@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} }