@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} }