organization}, doi = {10.1016/j.jebo.2021.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371218}, pages = {653-669}, year = {2021}, abstract = {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.}, language = {en} } @article{MuellerHassel2021, author = {M{\"u}ller, Christina and Hassel, Holger}, title = {Cooperative planning in childcare centers to improve physical activity: a qualitative investigation of directors' perspectives}, series = {Health Promotion International}, volume = {36(S2)}, journal = {Health Promotion International}, doi = {10.1093/heapro/daab171}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371207}, pages = {ii8-ii15}, year = {2021}, abstract = {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.}, language = {en} } @article{MossinkvanRhijnWangetal.2022, author = {Mossink, Britt and van Rhijn, Jon-Ruben and Wang, Shan and Linda, Katrin and Vitale, Maria R. and Z{\"o}ller, Johanna E. M and van Hugte, Eline J. H. and Bak, Jitske and Verboven, Anouk H. A. and Selten, Martijn and Negwer, Moritz and Latour, Brooke L. and van der Werf, Ilse and Keller, Jason M. and Klein Gunnewiek, Teun M. and Schoenmaker, Chantal and Oudakker, Astrid and Anania, Alessia and Jansen, Sophie and Lesch, Klaus-Peter and Frega, Monica and van Bokhoven, Hans and Schubert, Dirk and Kasri, Nael Nadif}, title = {Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks}, series = {Molecular Psychiatry}, volume = {27}, journal = {Molecular Psychiatry}, doi = {10.1038/s41380-021-01117-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371170}, pages = {1-18}, year = {2022}, abstract = {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.}, language = {en} } @article{MorgensternPeikertLuebbertetal.2021, author = {Morgenstern, Marcel and Peikert, Christian D. and L{\"u}bbert, Philipp and Suppanz, Ida and Klemm, Cinzia and Alka, Oliver and Steiert, Conny and Naumenko, Nataliia and Schendzielorz, Alexander and Melchionda, Laura and M{\"u}hlh{\"a}user, Wignand W. D. and Knapp, Bettina and Busch, Jakob D. and Stiller, Sebastian B. and Dannenmaier, Stefan and Lindau, Caroline and Licheva, Mariya and Eickhorst, Christopher and Galbusera, Riccardo and Zerbes, Ralf M. and Ryan, Michael T. and Kraft, Claudine and Kozjak-Pavlovic, Vera and Drepper, Friedel and Dennerlein, Sven and Oeljeklaus, Silke and Pfanner, Nikolaus and Wiedemann, Nils and Warscheid, Bettina}, title = {Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context}, series = {Cell Metabolism}, volume = {33}, journal = {Cell Metabolism}, doi = {10.1016/j.cmet.2021.11.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371114}, pages = {2464-2483}, year = {2021}, abstract = {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.}, language = {en} } @article{MorenoYruelaBakVrsanovaetal.2021, author = {Moreno-Yruela, Carlos and B{\ae}k, Michael and Vrsanova, Adela-Eugenie and Schulte, Clemens and Maric, Hans M. and Olsen, Christian A.}, title = {Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-020-20250-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371052}, year = {2021}, abstract = {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.}, language = {en} } @article{MorenoVelasquezPerez2021, author = {Moreno-Vel{\´a}squez, Sergio D. and P{\´e}rez, J. Christian}, title = {Imaging and Quantification of mRNA Molecules at Single-Cell Resolution in the Human Fungal Pathogen Candida albicans}, series = {mSphere}, volume = {6}, journal = {mSphere}, doi = {10.1128/mSphere.00411-21}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370999}, year = {2021}, abstract = {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.}, language = {en} } @article{MoreauxMeirelesSonneetal.2022, author = {Moreaux, C{\´e}line and Meireles, Desir{\´e}e A. L. and Sonne, Jesper and Badano, Ernesto I. and Classen, Alice and Gonz{\´a}lez-Chaves, Adrian and Hip{\´o}lito, Juliana and Klein, Alexandra-Maria and Maruyama, Pietro K. and Metzger, Jean Paul and Philpott, Stacy M. and Rahbek, Carsten and Saturni, Fernanda T. and Sritongchuay, Tuanjit and Tscharntke, Teja and Uno, Shinsuke and Vergara, Carlos H. and Viana, Blandina F. and Strange, Niels and Dalsgaard, Bo}, title = {The value of biotic pollination and dense forest for fruit set of Arabica coffee: A global assessment}, series = {Agriculture, Ecosystems \& Environment}, volume = {323}, journal = {Agriculture, Ecosystems \& Environment}, doi = {10.1016/j.agee.2021.107680}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370982}, year = {2022}, abstract = {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.}, language = {en} } @article{MoehnleHumpeBoecketal.2022, author = {M{\"o}hnle, Patrick and Humpe, Andreas and Boeck, Markus and Gruetzner, Stefanie and Hackstein, Holger and Offner, Robert and Hildebrandt, Martin}, title = {Emergency Use of Convalescent Plasma: Perception of the Regulatory Framework from a Clinical Perspective}, series = {Transfusion Medicine and Hemotherapy}, volume = {49}, journal = {Transfusion Medicine and Hemotherapy}, doi = {10.1159/000519841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311314}, pages = {119-124}, year = {2022}, abstract = {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.}, language = {en} } @article{MoellerVolzSeifritzetal.2021, author = {M{\"o}ller, Hans-J{\"u}rgen and Volz, Hans-Peter and Seifritz, Erich and M{\"u}ller, Heiko and Kenntner-Mabiala, Ramona and Kaussner, Yvonne and Schoch, Stefanie and Kasper, Siegfried}, title = {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}, series = {Journal of Psychiatric Research}, volume = {136}, journal = {Journal of Psychiatric Research}, doi = {https://doi.org/10.1016/j.jpsychires.2020.10.028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370908}, pages = {543-551}, year = {2021}, abstract = {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.}, language = {en} } @article{MiyazakiKamiyaWohlgemuthetal.2021, author = {Miyazaki, Mitsuhiko and Kamiya, Tairiku and Wohlgemuth, Matthias and Chatterjee, Kuntal and Mitrić, Roland and Dopfer, Otto and Fujii, Masaaki}, title = {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}, series = {Physical Chemistry Chemical Physics}, volume = {24}, journal = {Physical Chemistry Chemical Physics}, doi = {10.1039/d1cp03327a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370868}, pages = {73-85}, year = {2021}, abstract = {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.}, language = {en} } @article{MingMyallHernandezetal.2021, author = {Ming, Damien K. and Myall, Ashleigh C. and Hernandez, Bernard and Weiße, Andrea Y. and Peach, Robert L. and Barahona, Mauricio and Rawson, Timothy M. and Holmes, Alison H.}, title = {Informing antimicrobial management in the context of COVID-19: understanding the longitudinal dynamics of C-reactive protein and procalcitonin}, series = {BMC Infectious Diseases}, volume = {21}, journal = {BMC Infectious Diseases}, doi = {10.1186/s12879-021-06621-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370797}, year = {2021}, abstract = {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.}, language = {en} } @article{MilićCeppiBruzzoneetal.2021, author = {Milić, Mirta and Ceppi, Marcello and Bruzzone, Marco and Azqueta, Amaya and Brunborg, Gunnar and Godschalk, Roger and Koppen, Gudrun and Langie, Sabine and M{\o}ller, Peter and Teixeira, Jo{\~a}o Paulo and Alija, Avdulla and Anderson, Diana and Andrade, Vanessa and Andreoli, Cristina and Asllani, Fisnik and Bangkoglu, Ezgi Eyluel and Barančokov{\´a}, Magdalena and Basaran, Nursen and Boutet-Robinet, Elisa and Buschini, Annamaria and Cavallo, Delia and Costa Pereira, Cristiana and Costa, Carla and Costa, Solange and Da Silva, Juliana and Del Boˊ, Cristian and Dimitrijević Srećković, Vesna and Djelić, Ninoslav and Dobrzyńska, Malgorzata and Duračkov{\´a}, Zdenka and Dvoř{\´a}kov{\´a}, Monika and Gajski, Goran and Galati, Serena and Garc{\´i}a Lima, Omar and Giovannelli, Lisa and Goroshinskaya, Irina A. and Grindel, Annemarie and Gutzkow, Kristine B. and Hern{\´a}ndez, Alba and Hern{\´a}ndez, Carlos and Holven, Kirsten B. and Ibero-Baraibar, Idoia and Ottestad, Inger and Kadioglu, Ela and Kažimirov{\´a}, Alena and Kuznetsova, Elena and Ladeira, Carina and Laffon, Blanca and Lamonaca, Palma and Lebailly, Pierre and Louro, Henriqueta and Mandina Cardoso, Tania and Marcon, Francesca and Marcos, Ricard and Moretti, Massimo and Moretti, Silvia and Najafzadeh, Mojgan and Nemeth, Zsuzsanna and Neri, Monica and Novotna, Bozena and Orlow, Irene and Paduchova, Zuzana and Pastor, Susana and Perdry, Herv{\´e} and Spremo-Potparević, Biljana and Ramadhani, Dwi and Riso, Patrizia and Rohr, Paula and Rojas, Emilio and Rossner, Pavel and Safar, Anna and Sardas, Semra and Silva, Maria Jo{\~a}o and Sirota, Nikolay and Smolkova, Bozena and Staruchova, Marta and Stetina, Rudolf and Stopper, Helga and Surikova, Ekaterina I. and Ulven, Stine M. and Ursini, Cinzia Lucia and Valdiglesias, Vanessa and Valverde, Mahara and Vodicka, Pavel and Volkovova, Katarina and Wagner, Karl-Heinz and Živković, Lada and Dušinsk{\´a}, Maria and Collins, Andrew R. and Bonassi, Stefano}, title = {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}, series = {Mutation Research/Reviews in Mutation Research}, volume = {787}, journal = {Mutation Research/Reviews in Mutation Research}, doi = {10.1016/j.mrrev.2021.108371}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371614}, year = {2021}, abstract = {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.}, language = {en} } @article{MichelenManoharanElkheiretal.2021, author = {Michelen, Melina and Manoharan, Lakshmi and Elkheir, Natalie and Cheng, Vincent and Dagens, Andrew and Hastie, Claire and O'Hara, Margaret and Suett, Jake and Dahmash, Dania and Bugaeva, Polina and Rigby, Ishmeala and Munblit, Daniel and Harriss, Eli and Burls, Amanda and Foote, Carole and Scott, Janet and Carson, Gail and Olliaro, Piero and Sigfrid, Louise and Stavropoulou, Charitini}, title = {Characterising long COVID: a living systematic review}, series = {BMJ Global Health}, volume = {6}, journal = {BMJ Global Health}, doi = {10.1136/bmjgh-2021-005427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370762}, year = {2021}, abstract = {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.}, language = {en} } @article{MeyerSchloissnigFranchinietal.2021, author = {Meyer, Axel and Schloissnig, Siegfried and Franchini, Paolo and Du, Kang and Woltering, Joost M. and Irisarri, Iker and Wong, Wai Yee and Nowoshilow, Sergej and Kneitz, Susanne and Kawaguchi, Akane and Fabrizius, Andrej and Xiong, Peiwen and Dechaud, Corentin and Spaink, Herman P. and Volff, Jean-Nicolas and Simakov, Oleg and Burmester, Thorsten and Tanaka, Elly M. and Schartl, Manfred}, title = {Giant lungfish genome elucidates the conquest of land by vertebrates}, series = {Nature}, volume = {590}, journal = {Nature}, doi = {10.1038/s41586-021-03198-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370750}, pages = {284-289}, year = {2021}, abstract = {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.}, language = {en} } @article{MertensHofkensVandeHeyningetal.2021, author = {Mertens, Griet and Hofkens, Anouk and Van de Heyning, Paul and Van Rompaey, Vincent and Boudewyns, An and Di Gregorio, Maria Fernanda and Eikelboom, Robert H. and Marino, Roberta and Kurz, Anja and K{\"u}hn, Heike and Shehata-Dieler, Wafaa and Lorens, Artur and Pulibalathingal, Sasidharan and Rajeswaran, Ranjith and Tavora-Vieira, Dayse and Bellekom, Sandra R. and Topsakal, Vedat}, title = {Minimal outcome measurements in pediatric cochlear implant users: a consensus paper}, series = {B-ENT}, volume = {17}, journal = {B-ENT}, doi = {10.5152/B-ENT.2021.20195}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370700}, pages = {110-120}, year = {2021}, abstract = {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.}, language = {en} } @article{MelfsenRomanosJansetal.2021, author = {Melfsen, Siebke and Romanos, Marcel and Jans, Thomas and Walitza, Susanne}, title = {Betrayed by the nervous system: a comparison group study to investigate the 'unsafe world' model of selective mutism}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, doi = {10.1007/s00702-021-02404-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370681}, pages = {1433-1443}, year = {2021}, abstract = {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.}, language = {en} } @article{OPUS4-31406, title = {Search for heavy long-lived multicharged particles in proton-proton collisions at √\(s\)=13 TeV using the ATLAS detector}, series = {Physical Review D}, volume = {99}, journal = {Physical Review D}, number = {5}, organization = {The ATLAS Collaboration}, doi = {10.1103/PhysRevD.99.052003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314061}, pages = {1-26}, year = {2019}, abstract = {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.}, language = {en} } @article{MansourSolimanShehabetal.2017, author = {Mansour, Ahmed M. and Soliman, Fatma A. and Shehab, Ola R. and Abdel-Ghani, Nour T.}, title = {Photodegradation of sulfadiazine catalyzed by p-benzoquinones and picric acid: application to charge transfer complexes}, series = {RSC Advances}, volume = {7}, journal = {RSC Advances}, number = {63}, doi = {10.1039/c7ra05433e}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181507}, pages = {39989-39996}, year = {2017}, abstract = {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.}, language = {en} } @article{SharmaKhairnarMadunicetal.2017, author = {Sharma, Piyush and Khairnar, Vishal and Madunic, Ivana Vrhovac and Singh, Yogesh and Pandyra, Aleksandra and Salker, Madhuri S. and Koepsell, Hermann and Sabolic, Ivan and Lang, Florian and Lang, Pilipp A. and Lang, Karl S.}, title = {SGLT1 deficiency turns listeria infection into a lethal disease in mice}, series = {Cellular Physiology and Biochemistry}, volume = {42}, journal = {Cellular Physiology and Biochemistry}, number = {4}, doi = {10.1159/000479197}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181496}, pages = {1358-1365}, year = {2017}, abstract = {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.}, language = {en} } @article{MaGulbinsEdwardsetal.2017, author = {Ma, Jie and Gulbins, Erich and Edwards, Michael J. and Caldwell, Charles C. and Fraunholz, Martin and Becker, Katrin Anne}, title = {Staphylococcus aureus α-toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides}, series = {Cellular Physiology and Biochemistry}, volume = {43}, journal = {Cellular Physiology and Biochemistry}, number = {6}, doi = {10.1159/000484296}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181481}, pages = {2170-2184}, year = {2017}, abstract = {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.}, language = {en} } @article{WangZhangBaietal.2017, author = {Wang, Yiwen and Zhang, Zhen and Bai, Liying and Lin, Chongde and Osinsky, Roman and Hewig, Johannes}, title = {Ingroup/outgroup membership modulates fairness consideration: neural signatures from ERPs and EEG oscillations}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/srep39827}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181461}, year = {2017}, abstract = {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.}, language = {en} } @article{ScheunertCohenKullocketal.2017, author = {Scheunert, Gunther and Cohen, Sidney R. and Kullock, Ren{\´e} and McCarron, Ryan and Rechev, Katya and Kaplan-Ashiri, Ifat and Bitton, Ora and Dawson, Paul and Hecht, Bert and Oron, Dan}, title = {Grazing-incidence optical magnetic recording with super-resolution}, series = {Beilstein Journal of Nanotechnology}, volume = {8}, journal = {Beilstein Journal of Nanotechnology}, doi = {10.3762/bjnano.8.4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181457}, pages = {28-37}, year = {2017}, abstract = {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.}, language = {en} } @article{SzklarczykMorrisCooketal.2017, author = {Szklarczyk, Damian and Morris, John H. and Cook, Helen and Kuhn, Michael and Wyder, Stefan and Simonovic, Milan and Santos, Aalberto and Doncheva, Nadezhda T. and Roth, Alexander and Bork, Peer and Jensen, Lars J. and von Mering, Christian}, title = {The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkw937}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181445}, pages = {D362-D368}, year = {2017}, abstract = {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/.}, language = {en} } @article{RheeChoiKimetal.2017, author = {Rhee, Jae-Sung and Choi, Beom-Soon and Kim, Jaebum and Kim, Bo-Mi and Lee, Young-Mi and Kim, Il-Chan and Kanamori, Akira and Choi, Ik-Young and Schartl, Manfred and Lee, Jae-Seong}, title = {Diversity, distribution, and significance of transposable elements in the genome of the only selfing hermaphroditic vertebrate Kryptolebias marmoratus}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/srep40121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181329}, year = {2017}, abstract = {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.}, language = {en} } @phdthesis{Reichelt2024, author = {Reichelt, Niklas}, title = {Exploring the natural variation of heat-dependent metabolic rearrangements in \(Arabidopsis\) \(thaliana\) to identify genes involved in thermotolerance}, doi = {10.25972/OPUS-37132}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371324}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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.}, subject = {Schmalwand }, language = {en} } @phdthesis{Schneider2024, author = {Schneider, Philipp}, title = {Beeinflusst eine Pisotriquetralarthrose das mittel- und langfristige Ergebnis einer mediokarpalen Teilarthrodese des Handgelenks?}, doi = {10.25972/OPUS-37210}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-372106}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Ziel: Die mediokarpale Teilarthrodese (MKTA) des Handgelenks ist eine sehr h{\"a}ufig durchgef{\"u}hrte Rettungsoperation, wenn intolerable Schmerzen aufgrund eines KK ein operatives Vorgehen erforderlich machen. Zahlreiche Studien beschreiben eine deutliche Beschwerdelinderung durch die MKTA, aber keine vollst{\"a}ndige Schmerzfreiheit. Die Ursachen hierf{\"u}r sind vielf{\"a}ltig, unter anderem kommt eine Pisotriquetralarthrose in Be-tracht. Die Entstehung einer solchen wird durch die Handwurzelfehlstellung beim KK beg{\"u}nstigt [8]. In dieser Arbeit wurde der Einfluss einer PT-Arthrose auf das mittel- bis langfristige Ergebnis einer MKTA untersucht. Des Weiteren wurde untersucht, inwie-fern sich eine PT-Arthrose nach einer MKTA entwickeln kann, sofern diese nicht bereits zum Operationszeitpunkt bestand. Methode: Es wurden 48 Personen, die zwischen 2004 und 2016 eine MKTA erhielten und deren Status hinsichtlich einer PT-Arthrose zum OP-Zeitpunkt durch eine Schnitt-bilddiagnostik analysiert werden konnte, in die Studie eingeschlossen. Zum Zeitpunkt der MKTA hatten 25 Patienten eine ausgepr{\"a}gte PT-Arthrose und 23 Patienten keine PT-Arthrose. Die Patienten wurden durchschnittlich 75 Monate postoperativ klinisch und radiologisch nachuntersucht. Es wurde der Krimmer-Score und der DASH-Score erfasst. Ferner wurden klinische Untersuchungsparameter erhoben sowie die Handkraft und Handgelenksbeweglichkeit gemessen. Arthrose-Zeichen im pisotriquetralen und radiolun{\"a}ren Gelenk wurden durch R{\"o}ntgenaufnahmen des Handgelenks in zwei Ebe-nen und einer Pisiformen-Zielaufnahme beurteilt. Ergebnis: Es zeigte sich, dass eine PT-Arthrose keinen negativen Einfluss auf das Er-gebnis einer MKTA aus{\"u}bt. Dar{\"u}ber hinaus entwickelten einige Patienten auch nach einer MKTA eine PT-Arthrose, sodass die ver{\"a}nderte Biomechanik durch die Operation keinen protektiven Faktor hierf{\"u}r darstellt hat. Als klinischer Test erwies sich der Schmerz am Pisiforme bei passivem {\"U}berstrecken des Handgelenks als aussagekr{\"a}ftigs-ter Untersuchungsparameter hinsichtlich des Vorhandenseins einer PT-Arthrose. Diskussion: Selbst bei einer radiologisch nachgewiesenen PT-Arthrose kann ein KK ausschließlich mit einer MKTA behandelt werden. Halten nach einer MKTA ulnopalma-re Beschwerden am Handgelenk an oder treten neu auf, muss {\"a}tiologisch eine PT-Arthrose in Erw{\"a}gung gezogen, abgekl{\"a}rt und gegebenenfalls behandelt werden.}, subject = {Handgelenk}, language = {de} } @article{MegyDownesMorelKoppetal.2021, author = {Megy, Karyn and Downes, Kate and Morel-Kopp, Marie-Christine and Bastida, Jos{\´e} M. and Brooks, Shannon and Bury, Loredana and Leinoe, Eva and Gomez, Keith and Morgan, Neil V. and Othman, Maha and Ouwehand, Willem H. and Perez Botero, Juliana and Rivera, Jos{\´e} and Schulze, Harald and Tr{\´e}gou{\"e}t, David-Alexandre and Freson, Kathleen}, title = {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}, series = {Journal of Thrombosis and Haemostasis}, volume = {19}, journal = {Journal of Thrombosis and Haemostasis}, doi = {10.1111/jth.15459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370602}, pages = {2612-2617}, year = {2021}, abstract = {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.}, language = {en} } @article{MaynardRostaingSchaeferetal.2021, author = {Maynard, Stephanie A and Rostaing, Philippe and Schaefer, Natascha and Gemin, Olivier and Candat, Adrien and Dumoulin, Andr{\´e}a and Villmann, Carmen and Triller, Antoine and Specht, Christian G}, title = {Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses}, series = {eLife}, volume = {10}, journal = {eLife}, doi = {10.7554/eLife.74441}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370504}, year = {2021}, abstract = {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.}, language = {en} } @article{MaulanaKromidasWallstabeetal.2021, author = {Maulana, Tengku Ibrahim and Kromidas, Elena and Wallstabe, Lars and Cipriano, Madalena and Alb, Miriam and Zaupa, C{\´e}cile and Hudecek, Michael and Fogal, Birgit and Loskill, Peter}, title = {Immunocompetent cancer-on-chip models to assess immuno-oncology therapy}, series = {Advanced Drug Delivery Reviews}, volume = {173}, journal = {Advanced Drug Delivery Reviews}, doi = {10.1016/j.addr.2021.03.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370493}, pages = {281-305}, year = {2021}, abstract = {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.}, language = {en} } @article{MateosDimopoulosCavoetal.2021, author = {Mateos, Maria-Victoria and Dimopoulos, Meletios A. and Cavo, Michele and Suzuki, Kenshi and Knop, Stefan and Doyen, Chantal and Lucio, Paulo and Nagy, Zsolt and Pour, Ludek and Grosicki, Sebastian and Crepaldi, Andre and Liberati, Anna Marina and Campbell, Philip and Yoon, Sung-Soo and Iosava, Genadi and Fujisaki, Tomoaki and Garg, Mamta and Iida, Shinsuke and Blad{\´e}, Joan and Ukropec, Jon and Pei, Huiling and Van Rampelbergh, Rian and Kudva, Anupa and Qi, Ming and San-Miguel, Jesus}, title = {Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE}, series = {Clinical Lymphoma, Myeloma \& Leukemia}, volume = {21}, journal = {Clinical Lymphoma, Myeloma \& Leukemia}, doi = {10.1016/j.clml.2021.06.005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370456}, pages = {785-798}, year = {2021}, abstract = {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.}, language = {en} } @article{MatarranzGhoshKandanellietal.2021, author = {Matarranz, Beatriz and Ghosh, Goutam and Kandanelli, Ramesh and Sampedro, Angel and Kartha, Kalathil K. and Fern{\´a}ndez, Gustavo}, title = {Understanding the role of conjugation length on the self-assembly behaviour of oligophenyleneethynylenes}, series = {Chemical Communications}, volume = {57}, journal = {Chemical Communications}, doi = {10.1039/d1cc01054a}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370444}, pages = {4890-4893}, year = {2021}, abstract = {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.}, language = {en} } @article{MasiasCernaVelazcoJonesPerezetal.2021, author = {Masias, J. and Cerna-Velazco, N. and Jones-P{\´e}rez, J. and Porod, W.}, title = {Resolving a challenging supersymmetric low-scale seesaw scenario at the ILC}, series = {Physical Review D}, volume = {103}, journal = {Physical Review D}, doi = {10.1103/PhysRevD.103.115028}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370328}, year = {2021}, abstract = {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.}, language = {en} } @article{MartinezLenzSchindleretal.2021, author = {Martinez, Simon and Lenz, J{\"u}rgen and Schindler, Hans and Wendler, Willi and Rues, Stefan and Schweizerhof, Karl and Terebesi, Sophia and Giannakopoulos, Nikolaos Nikitas and Schmitter, Marc}, title = {Clinical Data-Driven Finite Element Analysis of the Kinetics of Chewing Cycles in Order to Optimize Occlusal Reconstructions}, series = {Computer Modeling in Engineering \& Sciences}, volume = {129}, journal = {Computer Modeling in Engineering \& Sciences}, doi = {10.32604/cmes.2021.017422}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370318}, pages = {1259-1281}, year = {2021}, abstract = {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.}, language = {en} } @article{MaronHaggenmuellervonKalleetal.2021, author = {Maron, Roman C. and Haggenm{\"u}ller, Sarah and von Kalle, Christof and Utikal, Jochen S. and Meier, Friedegund and Gellrich, Frank F. and Hauschild, Axel and French, Lars E. and Schlaak, Max and Ghoreschi, Kamran and Kutzner, Heinz and Heppt, Markus V. and Haferkamp, Sebastian and Sondermann, Wiebke and Schadendorf, Dirk and Schilling, Bastian and Hekler, Achim and Krieghoff-Henning, Eva and Kather, Jakob N. and Fr{\"o}hling, Stefan and Lipka, Daniel B. and Brinker, Titus J.}, title = {Robustness of convolutional neural networks in recognition of pigmented skin lesions}, series = {European Journal of Cancer}, volume = {145}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2020.11.020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370245}, pages = {81-91}, year = {2021}, abstract = {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.}, language = {en} } @article{MarcuSchlosserKeuppetal.2021, author = {Marcu, Ana and Schlosser, Andreas and Keupp, Anne and Trautwein, Nico and Johann, Pascal and W{\"o}lfl, Matthias and Lager, Johanna and Monoranu, Camelia Maria and Walz, Juliane S and Henkel, Lisa M and Krauß, J{\"u}rgen and Ebinger, Martin and Schuhmann, Martin and Thomale, Ulrich Wilhelm and Pietsch, Torsten and Klinker, Erdwine and Schlegel, Paul G and Oyen, Florian and Reisner, Yair and Rammensee, Hans-Georg and Eyrich, Matthias}, title = {Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors}, series = {Journal for ImmunoTherapy of Cancer}, volume = {9}, journal = {Journal for ImmunoTherapy of Cancer}, doi = {10.1136/jitc-2021-003404}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370214}, year = {2021}, abstract = {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.}, language = {en} } @article{MarcuBichmannKuchenbeckeretal.2021, author = {Marcu, Ana and Bichmann, Leon and Kuchenbecker, Leon and Kowalewski, Daniel Johannes and Freudenmann, Lena Katharina and Backert, Linus and M{\"u}hlenbruch, Lena and Szolek, Andr{\´a}s and L{\"u}bke, Maren and Wagner, Philipp and Engler, Tobias and Matovina, Sabine and Wang, Jian and Hauri-Hohl, Mathias and Martin, Roland and Kapolou, Konstantina and Walz, Juliane Sarah and Velz, Julia and Moch, Holger and Regli, Luca and Silginer, Manuela and Weller, Michael and L{\"o}ffler, Markus W. and Erhard, Florian and Schlosser, Andreas and Kohlbacher, Oliver and Stevanović, Stefan and Rammensee, Hans-Georg and Neidert, Marian Christoph}, title = {HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy}, series = {Journal for ImmunoTherapy of Cancer}, volume = {9}, journal = {Journal for ImmunoTherapy of Cancer}, doi = {10.1136/jitc-2020-002071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370160}, year = {2021}, abstract = {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 .}, language = {en} } @article{MannucciDangHuberetal.2021, author = {Mannucci, Ilaria and Dang, Nghi D. P. and Huber, Hannes and Murry, Jaclyn B. and Abramson, Jeff and Althoff, Thorsten and Banka, Siddharth and Baynam, Gareth and Bearden, David and Beleza-Meireles, Ana and Benke, Paul J. and Berland, Siren and Bierhals, Tatjana and Bilan, Frederic and Bindoff, Laurence A. and Braathen, Geir Julius and Busk, {\O}yvind L. and Chenbhanich, Jirat and Denecke, Jonas and Escobar, Luis F. and Estes, Caroline and Fleischer, Julie and Groepper, Daniel and Haaxma, Charlotte A. and Hempel, Maja and Holler-Managan, Yolanda and Houge, Gunnar and Jackson, Adam and Kellogg, Laura and Keren, Boris and Kiraly-Borri, Catherine and Kraus, Cornelia and Kubisch, Christian and Le Guyader, Gwenael and Ljungblad, Ulf W. and Brenman, Leslie Manace and Martinez-Agosto, Julian A. and Might, Matthew and Miller, David T. and Minks, Kelly Q. and Moghaddam, Billur and Nava, Caroline and Nelson, Stanley F. and Parant, John M. and Prescott, Trine and Rajabi, Farrah and Randrianaivo, Hanitra and Reiter, Simone F. and Schuurs-Hoeijmakers, Janneke and Shieh, Perry B. and Slavotinek, Anne and Smithson, Sarah and Stegmann, Alexander P. A. and Tomczak, Kinga and Tveten, Kristian and Wang, Jun and Whitlock, Jordan H. and Zweier, Christiane and McWalter, Kirsty and Juusola, Jane and Quintero-Rivera, Fabiola and Fischer, Utz and Yeo, Nan Cher and Kreienkamp, Hans-J{\"u}rgen and Lessel, Davor}, title = {Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders}, series = {Genome Medicine}, volume = {13}, journal = {Genome Medicine}, doi = {10.1186/s13073-021-00900-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306477}, year = {2021}, abstract = {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.}, language = {en} } @article{MaksimovaShalginskikhVlasovaetal.2021, author = {Maksimova, Varvara and Shalginskikh, Natalya and Vlasova, Olga and Usalka, Olga and Beizer, Anastasia and Bugaeva, Polina and Fedorov, Dmitry and Lizogub, Olga and Lesovaya, Ekaterina and Katz, Richard and Belitsky, Gennady and Kirsanov, Kirill and Yakubovskaya, Marianna}, title = {HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes}, series = {PLoS ONE}, volume = {16}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0252504}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370152}, year = {2021}, abstract = {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.}, language = {en} } @article{MaistrenkoScharfManskeetal.2021, author = {Maistrenko, Oleksii and Scharf, Benedikt and Manske, Dirk and Hankiewicz, Ewelina M.}, title = {Planar Josephson Hall effect in topological Josephson junctions}, series = {Physical Review B}, volume = {103}, journal = {Physical Review B}, doi = {10.1103/PhysRevB.103.054508}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370139}, year = {2021}, abstract = {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.}, language = {en} } @article{MainaPelliccioli2021, author = {Maina, Ezio and Pelliccioli, Giovanni}, title = {Polarized Z bosons from the decay of a Higgs boson produced in association with two jets at the LHC}, series = {The European Physical Journal C}, volume = {81}, journal = {The European Physical Journal C}, doi = {10.1140/epjc/s10052-021-09774-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370126}, year = {2021}, abstract = {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.}, language = {en} } @article{MaierWeissenbergerRudertetal.2021, author = {Maier, Gerrit S. and Weissenberger, Manuel and Rudert, Maximilian and Roth, Klaus E. and Horas, Konstantin}, title = {The role of vitamin D and vitamin D deficiency in orthopaedics and traumatology—a narrative overview of the literature}, series = {Annals of Translational Medicine}, volume = {9}, journal = {Annals of Translational Medicine}, doi = {10.21037/atm-21-779}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370110}, year = {2021}, abstract = {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.}, language = {en} } @article{MaguniaLedererVerbuechelnetal.2021, author = {Magunia, Harry and Lederer, Simone and Verbuecheln, Raphael and Gilot, Bryant Joseph and Koeppen, Michael and Haeberle, Helene A. and Mirakaj, Valbona and Hofmann, Pascal and Marx, Gernot and Bickenbach, Johannes and Nohe, Boris and Lay, Michael and Spies, Claudia and Edel, Andreas and Schiefenh{\"o}vel, Fridtjof and Rahmel, Tim and Putensen, Christian and Sellmann, Timur and Koch, Thea and Brandenburger, Timo and Kindgen-Milles, Detlef and Brenner, Thorsten and Berger, Marc and Zacharowski, Kai and Adam, Elisabeth and Posch, Matthias and Moerer, Onnen and Scheer, Christian S. and Sedding, Daniel and Weigand, Markus A. and Fichtner, Falk and Nau, Carla and Pr{\"a}tsch, Florian and Wiesmann, Thomas and Koch, Christian and Schneider, Gerhard and Lahmer, Tobias and Straub, Andreas and Meiser, Andreas and Weiss, Manfred and Jungwirth, Bettina and Wappler, Frank and Meybohm, Patrick and Herrmann, Johannes and Malek, Nisar and Kohlbacher, Oliver and Biergans, Stephanie and Rosenberger, Peter}, title = {Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort}, series = {Critical Care}, volume = {25}, journal = {Critical Care}, doi = {10.1186/s13054-021-03720-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306766}, year = {2021}, abstract = {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.}, language = {en} } @phdthesis{Weigel2024, author = {Weigel, Sandra Carina}, title = {Zum besseren Verst{\"a}ndnis von Evaluationen verschiedener Lehrformate: Wie Charisma der Dozierenden und studentische Technikaffinit{\"a}t die Wahrnehmung didaktischer Qualit{\"a}t beeinflussen}, doi = {10.25972/OPUS-37156}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371565}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Seit Beginn des neuen Jahrtausends haben Tablets in der medizinischen Lehre zunehmend an Bedeutung gewonnen. In dieser Studie wurden ein Tablet-basiertes und ein Dozierenden-zentriertes Lehrformat im Rahmen eines Radiologie-Seminars verglichen. Ziel war es, vergleichende Erkenntnisse {\"u}ber selbsteingesch{\"a}tzten und objektiven Lernzuwachs und empfundene didaktische Qualit{\"a}t zu erlangen und m{\"o}gliche Einfl{\"u}sse des Charismas der Dozierenden sowie der studentischen Technikaffinit{\"a}t auf diese Variablen zu untersuchen. Von n=366 Studierenden wurden {\"u}ber drei Semester hinweg Daten zu studentischer Technikaffinit{\"a}t generell sowie didaktischer Qualit{\"a}t und Zufriedenheit mit den Seminaren abh{\"a}ngig vom Lehrformat erhoben. Im letzten Studiensemester nahmen die Studierenden zudem eine Selbsteinsch{\"a}tzung ihres Lernzuwachses vor und legten ein Wissens- und Bildinterpretationstestat sowie eine Einsch{\"a}tzung des Charismas der Dozierenden ab. Mittels Maximum-Likelihood Faktorenanalyse erfolgte eine Strukturaufkl{\"a}rung der didaktischen Qualit{\"a}t und des Charismas. Pearson-Korrelationskoeffizienten wurden zur Untersuchung m{\"o}glicher Korrelationen zwischen den Variablen berechnet. Ein Strukturregressionsmodell des Charismas der Dozierenden, der studentischen Technikaffinit{\"a}t und der didaktischen Qualit{\"a}t wurde erstellt und daraus eine lineare Regressionsgleichung abgeleitet. Dem Tablet-basierten Lehrformat wurden signifikant h{\"o}here Werte in didaktischer Qualit{\"a}t und studentischer Zufriedenheit zugeschrieben. Das Dozierenden-zentrierte Format schnitt hingegen in selbsteingesch{\"a}tztem und objektivem Lernzuwachs signifikant besser ab. Ausschließlich im Tablet-basierten Unterricht korrelierte das Charisma der Dozierenden mit dem selbsteingesch{\"a}tzten Lernzuwachs. Die studentische Technikaffinit{\"a}t wirkte sich in diesem Format st{\"a}rker auf die didaktische Qualit{\"a}t aus. Zudem wurden gute Organisation, eindeutige Lernziele und ad{\"a}quate Lernformvariation als bedeutsame Faktoren identifiziert. Diese Studie hebt die Relevanz des dozentischen Charismas und der studentischen Technikaffinit{\"a}t f{\"u}r die Sicherstellung hoher didaktischer Qualit{\"a}t in Tablet-basiertem Unterricht hervor. Sie zeigt zudem die Wichtigkeit der Kongruenz von Lernzielen, Lehrkonzept und Pr{\"u}fungsmethode dieses Lehrformats auf, um hohe Studienleistungen sicherzustellen. Die untersuchten Faktoren sollten bei Entwurf digitaler Lehrkonzepte {\"u}ber spezifische Messinstrumente objektiviert und bei Bedarf geschult oder angepasst werden, um eine erfolgreiche Integration digitaler Medien in die medizinische Lehre zu gew{\"a}hrleisten.}, subject = {Didaktik}, language = {de} } @phdthesis{Mueller2024, author = {M{\"u}ller, Lisa}, title = {Der Reformbedarf des Stammzellgesetzes : eine sowohl retrospektive als auch prospektive Untersuchung unter besonderer Ber{\"u}cksichtigung der Stichtagsregelung}, doi = {10.25972/OPUS-37141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371416}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die vorliegende Dissertation beleuchtet den bestehenden Reformbedarf des Stammzellgesetzes, wobei {\"u}berdies eine Auseinandersetzung mit der bereits 2008 erfolgten Reform vorgenommen wird.}, language = {de} } @phdthesis{Seth2024, author = {Seth, Celina Marcella}, title = {Erfassung und Bewertung der Immunzell-Dynamik ausgehend vom Transkriptom der Milz}, doi = {10.25972/OPUS-37129}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371294}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Erfassung und Bewertung der Immunzell-Dynamik ausgehend vom Transkriptom der Milz, Dissertation zum Vergleich von DCQ-Vorhersagen einzelner Immunzellpopulationen w{\"a}hrend akuter und chronischer LCMV-Infektionen mit experimentellen Daten.}, subject = {Infektion}, language = {de} } @phdthesis{Koehler2024, author = {K{\"o}hler, Jonas}, title = {Predicting Future Snow Line Elevation Dynamics in the Alps - The Potential of Long Earth Observation Time Series}, doi = {10.25972/OPUS-37139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371392}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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.}, subject = {Fernerkundung}, language = {en} } @phdthesis{Scholl2024, author = {Scholl, Lena}, title = {Die Rolle des Typ-I-Rezeptors ALK1 in BMP-vermittelter Signaltransduktion}, doi = {10.25972/OPUS-37194}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371945}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Im experimentellen Ansatz sollte mithilfe der CRISPR-Cas9-Methode eine gerichtete ALK1-Rezeptor-Eliminierung in myoblastischen C2C12-Zellen durchgef{\"u}hrt werden. Nach erfolgreicher Klonierung der jeweiligen, f{\"u}r den Typ-I-Rezeptor ALK1-kodierenden, gRNA-Sequenzen in die Puro- und GFP-CRISPR-Plasmide gelang der mittels Lipofektion durchgef{\"u}hrte Transfer der vier klonierten Plasmide in die C2C12-Zellen. Parallel aufgetaut wurden C2C12*ALK2- sowie ALK3-Knockout-Zelllinien, welche zuvor durch die Masterandin L. Wiesmann, ebenfalls mithilfe der CRISPR-Cas9-Methode, induzierte Knockouts der jeweiligen Rezeptoren ALK2 sowie ALK3 enthielten. Anschließend erfolgte die Puromycin-Selektion der mit den Puro-Klonen transfizierten C2C12*ALK1-3, ALK1-4-, ALK2- sowie ALK3-KO-Zellpopulationen. Die Zellen der C2C12*ALK1-3-KO-Population {\"u}berlebten die Selektion trotz erneuter Durchf{\"u}hrung der Transfektion sowie Selektion nicht. Somit erfolgte die Kultivierung der verbliebenen Zellen der C2C12*ALK1 4-, C2C12*ALK2- sowie C2C12*ALK3-KO-Population. Anschließend galt es zu untersuchen, wie responsiv die einzelne KO-Zelle f{\"u}r verschiedene Liganden ist. Im Rahmen der Durchf{\"u}hrung differenter, zellbasierter Versuche wie der qPCR, des Western Blots und des ALP-Assays wirkten verschiedene BMPs auf die KO-Populationen ein. Somit konnten die BMP-induzierten, nachfolgenden Ereignisse wie die mRNA-Expression, die SMAD-Phosphorylierung sowie die Induktion der ALP-Expression innerhalb der KO-Populationen genauer betrachtet werden. Es ist allgemein bekannt, dass ALK1 sowohl bei der Angiogenese als auch bei der kardio-vaskul{\"a}ren Hom{\"o}ostase eine wichtige Rolle {\"u}bernimmt. ALK1 ist vermutlich f{\"u}r die Gef{\"a}ßneubildung in manchen Tumoren verantwortlich und auch die vaskul{\"a}re Erkrankung „Heredit{\"a}re h{\"a}morrhagische Teleangiektasie (HHT)" steht im Zusammenhang mit einer Mutation des ALK1-Rezeptorgens. BMP9 beeinflusst als ALK1-bindender Ligand neben der Tumorentwicklung und der Angiogenese auch die osteogene Differenzierung mesenchymaler Stammzellen. Im Hinblick auf zuk{\"u}nftige Versuche sind daher weitere, noch aussagekr{\"a}ftigere Ergebnisse erstrebenswert, allerdings unter der Verwendung von ausschließlich homozygoten KO-Zelllinien. Weitere Erkenntnisse {\"u}ber die Rolle des ALK1-Rezeptors in BMP-vermittelter Signaltransduktion k{\"o}nnten f{\"u}r therapeutische Ans{\"a}tze bei der Behandlung von vaskul{\"a}ren Erkrankungen und Tumorprogression sowie bei der F{\"o}rderung der Knochenregeneration und -heilung hilfreich sein.}, subject = {CRISPR/Cas-Methode}, language = {de} } @phdthesis{ValtaSeufzer2024, author = {Valta-Seufzer, David}, title = {Prognostischer und pr{\"a}diktiver Wert von CA 19-9 nach Induktionschemotherapie beim lokal fortgeschrittenem Pankreaskarzinom: Ergebnisse einer prospektiven, multizentrischen Phase-2-Studie (NEOLAP-AIO-PAK-0113)}, doi = {10.25972/OPUS-37199}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371996}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Zusammenfassend l{\"a}sst sich sagen, dass diese prospektive Studie sowohl den prognostischen als auch den pr{\"a}diktiven Nutzen eines Tumormarker-Abfalls von CA19- 9 auf eine Induktionschemotherapie bei Patienten mit LAPC best{\"a}tigt. Nicht die Ausgangswerte des Tumormarkers vor Therapie sollten zur Planung des weiteren Vorgehens herangezogen werden, sondern die Werte nach Abschluss der Induktionschemotherapie bzw. der Abfall unter der Induktionschemotherapie. Das biochemische Ansprechen von CA19-9 ist ein bedeutender Indikator f{\"u}r den Behandlungserfolg und verbessert die diagnostische Genauigkeit bei der Auswahl von Patienten f{\"u}r eine chirurgische Exploration. Sowohl die Betrachtung des biochemischen Ansprechens allein als auch in Kombination mit dem radiologischen Ansprechen verbessert Sensitivit{\"a}t und Spezifit{\"a}t hinsichtlich einer m{\"o}glichen R0-Resektion. Kombiniert man bei Patienten mit einer SD in Woche 16 ein gutes biochemisches Ansprechen (R{\"u}ckgang von CA19-9 > 55\%), so wird eine Sensitivit{\"a}t von 100\% hinsichtlich der m{\"o}glichen R0-Resektion erreicht. Zur Absch{\"a}tzung des Gesamt{\"u}berlebens von Patienten mit LAPC sollten dagegen eher die absoluten Werte von CA19-9 nach Induktionschemotherapie verwendet werden und nicht der relative R{\"u}ckgang des Markers. So zeigen Patienten, welche in Woche 16 einen CA19-9 Wert < 50 U/ml aufweisen mit 27,8 Monaten das beste mediane Gesamt{\"u}berleben.}, subject = {Bauchspeicheldr{\"u}senkrebs}, language = {de} } @phdthesis{Weber2024, author = {Weber, Paula Martika}, title = {Spinstrukturen in Manganoberfl{\"a}chen auf bcc- und fcc-Einkristallen aus 5d-Elementen, untersucht mittels spinpolarisierter Rastertunnelmikroskopie: Mn-W(001) und MnO\(_x\)-Ir(001)}, doi = {10.25972/OPUS-37163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371631}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die Entstehung kollinearer und nicht-kollinearer Spinstrukturen wird auf verschiedene magnetische Wechselwirkungen zur{\"u}ckgef{\"u}hrt. F{\"u}r Anwendungen in der Medizin und in der Datenspeicherung ist es notwendig zu verstehen, unter welchen Parametern Frustrationen auftreten, um diese entweder zu vermeiden oder zu nutzen. In dieser Arbeit werden kollineare und nicht-kollineare Spinstrukturen auf zwei verschiedenen Materialsystemen untersucht. Das erste Materialsystem besteht aus drei atomaren Lagen Mangan auf einer (001) Oberfl{\"a}che eines Wolfram-Einkristalls und das zweite Materialsystem enth{\"a}lt Mangan, welches verbunden mit Sauerstoff kettenf{\"o}rmig auf einer (001) Oberfl{\"a}che eines Iridium-Einkristalls vorliegt. Spinpolarisierte Rastertunnelmikroskopie (SP-RTM)-Messungen und -Simulationen der dreilagigen, pseudomorphen Manganoberfl{\"a}che ergeben eine nicht-kollineare Spinstruktur. Dichtefunktionaltheorie (DFT)-Berechnungen legen eine kollineare ↑↓↓- Spinkonstellation nahe. Unter Ber{\"u}cksichtigung der chiralen biquadratischen Paarwechselwirkung befinden sich konische Spinspiralen mit kleinem {\"O}ffnungswinkel nah an dem energetisch niedrigsten Zustand. Spinaufgel{\"o}ste DFT-Berechnungen sind abh{\"a}ngig von der gen{\"a}herten, geometrischen Relaxation der atomaren Struktur. Kombinierte SP-RTM-Methoden weisen auf einem dreilagigen Materialsystem Spinspiralen nach und zufolge der DFT ist der kollineare bzw. nicht-kollineare Zustand des Systems durch den Abstand seiner Lagen bedingt. SP-RTM-Messungen auf den Manganoxidketten weisen je nach Pr{\"a}paration eine kollineare antiferromagnetische (AFM) oder eine nicht-kollineare Spinstruktur nach. Zudem wird pr{\"a}sentiert, dass sich diese Spinstrukturen durch zwei verschiedene Sauerstoffdr{\"u}cke und die Zufuhr von W{\"a}rme w{\"a}hrend der Pr{\"a}paration ineinander umschalten lassen. Durch niederenergetische Elektronenbeugung mit variabler Spannung werden zwei atomare Strukturen bestimmt, welche sich durch ihren Oxidationsgrad unterscheiden. Die nicht-kollineare Spinstruktur ist bereits in der Fachliteratur als 120° chirale Spinspirale, verursacht durch die Dzyaloshinskii-Moriya-verst{\"a}rkte Ruderman-Kittel-Kasuya-Yosida (RKKY)-Wechselwirkung, bekannt. Nach aktuellen, kollinearen DFT-Berechnungen ist die kollineare Spinstruktur als AFM entlang der Ketten und als ferromagnetische Kopplung zwischen den Ketten ermittelt. Aufgrund des Nachweises eines h{\"o}heren Oxidationsgrades wird eine st{\"a}rkere RKKY-Austauschwechselwirkung auf der Basis der Heisenberg-Austauschwechselwirkung vermutet. Hier korreliert die Entstehung kollinearer oder nicht-kollinearer Spinstrukturen mit dem Oxidationsgrad.}, subject = {Frustration}, language = {de} } @phdthesis{Hesen2024, author = {Hesen, Nienke Aiyuan}, title = {The importance of antibody isotype and idiotype in FcγR-dependent agonism induced by anti-CD40 antibodies}, doi = {10.25972/OPUS-37187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371872}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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.}, subject = {Antigen CD40}, language = {en} } @phdthesis{Vialetto2024, author = {Vialetto, Elena}, title = {Outcomes of genome targeting with CRISPR-Cas systems in bacteria}, doi = {10.25972/OPUS-37126}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371264}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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.}, subject = {CRISPR/Cas-Methode}, language = {en} } @phdthesis{Hackenesch2024, author = {Hackenesch, Ulla}, title = {Variabilit{\"a}t der Penetranz und klinischen Manifestation der autosomal dominanten Osteopetrose Typ II}, doi = {10.25972/OPUS-37084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370842}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die autosomal dominante Osteopetrose Typ II ist eine seltene sklerosierende Skeletterkrankung, die durch heterozygote Varianten im CLCN7-Gen verursacht wird. Die klinische Manifestation umfasst ein breites Symptomspektrum. Charakteristisch sind die unvollst{\"a}ndige Penetranz und eine hohe Variabilit{\"a}t der Ph{\"a}notyp-Expression. Beide Ph{\"a}nomene f{\"u}hren wir am ehesten auf eine monoallelische Inaktivierung zur{\"u}ck. Diese Studie war eine retrospektive Datenauswertung, die 14 ADO II-Betroffene mit klinischer Manifestation der Erkrankung sowie 5 PatientInnen mit Carrier-Status eingeschlossen hat. Diese wurden im Rahmen einer ausf{\"u}hrlichen Diagnostik untersucht, bei der Parameter im Hinblick auf den Zustand des Skelettsystems, k{\"o}rperliche Funktionen und Symptome sowie die gesundheitsbezogene Lebensqualit{\"a}t und der Leidensdruck erfasst wurden. Diese Variablen wurden zwischen der Betroffenen- und Carrier-Gruppe verglichen, wobei die Ergebnisse humangenetischer Untersuchungen ber{\"u}cksichtigt wurden, welche Gene umfassten, deren Produkte im Knochenstoffwechsel eine Rolle spielen. In 6 Stammb{\"a}umen und einem sporadischen Fall konnten 5 verschiedene heterozygote CLCN7-Varianten festgestellt werden. Zus{\"a}tzlich wurden ALPL- und LRP5-Varianten entdeckt. Der Einfluss dieser zus{\"a}tzlichen Varianten auf die Penetranz und die klinische Manifestation des ADO II-Ph{\"a}notyps wurden diskutiert. Es konnte festgestellt werden, dass Betroffene in allen betrachteten Bereichen, d.h. klinisch, osteodensitometrisch und laborchemisch krankheitstypische Ver{\"a}nderungen zeigten, wohingegen Carrier keinerlei Auff{\"a}lligkeiten aufwiesen. Die nach Alter stratifizierte Auswertung der Funktionstestung und Lebensqualit{\"a}t offenbarte mit zunehmendem Alter st{\"a}rkere Einbußen in der Funktionsf{\"a}higkeit und der gesundheitsbezogenen Lebensqualit{\"a}t bei Betroffenen gegen{\"u}ber den Carriern. Eine Zunahme der Krankheitssymptome und eine Verschlechterung des Gesundheitszustandes im Laufe des Lebens k{\"o}nnten demnach angenommen werden.}, language = {de} } @phdthesis{Seal2024, author = {Seal, Rishav}, title = {Selective inhibition of the transcription factor NFAT in mitigating GvHD with small molecule inhibitors}, doi = {10.25972/OPUS-37053}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370537}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {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.}, subject = {Transplantat-Wirt-Reaktion}, language = {en} } @article{MagneaPelliccioliSignorileSignorileetal.2021, author = {Magnea, Lorenzo and Pelliccioli, Giovanni and Signorile-Signorile, Chiara and Torrielli, Paolo and Uccirati, Sandro}, title = {Analytic integration of soft and collinear radiation in factorised QCD cross sections at NNLO}, series = {Journal of High Energy Physics}, volume = {2021}, journal = {Journal of High Energy Physics}, doi = {10.1007/JHEP02(2021)037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370064}, year = {2021}, abstract = {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.}, language = {en} } @article{MacLeodSurulirajGalletal.2021, author = {MacLeod, Lucy and Suruliraj, Banuchitra and Gall, Dominik and Bessenyei, Kitti and Hamm, Sara and Romkey, Isaac and Bagnell, Alexa and Mattheisen, Manuel and Muthukumaraswamy, Viswanath and Orji, Rita and Meier, Sandra}, title = {A Mobile Sensing App to Monitor Youth Mental Health: Observational Pilot Study}, series = {JMIR mHealth and uHealth}, volume = {9}, journal = {JMIR mHealth and uHealth}, doi = {10.2196/20638}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370054}, year = {2021}, abstract = {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.}, language = {en} } @article{MacchiaroliPrezaGastonPerezetal.2021, author = {Macchiaroli, Natalia and Preza, Mat{\´i}as and Gast{\´o}n P{\´e}rez, Mat{\´i}as and Kamenetzky, Laura and Cucher, Marcela and Koziol, Uriel and Castillo, Estela and Berriman, Matthew and Brehm, Klaus and Rosenzvit, Mara Cecilia}, title = {Expression profiling of Echinococcus multilocularis miRNAs throughout metacestode development in vitro}, series = {PLOS Neglected Tropical Diseases}, volume = {15}, journal = {PLOS Neglected Tropical Diseases}, doi = {10.1371/journal.pntd.0009297}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370046}, year = {2021}, abstract = {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.}, language = {en} } @article{MaasBrandlHussainetal.2021, author = {Maas, Bea and Brandl, Manuela and Hussain, Raja Imran and Frank, Thomas and Zulka, Klaus Peter and Rabl, Dominik and Walcher, Ronnie and Moser, Dietmar}, title = {Functional traits driving pollinator and predator responses to newly established grassland strips in agricultural landscapes}, series = {Journal of Applied Ecology}, volume = {58}, journal = {Journal of Applied Ecology}, doi = {10.1111/1365-2664.13892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369992}, pages = {1728-1737}, year = {2021}, abstract = {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.}, language = {en} } @article{LuxSchneeweissHartkopfetal.2021, author = {Lux, Michael P. and Schneeweiss, Andreas and Hartkopf, Andreas D. and M{\"u}ller, Volkmar and Janni, Wolfgang and Belleville, Erik and Stickeler, Elmar and Thill, Marc and Fasching, Peter A. and Kolberg, Hans-Christian and Untch, Michael and Harbeck, Nadia and W{\"o}ckel, Achim and Thomssen, Christoph and Schulmeyer, Carla E. and Welslau, Manfred and Overkamp, Friedrich and Sch{\"u}tz, Florian and L{\"u}ftner, Diana and Ditsch, Nina}, title = {Update Breast Cancer 2020 Part 5 - Moving Therapies From Advanced to Early Breast Cancer Patients}, series = {Geburtshilfe und Frauenheilkunde}, volume = {81}, journal = {Geburtshilfe und Frauenheilkunde}, doi = {10.1055/a-1397-7170}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369989}, pages = {469-480}, year = {2021}, abstract = {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.}, language = {en} } @article{LuuRiesterBaldrichetal.2021, author = {Luu, Maik and Riester, Zeno and Baldrich, Adrian and Reichardt, Nicole and Yuille, Samantha and Busetti, Alessandro and Klein, Matthias and Wempe, Anne and Leister, Hanna and Raifer, Hartmann and Picard, Felix and Muhammad, Khalid and Ohl, Kim and Romero, Rossana and Fischer, Florence and Bauer, Christian A. and Huber, Magdalena and Gress, Thomas M. and Lauth, Matthias and Danhof, Sophia and Bopp, Tobias and Nerreter, Thomas and Mulder, Imke E. and Steinhoff, Ulrich and Hudecek, Michael and Visekruna, Alexander}, title = {Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-021-24331-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-309332}, year = {2021}, abstract = {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.}, language = {en} } @article{LuoLingLiuetal.2021, author = {Luo, Yueming and Ling, Chuanren and Liu, Yangchen and Deng, Chong and Waaga-Gasser, Ana Maria and Chen, Minggui and He, Zehui and Chen, Erhui and Wei, Lin and Luo, Shimiao and Gong, Xiaozhen and Ye, Hong and Zhu, Jing and Song, Shan and Wang, Qiuting and Li, Shunmin and Gasser, Martin and Lin, Meizhen}, title = {The Beneficial Role of Auricular Point Pressure in Insomnia and Anxiety in Isolated COVID-19 Patients}, series = {Evidence-Based Complementary and Alternative Medicine}, volume = {2021}, journal = {Evidence-Based Complementary and Alternative Medicine}, doi = {10.1155/2021/6611942}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369658}, year = {2021}, abstract = {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.}, language = {en} } @article{LuijtenLeonhardvanderEijketal.2021, author = {Luijten, Linda W G and Leonhard, Sonja E and van der Eijk, Annemiek A and Doets, Alex Y and Appeltshauser, Luise and Arends, Samuel and Attarian, Shahram and Benedetti, Luana and Briani, Chiara and Casasnovas, Carlos and Castellani, Francesca and Dardiotis, Efthimios and Echaniz-Laguna, Andoni and Garssen, Marcel P J and Harbo, Thomas and Huizinga, Ruth and Humm, Andrea M and Jellema, Korn{\´e} and van der Kooi, Anneke J and Kuitwaard, Krista and Kuntzer, Thierry and Kusunoki, Susumu and Lascano, Agustina M and Martinez-Hernandez, Eugenia and Rinaldi, Simon and Samijn, Johnny P A and Scheidegger, Olivier and Tsouni, Pinelopi and Vicino, Alex and Visser, Leo H and Walgaard, Christa and Wang, Yuzhong and Wirtz, Paul W and Ripellino, Paolo and Jacobs, Bart C}, title = {Guillain-Barr{\´e} syndrome after SARS-CoV-2 infection in an international prospective cohort study}, series = {Brain}, volume = {144}, journal = {Brain}, organization = {The IGOS consortium}, doi = {10.1093/brain/awab279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371609}, pages = {3392-3404}, year = {2021}, abstract = {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-Barr{\´e} 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.}, language = {en} } @article{LuedersPukropRozasetal.2021, author = {L{\"u}ders, Carolin and Pukrop, Matthias and Rozas, Elena and Schneider, Christian and H{\"o}fling, Sven and Sperling, Jan and Schumacher, Stefan and Aßmann, Marc}, title = {Quantifying Quantum Coherence in Polariton Condensates}, series = {PRX Quantum}, volume = {2}, journal = {PRX Quantum}, doi = {10.1103/PRXQuantum.2.030320}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369644}, year = {2021}, abstract = {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.}, language = {en} } @article{LudwigDignathLukas2021, author = {Ludwig, Jonas and Dignath, David and Lukas, Sarah}, title = {Positive and negative action-effects improve task-switching performance}, series = {Acta Psychologica}, volume = {221}, journal = {Acta Psychologica}, doi = {10.1016/j.actpsy.2021.103440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369638}, year = {2021}, abstract = {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.}, language = {en} } @article{LuBierbachOrmannsetal.2021, author = {Lu, Yuan and Bierbach, David and Ormanns, Jenny and Warren, Wesley C. and Walter, Ronald B. and Schartl, Manfred}, title = {Fixation of allelic gene expression landscapes and expression bias pattern shape the transcriptome of the clonal Amazon molly}, series = {Genome Research}, volume = {31}, journal = {Genome Research}, doi = {10.1101/gr.268870.120}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369578}, pages = {372-379}, year = {2021}, abstract = {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.}, language = {en} } @article{LozaValdesMayerKassoufetal.2021, author = {Loza-Valdes, Angel and Mayer, Alexander E and Kassouf, Toufic and Trujillo-Viera, Jonathan and Schmitz, Werner and Dziaczkowski, Filip and Leitges, Michael and Schlosser, Andreas and Sumara, Grzegorz}, title = {A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism}, series = {Life Science Alliance}, volume = {4}, journal = {Life Science Alliance}, doi = {10.26508/lsa.202000863}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369560}, year = {2021}, abstract = {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.}, language = {en} } @article{LotanGakisManfredietal.2021, author = {Lotan, Yair and Gakis, Georgios and Manfredi, Matteo and Morote, Juan and Mostafid, Hugh and Porpiglia, Francesco and Poyet, Cedric and Roupret, Morgan and Schulman, Claude and Shariat, Shahrokh F. and Witjes, Johannes Alfred}, title = {Alternating Cystoscopy with Bladder EpiCheck® in the Surveillance of Low-Grade Intermediate-Risk NMIBC: A Cost Comparison Model}, series = {Bladder Cancer}, volume = {7}, journal = {Bladder Cancer}, doi = {10.3233/BLC-211528}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369512}, pages = {307-315}, year = {2021}, abstract = {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\pounds 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.}, language = {en} } @article{LoscherLoehleinLenz2021, author = {Loscher, Georg and L{\"o}hlein, Lukas and Lenz, Hansrudi}, title = {Dual Roles and Blurred Identities: A Framing Contest between Professional Associations in a Local Strategic Action Field}, series = {European Accounting Review}, volume = {30}, journal = {European Accounting Review}, doi = {10.1080/09638180.2021.1882319}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369504}, pages = {503-529}, year = {2021}, abstract = {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.}, language = {en} } @article{LoewUllmannConrad2021, author = {L{\"o}w, Johannes and Ullmann, Tobias and Conrad, Christopher}, title = {The Impact of Phenological Developments on Interferometric and Polarimetric Crop Signatures Derived from Sentinel-1: Examples from the DEMMIN Study Site (Germany)}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, doi = {10.3390/rs13152951}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369452}, year = {2021}, abstract = {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.}, language = {en} } @article{LoebleinLorsonKommaetal.2021, author = {L{\"o}blein, Jochen and Lorson, Thomas and Komma, Miriam and Kielholz, Tobias and Windbergs, Maike and Dalton, Paul D. and Luxenhofer, Robert}, title = {An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone)}, series = {Beilstein Journal of Organic Chemistry}, volume = {17}, journal = {Beilstein Journal of Organic Chemistry}, doi = {10.3762/bjoc.17.136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369433}, pages = {2095-2101}, year = {2021}, abstract = {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.}, language = {en} } @article{LockReimerPietrygaetal.2021, author = {Lock, Johan F and Reimer, Stanislaus and Pietryga, Sebastian and Jakubietz, Rafael and Flemming, Sven and Meining, Alexander and Germer, Christoph-Thomas and Seyfried, Florian}, title = {Managing esophagocutaneous fistula after secondary gastric pull-up: A case report}, series = {World Journal of Gastroenterology}, volume = {27}, journal = {World Journal of Gastroenterology}, doi = {10.3748/wjg.v27.i16.1841}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369417}, pages = {1841-1846}, year = {2021}, abstract = {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.}, language = {en} } @article{LjubojevićHolzerKralerDjalinacetal.2022, author = {Ljubojević-Holzer, Senka and Kraler, Simon and Djalinac, Nataša and Abdellatif, Mahmoud and Voglhuber, Julia and Schipke, Julia and Schmidt, Marlene and Kling, Katharina-Maria and Franke, Greta Therese and Herbst, Viktoria and Zirlik, Andreas and von Lewinski, Dirk and Scherr, Daniel and Rainer, Peter P and Kohlhaas, Michael and Nickel, Alexander and M{\"u}hlfeld, Christian and Maack, Christoph and Sedej, Simon}, title = {Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling}, series = {Cardiovascular Research}, volume = {118}, journal = {Cardiovascular Research}, doi = {10.1093/cvr/cvab112}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369345}, pages = {1492-1505}, year = {2022}, abstract = {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.}, language = {en} } @article{LinzBrandsKertelsetal.2021, author = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte}, title = {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}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, doi = {10.1007/s00259-021-05422-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369331}, pages = {3951-3960}, year = {2021}, abstract = {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-na{\"i}ve 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.}, language = {en} } @article{LinzBrandsHerterichetal.2021, author = {Linz, Christian and Brands, Roman C. and Herterich, Theresia and Hartmann, Stefan and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander C. and Haug, Lukas and Kertels, Olivia and Bley, Thorsten A. and Dierks, Alexander and Buck, Andreas K. and Lapa, Constantin and Brumberg, Joachim}, title = {Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity}, series = {JAMA Network Open}, volume = {4}, journal = {JAMA Network Open}, doi = {10.1001/jamanetworkopen.2021.7083}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369313}, year = {2021}, abstract = {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.}, language = {en} } @article{LinzHohlLangetal.2021, author = {Linz, Benedikt and Hohl, Mathias and Lang, Lisa and Wong, Dickson W. L. and Nickel, Alexander G. and De La Torre, Carolina and Sticht, Carsten and Wirth, Klaus and Boor, Peter and Maack, Christoph and Speer, Thimoteus and Jespersen, Thomas and Schotten, Ulrich and Sanders, Prashanthan and B{\"o}hm, Michael and Linz, Dominik}, title = {Repeated exposure to transient obstructive sleep apnea-related conditions causes an atrial fibrillation substrate in a chronic rat model}, series = {Heart Rhythm}, volume = {18}, journal = {Heart Rhythm}, doi = {10.1016/j.hrthm.2020.10.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369298}, pages = {455-464}, year = {2021}, abstract = {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.}, language = {en} } @article{LinhoffSandrockKadleretal.2021, author = {Linhoff, Lena and Sandrock, Alexander and Kadler, Matthias and Els{\"a}sser, Dominik and Rhode, Wolfgang}, title = {Excluding possible sites of high-energy emission in 3C 84}, series = {Monthly Notices of the Royal Astronomical Society}, volume = {500}, journal = {Monthly Notices of the Royal Astronomical Society}, doi = {10.1093/mnras/staa3521}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369287}, pages = {4671-4677}, year = {2021}, abstract = {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.}, language = {en} } @article{LiebersDuellFitzgeraldetal.2021, author = {Liebers, Nora and Duell, Johannes and Fitzgerald, Donnacha and Kerkhoff, Andrea and Noerenberg, Daniel and Kaebisch, Eva and Acker, Fabian and Fuhrmann, Stephan and Leng, Corinna and Welslau, Manfred and Chemnitz, Jens and Middeke, Jan-Moritz and Weber, Thomas and Holtick, Udo and Trappe, Ralf and Pfannes, Roald and Liersch, Ruediger and Spoer, Christian and Fuxius, Stefan and Gebauer, Niklas and Caill{\´e}, L{\´e}andra and Geer, Thomas and Koenecke, Christian and Keller, Ulrich and Claus, Rainer and Mougiakakos, Dimitrios and Mayer, Stephanie and Huettmann, Andreas and Pott, Christiane and Trummer, Arne and Wulf, Gerald and Brunnberg, Uta and Bullinger, Lars and Hess, Georg and Mueller-Tidow, Carsten and Glass, Bertram and Lenz, Georg and Dreger, Peter and Dietrich, Sascha}, title = {Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas}, series = {Blood Advances}, volume = {5}, journal = {Blood Advances}, doi = {10.1182/bloodadvances.2020004155}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369173}, pages = {2707-2716}, year = {2021}, abstract = {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.}, language = {en} } @article{LiangCostanzaPrutschetal.2021, author = {Liang, Huan-Chang and Costanza, Mariantonia and Prutsch, Nicole and Zimmerman, Mark W. and Gurnhofer, Elisabeth and Montes-Mojarro, Ivonne A. and Abraham, Brian J. and Prokoph, Nina and Stoiber, Stefan and Tangermann, Simone and Lobello, Cosimo and Oppelt, Jan and Anagnostopoulos, Ioannis and Hielscher, Thomas and Pervez, Shahid and Klapper, Wolfram and Zammarchi, Francesca and Silva, Daniel-Adriano and Garcia, K. Christopher and Baker, David and Janz, Martin and Schleussner, Nikolai and Fend, Falko and Posp{\´i}šilov{\´a}, Š{\´a}rka and Janikov{\´a}, Andrea and Wallwitz, Jacqueline and Stoiber, Dagmar and Simonitsch-Klupp, Ingrid and Cerroni, Lorenzo and Pileri, Stefano and de Leval, Laurence and Sibon, David and Fataccioli, Virginie and Gaulard, Philippe and Assaf, Chalid and Kn{\"o}rr, Fabian and Damm-Welk, Christine and Woessmann, Wilhelm and Turner, Suzanne D. and Look, A. Thomas and Mathas, Stephan and Kenner, Lukas and Merkel, Olaf}, title = {Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma}, series = {Nature Communications}, volume = {12}, journal = {Nature Communications}, doi = {10.1038/s41467-021-25379-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371581}, year = {2021}, abstract = {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.}, language = {en} }