@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} }