@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{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{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{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{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} }