@phdthesis{Dorband2024, author = {Dorband, Moritz}, title = {Geometric Phases and Factorisation in Quantum Physics and Gravity}, doi = {10.25972/OPUS-37093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370937}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In this thesis I explore the interplay of geometry and quantum information theory via the holographic principle, with a specific focus on geometric phases in quantum systems like two interacting qubits, and how they relate to entanglement measures and Hilbert space factorisation. I establish geometric phases as an indicator for Hilbert space factorsiation, both in an abstract sense using von Neumann operator algebras as well as applied to the eternal black hole within the AdS/CFT correspondence. For the latter case I show that geometric phases allow to diagnose non-factorisation from a boundary point of view. I also introduce geometric quantum discord as a second geometric measure for non-factorisation and reveals its potential implications for the study of black hole microstates.}, subject = {AdS-CFT-Korrespondenz}, language = {en} } @phdthesis{Kappenberger2024, author = {Kappenberger, Jeannette Sarah}, title = {Biochemical characterization of the TFIIH translocase XPB from \(Chaetomium\) \(thermophilum\)}, doi = {10.25972/OPUS-24409}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244096}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {DNA repair and gene expression are two major cellular processes that are fundamental for the maintenance of biological life. Both processes require the enzymatic activity of the super family 2 helicase XBP, which is an integral subunit of the general transcription factor TFIIH. During transcription initiation, XPB catalyzes the initial melting of promoter DNA enabling RNA polymerase II to engage with the coding DNA strand and start gene transcription. In nucleotide excision repair, XPB acts in concert with the other TFIIH helicase XPD causing strand separation around a lesion site. Mutations within the genes encoding XPB or other TFIIH subunits are associated with different cancer types as well as with the autosomal recessive disorders Xeroderma Pigmentosum and trichothiodystrophy and rarely combined features of Xeroderma Pigmentosum and Cockayne syndrome. In the last few years, great progress has been made towards unraveling the structure of TFIIH and its individual subunits including XPB. These structural insights tremendously improved our understandings with respect to the molecular interactions within this intriguing protein complex. However, the underlying regulation mechanisms that functionally control XPB during transcription and repair remained largely elusive. We thus executed the biochemical characterization of this protein to investigate the functional network that regulates XPB within the scaffold of TFIIH. Due to their enhanced stability compared to the human proteins, we utilized the proteins that originate from the thermophilic fungus Chaetomium thermophilum for this purpose as a model organism for eukaryotic TFIIH. The present work provides novel insights into the enzymatic function and regulation of XPB. We could show that both, DNA and the TFIIH subunit p52 stimulate XPB's ATPase activity and that the p52-mediated activity is further boosted by p8, another subunit within TFIIH. Surprisingly, DNA can activate XPB's ATPase activity to a greater extent than its TFIIH interaction partners p52/p8, but when both, i.e. p52/p8 and DNA are present at the same time, p52 dominates the activation and the enzymatic speed is maintained at the level observed through the sole activation of p52/p8. We thus defined p52 as the master regulator of XPB that simultaneously activates and represses XPB's enzymatic activity. Based on a correlative mutagenesis study of the main interface between p52 and XPB that was set into context with recent structural data, a model for the p52-mediated activation and speed limitation of XPB's ATPase was proposed. The research on XPB's ATPase was expanded with the investigation of the inhibition mechanism of XPB's ATPase via the natural compound Triptolide. Furthermore, we investigated XPB's DNA translocase function and could observe that XPB can only perform its translocase movement when it is fully incorporated into core TFIIH and this translocase movement is further enhanced by the nucleotide excision repair factor XPA. Fluorescence polarization measurements with nucleotide analogues revealed that XPB displays the highest affinity towards DNA in the ADP + Pi bound state and its binding is weakened when ADP is bound or the nucleotide is dissociated from the enzyme, suggesting a movement on the DNA during the distinct states of the ATPase cycle. Finally, the well-known and highly conserved RED motif was found to be the crucial element in XPB to enable this translocase movement. Combined, the data presented in this work provide novel insights into the intricate regulation network that controls XPB's enzymatic activity within TFIIH and furthermore show that XPB's enzymatic activity is tightly controlled by various factors.}, subject = {DNS-Reparatur}, language = {en} } @article{OPUS4-31409, title = {Electron and photon energy calibration with the ATLAS detector using 2015-2016 LHC proton-proton collision data}, series = {Journal of Instrumentation}, volume = {14}, journal = {Journal of Instrumentation}, organization = {The ATLAS Collaboration}, doi = {10.1088/1748-0221/14/03/P03017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314093}, pages = {1-58}, year = {2019}, abstract = {This paper presents the electron and photon energy calibration obtained with the ATLAS detector using about 36 fb(-1) of LHC proton-proton collision data recorded at root s = 13 TeV in 2015 and 2016. The different calibration steps applied to the data and the optimization of the reconstruction of electron and photon energies are discussed. The absolute energy scale is set using a large sample of Z boson decays into electron-positron pairs. The systematic uncertainty in the energy scale calibration varies between 0.03\% to 0.2\% in most of the detector acceptance for electrons with transverse momentum close to 45 GeV. For electrons with transverse momentum of 10 GeV the typical uncertainty is 0.3\% to 0.8\% and it varies between 0.25\% and 1\% for photons with transverse momentum around 60 GeV. Validations of the energy calibration with J/psi -> e(+)e(-) decays and radiative Z boson decays are also presented.}, language = {en} } @article{MuentzeGenslerManiucetal.2019, author = {M{\"u}ntze, Jonas and Gensler, Daniel and Maniuc, Octavian and Liu, Dan and Cairns, Tereza and Oder, Daniel and Hu, Kai and Lorenz, Kristina and Frantz, Stefan and Wanner, Christoph and Nordbeck, Peter}, title = {Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year}, series = {Clinical Pharmacology \& Therapeutics}, volume = {105}, journal = {Clinical Pharmacology \& Therapeutics}, doi = {10.1002/cpt.1321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231626}, pages = {1224-1233}, year = {2019}, abstract = {Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06-0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137-130 g/m2; P = 0.037), and serum creatinine (0.94-1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87-78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = -0.546; P = 0.044) but not with renal function (r = -0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9-6.0 ng/mL; P = 0.021) and stable (9.6-12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations.}, language = {en} } @article{SchubertHagedornYoshiietal.2018, author = {Schubert, Frank K. and Hagedorn, Nicolas and Yoshii, Taishi and Helfrich-F{\"o}rster, Charlotte and Rieger, Dirk}, title = {Neuroanatomical details of the lateral neurons of Drosophila melanogaster support their functional role in the circadian system}, series = {Journal of Comparative Neurology}, volume = {526}, journal = {Journal of Comparative Neurology}, doi = {10.1002/cne.24406}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234477}, pages = {1209-1231}, year = {2018}, abstract = {Drosophila melanogaster is a long-standing model organism in the circadian clock research. A major advantage is the relative small number of about 150 neurons, which built the circadian clock in Drosophila. In our recent work, we focused on the neuroanatomical properties of the lateral neurons of the clock network. By applying the multicolor-labeling technique Flybow we were able to identify the anatomical similarity of the previously described E2 subunit of the evening oscillator of the clock, which is built by the 5th small ventrolateral neuron (5th s-LNv) and one ITP positive dorsolateral neuron (LNd). These two clock neurons share the same spatial and functional properties. We found both neurons innervating the same brain areas with similar pre- and postsynaptic sites in the brain. Here the anatomical findings support their shared function as a main evening oscillator in the clock network like also found in previous studies. A second quite surprising finding addresses the large lateral ventral PDF-neurons (l-LNvs). We could show that the four hardly distinguishable l-LNvs consist of two subgroups with different innervation patterns. While three of the neurons reflect the well-known branching pattern reproduced by PDF immunohistochemistry, one neuron per brain hemisphere has a distinguished innervation profile and is restricted only to the proximal part of the medulla-surface. We named this neuron "extra" l-LNv (l-LNvx). We suggest the anatomical findings reflect different functional properties of the two l-LNv subgroups.}, language = {en} } @article{SchwarzScharfScherpfetal.2019, author = {Schwarz, Christopher and Scharf, Lennart T. and Scherpf, Thorsten and Weismann, Julia and Gessner, Viktoria H.}, title = {Isolation of the Metalated Ylides [Ph3P-C-CN]M (M=Li, Na, K): Influence of the Metal Ion on the Structure and Bonding Situation}, series = {Chemistry - A European Journal}, volume = {25}, journal = {Chemistry - A European Journal}, doi = {10.1002/chem.201805421}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235445}, pages = {2793-2802}, year = {2019}, abstract = {The isolation and structural characterization of the cyanido-substituted metalated ylides [Ph3P-C-CN]M (1-M; M=Li, Na, K) are reported with lithium, sodium, and potassium as metal cations. In the solid-state, most different aggregates could be determined depending on the metal and additional Lewis bases. The crown-ether complexes of sodium (1-Na) and potassium (1-K) exhibited different structures, with sodium preferring coordination to the nitrogen end, whereas potassium binds in an unusual η2-coordination mode to the two central carbon atoms. The formation of the yldiide was accompanied by structural changes leading to shorter C-C and longer C-N bonds. This could be attributed to the delocalization of the free electron pairs at the carbon atom into the antibonding orbitals of the CN moiety, which was confirmed by IR spectroscopy and computational studies. Detailed density functional theory calculations show that the changes in the structure and the bonding situation were most pronounced in the lithium compounds due to the higher covalency.}, language = {en} } @article{ChenGehringerLorenz2018, author = {Chen, Dan and Gehringer, Matthias and Lorenz, Sonja}, title = {Developing Small-Molecule Inhibitors of HECT-Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities}, series = {ChemBioChem}, volume = {19}, journal = {ChemBioChem}, doi = {10.1002/cbic.201800321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222412}, pages = {2123-2135}, year = {2018}, abstract = {The ubiquitin system regulates countless physiological and disease-associated processes and has emerged as an attractive entryway for therapeutic efforts. With over 600 members in the human proteome, ubiquitin ligases are the most diverse class of ubiquitylation enzymes and pivotal in encoding specificity in ubiquitin signaling. Although considerable progress has been made in the identification of small molecules targeting RING ligases, relatively little is known about the "druggability" of HECT (homologous to E6AP C terminus) ligases, many of which are critically implicated in human pathologies. A major obstacle to optimizing the few available ligands is our incomplete understanding of their inhibitory mechanisms and the structural basis of catalysis in HECT ligases. Here, we survey recent approaches to manipulate the activities of HECT ligases with small molecules to showcase the particular challenges and opportunities these enzymes hold as therapeutic targets.}, language = {en} } @article{WilsonAmblerLeeetal.2019, author = {Wilson, Duncan and Ambler, Gareth and Lee, Keon-Joo and Lim, Jae-Sung and Shiozawa, Masayuki and Koga, Masatoshi and Li, Linxin and Lovelock, Caroline and Chabriat, Hugues and Hennerici, Michael and Wong, Yuen Kwun and Mak, Henry Ka Fung and Prats-S{\´a}nchez, Luis and Mart{\´i}nez-Dome{\~n}o, Alejandro and Inamura, Shigeru and Yoshifuji, Kazuhisa and Arsava, Ethem Murat and Horstmann, Solveig and Purrucker, Jan and Lam, Bonnie Yin Ka and Wong, Adrian and Kim, Young Dae and Song, Tae-Jin and Schrooten, Maarten and Lemmens, Robin and Eppinger, Sebastian and Gattringer, Thomas and Uysal, Ender and Tanriverdi, Zeynep and Bornstein, Natan M and Ben Assayag, Einor and Hallevi, Hen and Tanaka, Jun and Hara, Hideo and Coutts, Shelagh B and Hert, Lisa and Polymeris, Alexandros and Seiffge, David J and Lyrer, Philippe and Algra, Ale and Kappelle, Jaap and Salman, Rustam Al-Shahi and J{\"a}ger, Hans R and Lip, Gregory Y H and Mattle, Heinrich P and Panos, Leonidas D and Mas, Jean-Louis and Legrand, Laurence and Karayiannis, Christopher and Phan, Thanh and Gunkel, Sarah and Christ, Nicolas and Abrigo, Jill and Leung, Thomas and Chu, Winnie and Chappell, Francesca and Makin, Stephen and Hayden, Derek and Williams, David J and Kooi, M Eline and van Dam-Nolen, Dianne H K and Barbato, Carmen and Browning, Simone and Wiegertjes, Kim and Tuladhar, Anil M and Maaijwee, Noortje and Guevarra, Christine and Yatawara, Chathuri and Mendyk, Anne-Marie and Delmaire, Christine and K{\"o}hler, Sebastian and van Oostenbrugge, Robert and Zhou, Ying and Xu, Chao and Hilal, Saima and Gyanwali, Bibek and Chen, Christopher and Lou, Min and Staals, Julie and Bordet, R{\´e}gis and Kandiah, Nagaendran and de Leeuw, Frank-Erik and Simister, Robert and van der Lugt, Aad and Kelly, Peter J and Wardlaw, Joanna M and Soo, Yannie and Fluri, Felix and Srikanth, Velandai and Calvet, David and Jung, Simon and Kwa, Vincent I H and Engelter, Stefan T and Peters, Nils and Smith, Eric E and Yakushiji, Yusuke and Necioglu Orken, Dilek and Fazekas, Franz and Thijs, Vincent and Heo, Ji Hoe and Mok, Vincent and Veltkamp, Roland and Ay, Hakan and Imaizumi, Toshio and Gomez-Anson, Beatriz and Lau, Kui Kai and Jouvent, Eric and Rothwell, Peter M and Toyoda, Kazunori and Bae, Hee-Yoon and Marti-Fabregas, Joan and Werring, David J}, title = {Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies}, series = {The Lancet Neurology}, volume = {18}, journal = {The Lancet Neurology}, organization = {Microbleeds International Collaborative Network}, doi = {10.1016/S1474-4422(19)30197-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233710}, pages = {653-665}, year = {2019}, abstract = {Background Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. Methods We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. Findings Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95\% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95\% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95\% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). Interpretation In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.}, language = {en} } @article{WaszakNorthcottBuchhalteretal.2018, author = {Waszak, Sebastian M and Northcott, Paul A and Buchhalter, Ivo and Robinson, Giles W and Sutter, Christian and Groebner, Susanne and Grund, Kerstin B and Brugi{\`e}res, Laurence and Jones, David T W and Pajtler, Kristian W and Morrissy, A Sorana and Kool, Marcel and Sturm, Dominik and Chavez, Lukas and Ernst, Aurelie and Brabetz, Sebastian and Hain, Michael and Zichner, Thomas and Segura-Wang, Maia and Weischenfeldt, Joachim and Rausch, Tobias and Mardin, Balca R and Zhou, Xin and Baciu, Cristina and Lawerenz, Christian and Chan, Jennifer A and Varlet, Pascale and Guerrini-Rousseau, Lea and Fults, Daniel W and Grajkowska, Wiesława and Hauser, Peter and Jabado, Nada and Ra, Young-Shin and Zitterbart, Karel and Shringarpure, Suyash S and De La Vega, Francisco M and Bustamante, Carlos D and Ng, Ho-Keung and Perry, Arie and MacDonald, Tobey J and Driever, Pablo Hern{\´a}iz and Bendel, Anne E and Bowers, Daniel C and McCowage, Geoffrey and Chintagumpala, Murali M and Cohn, Richard and Hassall, Timothy and Fleischhack, Gudrun and Eggen, Tone and Wesenberg, Finn and Feychting, Maria and Lannering, Birgitta and Sch{\"u}z, Joachim and Johansen, Christoffer and Andersen, Tina V and R{\"o}{\"o}sli, Martin and Kuehni, Claudia E and Grotzer, Michael and Kjaerheim, Kristina and Monoranu, Camelia M and Archer, Tenley C and Duke, Elizabeth and Pomeroy, Scott L and Shelagh, Redmond and Frank, Stephan and Sumerauer, David and Scheurlen, Wolfram and Ryzhova, Marina V and Milde, Till and Kratz, Christian P and Samuel, David and Zhang, Jinghui and Solomon, David A and Marra, Marco and Eils, Roland and Bartram, Claus R and von Hoff, Katja and Rutkowksi, Stefan and Ramaswamy, Vijay and Gilbertson, Richard J and Korshunov, Andrey and Taylor, Michael D and Lichter, Peter and Malkin, David and Gajjar, Amar and Korbel, Jan O and Pfister, Stefan M}, title = {Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort}, series = {The Lancet Oncology}, volume = {19}, journal = {The Lancet Oncology}, doi = {10.1016/S1470-2045(18)30242-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233425}, pages = {785-798}, year = {2018}, abstract = {Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6\% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20\% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5\% of medulloblastoma diagnoses, with the highest prevalence [14\%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71\%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57\%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52\% (95\% CI 40-69) and 5-year overall survival was 65\% (95\% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.}, language = {en} } @article{KampfReiterBauer2018, author = {Kampf, Thomas and Reiter, Theresa and Bauer, Wolfgang Rudolf}, title = {An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery - Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325498}, pages = {150-157}, year = {2018}, abstract = {Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner.}, language = {en} } @article{KampfBauerReiter2018, author = {Kampf, Thomas and Bauer, Wolfgang Rudolf and Reiter, Theresa}, title = {Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325481}, pages = {25-35}, year = {2018}, abstract = {Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. Materials and methods All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. Results Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25\% (18-33\%; SD 0.03) in the healthy, 30\% (22-40\%; SD 0.04) in patients with DCM and 45\% (30-60\%; SD 0.9) in patients with amyloidosis. Conclusion The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases.}, language = {en} } @article{GermainElliottFalissardetal.2019, author = {Germain, Dominique P. and Elliott, Perry M. and Falissard, Bruno and Fomin, Victor V. and Hilz, Max J. and Jovanovic, Ana and Kantola, Ilkka and Linhart, Aleš and Renzo, Mignani and Namdar, Mehdi and Nowak, Albina and Oliveira, Jo{\~a}o-Paulo and Pieroni, Maurizio and Viana-Baptista, Miguel and Wanner, Christoph and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism Reports}, volume = {19}, journal = {Molecular Genetics and Metabolism Reports}, doi = {10.1016/j.ymgmr.2019.100454}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232987}, year = {2019}, abstract = {Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.}, language = {en} } @article{UeceylerUrlaubMayeretal.2019, author = {{\"U}{\c{c}}eyler, Nurcan and Urlaub, Daniela and Mayer, Christine and Uehlein, Sabrina and Held, Melissa and Sommer, Claudia}, title = {Tumor necrosis factor-α links heat and inflammation with Fabry pain}, series = {Molecular Genetics and Metabolism}, volume = {127}, journal = {Molecular Genetics and Metabolism}, doi = {https://doi.org/10.1016/j.ymgme.2019.05.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229190}, pages = {200-206}, year = {2019}, abstract = {Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.}, language = {en} } @article{GermainAradBurlinaetal.2019, author = {Germain, Dominique P. and Arad, Michael and Burlina, Alessandro and Elliott, Perry M. and Falissard, Bruno and Feldt-Rasmussen, Ulla and Hilz, Max J. and Hughes, Derralynn A. and Ortiz, Alberto and Wanner, Christoph and Weidemann, Frank and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.09.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232963}, pages = {224-235}, year = {2019}, abstract = {Background Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. Methods A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. Results Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. Conclusions This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.}, language = {en} } @article{SpadaBaronElliottetal.2019, author = {Spada, Marco and Baron, Ralf and Elliott, Perry M. and Falissard, Bruno and Hilz, Max J. and Monserrat, Lorenzo and T{\o}ndel, Camilla and Tylki-Szymańska, Anna and Wanner, Christoph and Germain, Dominique P.}, title = {The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.04.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239287}, pages = {212-223}, year = {2019}, abstract = {Background Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. Methods A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Results Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Conclusions Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage.}, language = {en} } @article{FlunkertMaierhoferDittrichetal.2018, author = {Flunkert, Julia and Maierhofer, Anna and Dittrich, Marcus and M{\"u}ller, Tobias and Horvath, Steve and Nanda, Indrajit and Haaf, Thomas}, title = {Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts}, series = {Experimental Cell Research}, volume = {370}, journal = {Experimental Cell Research}, doi = {10.1016/j.yexcr.2018.06.034}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228177}, pages = {322-332}, year = {2018}, abstract = {To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for variation in radiation sensitivity, all experiments were performed with two different fibroblast strains. After a single X-ray dose of 2 Gy more than half of the irradiated clones exhibited radiation-induced genome instability (RIGI). Irradiated clones displayed an increased rate of loss of chromosome Y (LOY) and copy number variations (CNVs), compared to controls. CNV breakpoints clustered in specific chromosome regions, in particular 3p14.2 and 7q11.21, coinciding with common fragile sites. CNVs affecting the FHIT gene in FRA3B were observed in independent unstable clones and may drive RIGI. Bisulfite pyrosequencing of control clones and the respective primary culture revealed global hypomethylation of ALU, LINE-1, and alpha-satellite repeats as well as rDNA hypermethylation during in vitro ageing. Irradiated clones showed further reduced ALU and alpha-satellite methylation and increased rDNA methylation, compared to controls. Methylation arrays identified several hundred differentially methylated genes and several enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic (LOY and CNVs) and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis. We did not observe epigenetic differences between stable and unstable irradiated clones. The fact that the DNA methylation (DNAm) age of clones derived from the same primary culture varied greatly suggests that DNAm age of a single cell (represented by a clone) can be quite different from the DNAm age of a tissue. We propose that DNAm age reflects the emergent property of a large number of individual cells whose respective DNAm ages can be highly variable.}, language = {en} } @article{OmenacaVazquezGarciaCorbeiraetal.2018, author = {Ome{\~n}aca, Felix and V{\´a}zquez, Liliana and Garcia-Corbeira, Pilar and Mesaros, Narcisa and Hanssens, Linda and Dolhain, Jan and Puente G{\´o}mez, Ivonne and Liese, Johannes and Knuf, Markus}, title = {Immunization of preterm infants with GSK's hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine: A review of safety and immunogenicity}, series = {Vaccine}, volume = {36}, journal = {Vaccine}, doi = {10.1016/j.vaccine.2018.01.005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234450}, pages = {986-996}, year = {2018}, abstract = {Background Infants with history of prematurity (<37 weeks gestation) and low birth weight (LBW, <2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed. Methods Here we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK's hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials. Results At least 92.5\% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13-30\% of medically stable infants with history of prematurity developed apnea after vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK's hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens. Conclusion GSK's hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK's hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age.}, language = {en} } @article{FeistauerRichter2018, author = {Feistauer, Daniela and Richter, Tobias}, title = {Validity of students' evaluations of teaching: Biasing effects of likability and prior subject interest}, series = {Studies in Educational Evaluation}, volume = {59}, journal = {Studies in Educational Evaluation}, doi = {10.1016/j.stueduc.2018.07.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228005}, pages = {168-178}, year = {2018}, abstract = {This study examined the validity of students' evaluations of teaching as an instrument for measuring teaching quality by examining the effects of likability and prior subject interest as potential biasing effects, measured at the beginning of the course and at the time of evaluation. University students (N = 260) evaluated psychology courses in one semester at a German university with a standardized questionnaire, yielding 517 data points. Cross-classified multilevel analyses revealed fixed effects of likability at both times of measurement and fixed effects of prior subject interest measured at the beginning of the course. Likability seems to exert a substantial bias on student evaluations of teaching, albeit one that is overestimated when measured at the time of evaluation. In contrast, prior subject interest seems to introduce a weak bias. Considering that likability bears no conceptual relationship to teaching quality, these findings point to a compromised validity of students' evaluations of teaching.}, language = {en} } @article{GraystonCzannerElhaddetal.2019, author = {Grayston, Rebecca and Czanner, Gabriela and Elhadd, Kareim and Goebel, Andreas and Frank, Bernhard and {\"U}{\c{c}}eyler, Nurcan and Malik, Rayaz A and Alam, Uazman}, title = {A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis}, series = {Seminars in Arthritis and Rheumatism}, volume = {48}, journal = {Seminars in Arthritis and Rheumatism}, doi = {10.1016/j.semarthrit.2018.08.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227566}, pages = {933-940}, year = {2019}, abstract = {Objectives Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia. Methods An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95\% CI. Results Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49\% (95\% CI: 38-60\%) with a moderate degree of heterogeneity, (I2= 68\%). The prevalence estimate attained by a skin biopsy was 45\% (95\% CI: 32-59\%, I2= 70\%) and for corneal confocal microscopy it was 59\% (95\% CI: 40-78\%, I2= 51\%). Conclusion There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy.}, language = {en} } @article{TaubenboeckWeigandEschetal.2019, author = {Taubenb{\"o}ck, H. and Weigand, M. and Esch, T. and Staab, J. and Wurm, M. and Mast, J. and Dech, S.}, title = {A new ranking of the world's largest cities—Do administrative units obscure morphological realities?}, series = {Remote Sensing of Environment}, volume = {232}, journal = {Remote Sensing of Environment}, doi = {10.1016/j.rse.2019.111353}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240634}, year = {2019}, abstract = {With 37 million inhabitants, Tokyo is the world's largest city in UN statistics. With this work we call this ranking into question. Usually, global city rankings are based on nationally collected population figures, which rely on administrative units. Sprawling urban growth, however, leads to morphological city extents that may surpass conventional administrative units. In order to detect spatial discrepancies between the physical and the administrative city, we present a methodology for delimiting Morphological Urban Areas (MUAs). We understand MUAs as a territorially contiguous settlement area that can be distinguished from low-density peripheral and rural hinterlands. We design a settlement index composed of three indicators (settlement area, settlement area proportion and density within the settlements) describing a gradient of built-up density from the urban center to the periphery applying a sectoral monocentric city model. We assume that the urban-rural transition can be defined along this gradient. With it, we re-territorialize the conventional administrative units. Our data basis are recent mapping products derived from multi-sensoral Earth observation (EO) data - namely the Global Urban Footprint (GUF) and the GUF Density (GUF-DenS) - providing globally consistent knowledge about settlement locations and densities. For the re-territorialized MUAs we calculate population numbers using WorldPop data. Overall, we cover the 1692 cities with >300,000 inhabitants on our planet. In our results we compare the consistently re-territorialized MUAs and the administrative units as well as their related population figures. We find the MUA in the Pearl River Delta the largest morphologically contiguous urban agglomeration in the world with a calculated population of 42.6 million. Tokyo, in this new list ranked number 2, loses its top position. In rank-size distributions we present the resulting deviations from previous city rankings. Although many MUAs outperform administrative units by area, we find that, contrary to what we assumed, in most cases MUAs are considerably smaller than administrative units. Only in Europe we find MUAs largely outweighing administrative units in extent.}, language = {en} } @article{NanadikarVergelLeonBorowiketal.2019, author = {Nanadikar, Maithily S. and Vergel Leon, Ana M. and Borowik, Sergej and Hillemann, Annette and Zieseniss, Anke and Belousov, Vsevolod V. and Bogeski, Ivan and Rehling, Peter and Dudek, Jan and Katschinski, D{\"o}rthe M.}, title = {O2 affects mitochondrial functionality ex vivo}, series = {Redox Biology}, volume = {22}, journal = {Redox Biology}, doi = {10.1016/j.redox.2019.101152}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232217}, year = {2019}, abstract = {Mitochondria have originated in eukaryotic cells by endosymbiosis of a specialized prokaryote approximately 2 billion years ago. They are essential for normal cell function by providing energy through their role in oxidizing carbon substrates. Glutathione (GSH) is a major thiol-disulfide redox buffer of the cell including the mitochondrial matrix and intermembrane space. We have generated cardiomyocyte-specific Grx1-roGFP2 GSH redox potential (EGSH) biosensor mice in the past, in which the sensor is targeted to the mitochondrial matrix. Using this mouse model a distinct EGSH of the mitochondrial matrix (-278.9 ± 0.4 mV) in isolated cardiomyocytes is observed. When analyzing the EGSH in isolated mitochondria from the transgenic hearts, however, the EGSH in the mitochondrial matrix is significantly oxidized (-247.7 ± 8.7 mV). This is prevented by adding N-Ethylmaleimide during the mitochondria isolation procedure, which precludes disulfide bond formation. A similar reducing effect is observed by isolating mitochondria in hypoxic (0.1-3\% O2) conditions that mimics mitochondrial pO2 levels in cellulo. The reduced EGSH is accompanied by lower ROS production, reduced complex III activity but increased ATP levels produced at baseline and after stimulation with succinate/ADP. Altogether, we demonstrate that oxygenation is an essential factor that needs to be considered when analyzing mitochondrial function ex vivo.}, language = {en} } @article{KiserPoppSchmittBoehreretal.2019, author = {Kiser, Dominik P. and Popp, Sandy and Schmitt-B{\"o}hrer, Angelika G. and Strekalova, Tatyana and van den Hove, Daniel L. and Lesch, Klaus-Peter and Rivero, Olga}, title = {Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice}, series = {Progress in Neuropsychopharmacology \& Biological Psychiatry}, volume = {89}, journal = {Progress in Neuropsychopharmacology \& Biological Psychiatry}, doi = {10.1016/j.pnpbp.2018.08.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325859}, pages = {158-168}, year = {2019}, abstract = {Objective Cadherin-13 (CDH13), a member of the calcium-dependent cell adhesion molecule family, has been linked to neurodevelopmental disorders, including autism spectrum (ASD) and attention-deficit/hyperactivity (ADHD) disorders, but also to depression. In the adult brain, CDH13 expression is restricted e.g. to the presynaptic compartment of inhibitory GABAergic synapses in the hippocampus and Cdh13 knockout mice show an increased inhibitory drive onto hippocampal CA1 pyramidal neurons, leading to a shift in excitatory/inhibitory balance. CDH13 is also moderating migration of serotonergic neurons in the dorsal raphe nucleus, establishing projections preferentially to the thalamus and cerebellum during brain development. Furthermore, CDH13 is upregulated by chronic stress as well as in depression, suggesting a role in early-life adaptation to stressful experience. Here, we therefore investigated the interaction between Cdh13 variation and neonatal maternal separation (MS) in mice. Methods Male and female wild-type (Cdh13+/+), heterozygous (Cdh13+/-) and homozygous (Cdh13-/-) knockout mice exposed to MS, or daily handling as control, were subjected to a battery of behavioural tests to assess motor activity, learning and memory as well as anxiety-like behaviour. A transcriptome analysis of the hippocampus was performed in an independent cohort of mice which was exposed to MS or handling, but remained na{\"i}ve for behavioural testing. Results MS lead to increased anxiety-like behaviour in Cdh13-/- mice compared to the other two MS groups. Cdh13-/- mice showed a context-dependent effect on stress- and anxiety-related behaviour, impaired extinction learning following contextual fear conditioning and decreased impulsivity, as well as a mild decrease in errors in the Barnes maze and reduced risk-taking in the light-dark transition test after MS. We also show sex differences, with increased locomotor activity in female Cdh13-/- mice, but unaltered impulsivity and activity in male Cdh13-/- mice. Transcriptome analysis revealed several pathways associated with cell surface/adhesion molecules to be altered following Cdh13 deficiency, together with an influence on endoplasmic reticulum function. Conclusion MS resulted in increased stress resilience, increased exploration and an overall anxiolytic behavioural phenotype in male Cdh13+/+ and Cdh13+/- mice. Cdh13 deficiency, however, obliterated most of the effects caused by early-life stress, with Cdh13-/- mice exhibiting delayed habituation, no reduction of anxiety-like behaviour and decreased fear extinction. Our behavioural findings indicate a role of CDH13 in the programming of and adaptation to early-life stress. Finally, our transcriptomic data support the view of CDH13 as a neuroprotective factor as well as a mediator in cell-cell interactions, with an impact on synaptic plasticity.}, language = {en} } @article{FaberHudecMalinskyetal.2018, author = {Faber, T. and Hudec, M. and Malinsk{\´y}, M. and Meinzinger, P. and Porod, W. and Staub, F.}, title = {A unified leptoquark model confronted with lepton non-universality in B-meson decays}, series = {Physics Letters B}, volume = {787}, journal = {Physics Letters B}, doi = {10.1016/j.physletb.2018.10.051}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227419}, pages = {159-166}, year = {2018}, abstract = {The anomalies in the B-meson sector, in particular R-K(*) and R-D(*), are often interpreted as hints for physics beyond the Standard Model. To this end, leptoquarks or a heavy Z' represent the most popular SM extensions which can explain the observations. However, adding these fields by hand is not very satisfactory as it does not address the big questions like a possible embedding into a unified gauge theory. On the other hand, light leptoquarks within a unified framework are challenging due to additional constraints such as lepton flavor violation. The existing accounts typically deal with this issue by providing estimates on the relevant couplings. In this letter we consider a complete model based on the SU(4)(C) circle times SU(2)(L) circle times U(1) R gauge symmetry, a subgroup of SO(10), featuring both scalar and vector leptoquarks. We demonstrate that this setup has, in principle, all the potential to accommodate R-K(*) and R-D(*) while respecting bounds from other sectors usually checked in this context. However, it turns out that K-L -> e(+/-)mu(-/+) severely constraints not only the vector but also the scalar leptoquarks and, consequently, also the room for any sizeable deviations of R-K(*) from 1. We briefly comment on the options for extending the model in order to conform this constraint. Moreover, we present a simple criterion for all-orders proton stability within this class of models.}, language = {en} } @techreport{Gessner2024, type = {Working Paper}, author = {Geßner, Daniel}, title = {Rethinking renewable energy policies for hydrogen - How the intercept of electricity and hydrogen markets can be addressed}, doi = {10.25972/OPUS-37097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370973}, pages = {30}, year = {2024}, abstract = {A lot of countries have recently published updated hydrogen strategies, often including more ambitious targets for hydrogen production. In parallel, accompanying ramp-up mechanisms are increasingly coming into focus with the first ones already being released. However, these proposals usually translate mechanisms from renewable energy (RE) policy without considering the specific uncertainties, spillovers, and externalities of integrating hydrogen electrolysis into electricity grids. This article details how different aspects of a policy can address the specific issues, namely funding, risk-mitigation, and the complex relation with electricity markets. It shows that, compared to RE policy, subsidies need to emphasize the input side more strongly as price risks and intermittency from electricity markets are more prominent than from hydrogen markets. Also, it proposes a targeted mechanism to capture the positive externality of mitigating excess electricity in the grid while keeping investment security high. Economic policy should consider such approaches before massively scaling support and avoid the design shortcomings experienced with early RE policy.}, subject = {Wasserstoff}, language = {en} } @article{HaukeHorvathGrossetal.2018, author = {Hauke, Jan and Horvath, Judit and Groß, Eva and Gehrig, Andrea and Honisch, Ellen and Hackmann, Karl and Schmidt, Gunnar and Arnold, Norbert and Faust, Ulrike and Sutter, Christian and Hentschel, Julia and Wang-Gohrke, Shan and Smogavec, Mateja and Weber, Bernhard H. F. and Weber-Lassalle, Nana and Weber-Lassalle, Konstantin and Borde, Julika and Ernst, Corinna and Altm{\"u}ller, Janine and Volk, Alexander E. and Thiele, Holger and H{\"u}bbel, Verena and N{\"u}rnberg, Peter and Keupp, Katharina and Versmold, Beatrix and Pohl, Esther and Kubisch, Christian and Grill, Sabine and Paul, Victoria and Herold, Natalie and Lichey, Nadine and Rhiem, Kerstin and Ditsch, Nina and Ruckert, Christian and Wappenschmidt, Barbara and Auber, Bernd and Rump, Andreas and Niederacher, Dieter and Haaf, Thomas and Ramser, Juliane and Dworniczak, Bernd and Engel, Christoph and Meindl, Alfons and Schmutzler, Rita K. and Hahnen, Eric}, title = {Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer}, series = {Cancer Medicine}, journal = {Cancer Medicine}, doi = {10.1002/cam4.1376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227902}, pages = {1349-1358}, year = {2018}, abstract = {The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5\%), followed by ATM (1.5\%) and PALB2 (1.2\%). The mutation prevalence in each of the remaining genes was 0.3\% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95\%CI: 2.67-4.94), CDH1 (OR: 17.04, 95\%CI: 3.54-82), CHEK2 (OR: 2.93, 95\%CI: 2.29-3.75), PALB2 (OR: 9.53, 95\%CI: 6.25-14.51), and TP53 (OR: 7.30, 95\%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95\%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2\%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.}, language = {en} } @article{LummaValkBoeckleretal.2018, author = {Lumma, Anna-Lena and Valk, Sofie L. and B{\"o}ckler, Anne and Vrtička, Pascal and Singer, Tania}, title = {Change in emotional self-concept following socio-cognitive training relates to structural plasticity of the prefrontal cortex}, series = {Brain and Behavior}, volume = {8}, journal = {Brain and Behavior}, doi = {10.1002/brb3.940}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237395}, year = {2018}, abstract = {Introduction Self-referential processing is a key component of the emotional self-concept. Previous studies have shown that emotional self-referential processing is related to structure and function of cortical midline areas such as medial prefrontal cortex (mPFC), and that it can be altered on a behavioral level by specific mental training practices. However, it remains unknown how behavioral training-related change in emotional self-concept content relates to structural plasticity. Methods To address this issue, we examined the relationship between training-induced change in participant's emotional self-concept measured through emotional word use in the Twenty Statement Test and change in cortical thickness in the context of a large-scale longitudinal mental training study called the ReSource Project. Results Based on prior behavioral findings showing increased emotional word use particularly after socio-cognitive training targeting perspective-taking capacities, this study extended these results by revealing that individual differences in the degree to which participants changed their emotional self-concept after training was positively related to cortical thickness change in right mPFC extending to dorsolateral PFC (dlPFC). Furthermore, increased self-related negative emotional word use after training was positively associated with cortical thickness change in left pars orbitalis and bilateral dlPFC. Conclusions Our findings reveal training-related structural brain change in regions known to be involved in self-referential processing and cognitive control, and could indicate a relationship between restructuring of the emotional self-concept content as well as reappraisal of negative aspects and cortical thickness change. As such, our findings can guide the development of psychological interventions targeted to alter specific facets of the self-concept.}, language = {en} } @article{BaeumerKarthaKumarAllampallyetal.2019, author = {B{\"a}umer, Nils and Kartha, Kalathil K. and Kumar Allampally, Naveen and Yagai, Shiki and Albuquerque, Rodrigo Q. and Fern{\´a}ndez, Gustavo}, title = {Exploiting Coordination Isomerism for Controlled Self-Assembly}, series = {Angewandte Chemie International Edition}, volume = {58}, journal = {Angewandte Chemie International Edition}, doi = {10.1002/anie.201908002}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221362}, pages = {15626-15630}, year = {2019}, abstract = {We exploited the inherent geometrical isomerism of a PtII complex as a new tool to control supramolecular assembly processes. UV irradiation and careful selection of solvent, temperature, and concentration leads to tunable coordination isomerism, which in turn allows fully reversible switching between two distinct aggregate species (1D fibers↔2D lamellae) with different photoresponsive behavior. Our findings not only broaden the scope of coordination isomerism, but also open up exciting possibilities for the development of novel stimuli-responsive nanomaterials.}, language = {en} } @article{SolDehmHechtetal.2018, author = {Sol, Jeroen A. H. P. and Dehm, Volker and Hecht, Reinhard and W{\"u}rthner, Frank and Schenning, Albertus P. H. J. and Debije, Michael G.}, title = {Temperature-Responsive Luminescent Solar Concentrators: Tuning Energy Transfer in a Liquid Crystalline Matrix}, series = {Angewandte Chemie International Edition}, volume = {57}, journal = {Angewandte Chemie International Edition}, doi = {10.1002/anie.201710487}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238778}, pages = {1030-1033}, year = {2018}, abstract = {Temperature-responsive luminescent solar concentrators (LSCs) have been fabricated in which the F{\"o}rster resonance energy transfer (FRET) between a donor-acceptor pair in a liquid crystalline solvent can be tuned. At room temperatures, the perylene bisimide (PBI) acceptor is aggregated and FRET is inactive; while after heating to a temperature above the isotropic phase of the liquid crystal solvent, the acceptor PBI completely dissolves and FRET is activated. This unusual temperature control over FRET was used to design a color-tunable LSC. The device has been shown to be highly stable towards consecutive heating and cooling cycles, making it an appealing device for harvesting otherwise unused solar energy.}, language = {en} } @article{GoleStepanenkoRageretal.2018, author = {Gole, Bappaditya and Stepanenko, Vladimir and Rager, Sabrina and Gr{\"u}ne, Matthias and Medina, Dana D. and Bein, Thomas and W{\"u}rthner, Frank and Beuerle, Florian}, title = {Microtubular Self-Assembly of Covalent Organic Frameworks}, series = {Angewandte Chemie International Edition}, volume = {57}, journal = {Angewandte Chemie International Edition}, doi = {10.1002/anie.201708526}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227373}, pages = {846-850}, year = {2018}, abstract = {Despite significant progress in the synthesis of covalent organic frameworks (COFs), reports on the precise construction of template-free nano- and microstructures of such materials have been rare. In the quest for dye-containing porous materials, a novel conjugated framework DPP-TAPP-COF with an enhanced absorption capability up to λ=800 nm has been synthesized by utilizing reversible imine condensations between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin (TAPP) and a diketopyrrolopyrrole (DPP) dialdehyde derivative. Surprisingly, the obtained COF exhibited spontaneous aggregation into hollow microtubular assemblies with outer and inner tube diameters of around 300 and 90 nm, respectively. A detailed mechanistic investigation revealed the time-dependent transformation of initial sheet-like agglomerates into the tubular microstructures.}, language = {en} } @article{GriemertSchwarzmaierHummeletal.2019, author = {Griemert, Eva-Verena and Schwarzmaier, Susanne M. and Hummel, Regina and G{\"o}lz, Christina and Yang, Dong and Neuhaus, Winfried and Burek, Malgorzata and F{\"o}rster, Carola Y. and Petkovic, Ivan and Trabold, Raimund and Plesnila, Nikolaus and Engelhard, Kristin and Sch{\"a}fer, Michael K. and Thal, Serge C.}, title = {Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury}, series = {Annals of Neurology}, volume = {85}, journal = {Annals of Neurology}, doi = {10.1002/ana.25458}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228682}, pages = {667-680}, year = {2019}, abstract = {Objective Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma. Methods We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals. Results PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26\% at 24 hours and 43\% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13\% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25\% compared with vehicle. Interpretation This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680}, language = {en} } @article{CharbonnierBaradaranSatoetal.2019, author = {Charbonnier, Baptiste and Baradaran, Aslan and Sato, Daisuke and Alghamdi, Osama and Zhang, Zishuai and Zhang, Yu-Ling and Gbureck, Uwe and Gilardino, Mirko and Harvey, Edward and Makhoul, Nicholas and Barralet, Jake}, title = {Material-Induced Venosome-Supported Bone Tubes}, series = {Advanced Science}, volume = {6}, journal = {Advanced Science}, doi = {10.1002/advs.201900844}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222318}, year = {2019}, abstract = {The development of alternatives to vascular bone grafts, the current clinical standard for the surgical repair of large segmental bone defects still today represents an unmet medical need. The subcutaneous formation of transplantable bone has been successfully achieved in scaffolds axially perfused by an arteriovenous loop (AVL) and seeded with bone marrow stromal cells or loaded with inductive proteins. Although demonstrating clinical potential, AVL-based approaches involve complex microsurgical techniques and thus are not in widespread use. In this study, 3D-printed microporous bioceramics, loaded with autologous total bone marrow obtained by needle aspiration, are placed around and next to an unoperated femoral vein for 8 weeks to assess the effect of a central flow-through vein on bone formation from marrow in a subcutaneous site. A greater volume of new bone tissue is observed in scaffolds perfused by a central vein compared with the nonperfused negative control. These analyses are confirmed and supplemented by calcified and decalcified histology. This is highly significant as it indicates that transplantable vascularized bone can be grown using dispensable vein and marrow tissue only. This is the first report illustrating the capacity of an intrinsic vascularization by a single vein to support ectopic bone formation from untreated marrow.}, language = {en} } @article{KirschHassinBaerMatthiesetal.2018, author = {Kirsch, Anna Dalal and Hassin-Baer, Sharon and Matthies, Cordula and Volkmann, Jens and Steigerwald, Frank}, title = {Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects}, series = {Parkinsonism and Related Disorders}, volume = {55}, journal = {Parkinsonism and Related Disorders}, doi = {10.1016/j.parkreldis.2018.05.015}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325820}, pages = {61-67}, year = {2018}, abstract = {Introduction Stimulation settings of deep brain stimulation (DBS) have evolved empirically within a limited parameter space dictated by first generation devices. There is a need for controlled clinical studies, which evaluate efficacy and safety of established programming practice against novel programming options provided by modern neurostimulation devices. Methods Here, we tested a polarity reversal from conventional monopolar cathodic to anodic stimulation in an acute double-blind, randomized, cross-over study in patients with PD implanted with bilateral STN DBS. The primary outcome measure was the difference between efficacy and side-effect thresholds (current amplitude, mA) in a monopolar review and the severity of motor symptoms (as assessed by MDS-UPDRS III ratings) after 30 min of continuous stimulation in the medication off-state. Results Effect and side effect thresholds were significantly higher with anodic compared to cathodic stimulation (3.36 ± 1.58 mA vs. 1.99 ± 1.37 mA; 6.05 ± 1.52 mA vs. 4.15 ± 1.13 mA; both p < 0.0001). However, using a predefined amplitude of 0.5 mA below the respective adverse effect threshold, blinded MDS-UPDRS-III-ratings were significantly lower with anodic stimulation (anodic: median 17 [min: 12, max: 25]; cathodic: 23 [12, 37]; p < 0.005). Conclusion Effective anodic stimulation requires a higher charge injection into the tissue, but may provide a better reduction of off-period motor symptoms within the individual therapeutic window. Therefore, a programming change to anodic stimulation may be considered in patients suffering from residual off-period motor symptoms of PD despite reaching the adverse effect threshold of cathodic stimulation in the subthalamic nucleus.}, language = {en} } @article{CounsellKardaDiazetal.2018, author = {Counsell, John R. and Karda, Rajvinder and Diaz, Juan Antiano and Carey, Louise and Wiktorowicz, Tatiana and Buckley, Suzanne M. K. and Ameri, Shima and Ng, Joanne and Baruteau, Julien and Almeida, Filipa and de Silva, Rohan and Simone, Roberto and Lugar{\`a}, Eleonora and Lignani, Gabriele and Lindemann, Dirk and Rethwilm, Axel and Rahim, Ahad A. and Waddington, Simon N. and Howe, Steven J.}, title = {Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice}, series = {Molecular Therapy: Nucleic Acids}, volume = {12}, journal = {Molecular Therapy: Nucleic Acids}, doi = {10.1016/j.omtn.2018.07.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223379}, pages = {626-634}, year = {2018}, abstract = {Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders.}, language = {en} } @article{ArgyrousideNijsLagattaetal.2019, author = {Argyrousi, Elentina K. and de Nijs, Laurence and Lagatta, Davi C. and Schl{\"u}tter, Anna and Weidner, Magdalena T. and Z{\"o}ller, Johanna and van Goethem, Nick P. and Joca, S{\^a}mia R. L. and van den Hove, Daniel L. A. and Prickaerts, Jos}, title = {Effects of DNA methyltransferase inhibition on pattern separation performance in mice}, series = {Neurobiology of Learning and Memory}, volume = {159}, journal = {Neurobiology of Learning and Memory}, doi = {https://doi.org/10.1016/j.nlm.2019.02.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221226}, pages = {6-15}, year = {2019}, abstract = {Enhancement of synaptic plasticity through changes in neuronal gene expression is a prerequisite for improved cognitive performance. Moreover, several studies have shown that DNA methylation is able to affect the expression of (e.g. plasticity) genes that are important for several cognitive functions. In this study, the effect of the DNA methyltransferase (DNMT) inhibitor RG108 was assessed on object pattern separation (OPS) task in mice. In addition, its effect on the expression of target genes was monitored. Administration of RG108 before the test led to a short-lasting, dose-dependent increase in pattern separation memory that was not present anymore after 48 h. Furthermore, treatment with RG108 did not enhance long-term memory of the animals when tested after a 24 h inter-trial interval in the same task. At the transcriptomic level, acute treatment with RG108 was accompanied by increased expression of Bdnf1, while expression of Bdnf4, Bdnf9, Gria1 and Hdac2 was not altered within 1 h after treatment. Methylation analysis of 14 loci in the promoter region of Bdnf1 revealed a counterintuitive increase in the levels of DNA methylation at three CpG sites. Taken together, these results indicate that acute administration of RG108 has a short-lasting pro-cognitive effect on object pattern separation that could be explained by increased Bdnf1 expression. The observed increase in Bdnf1 methylation suggests a complex interplay between Bdnf methylation-demethylation that promotes Bdnf1 expression and associated cognitive performance. Considering that impaired pattern separation could constitute the underlying problem of a wide range of mental and cognitive disorders, pharmacological agents including DNA methylation inhibitors that improve pattern separation could be compelling targets for the treatment of these disorders. In that respect, future studies are needed in order to determine the effect of chronic administration of such agents.}, language = {en} } @article{FigelBrinkmannBuffetal.2019, author = {Figel, Benedikt and Brinkmann, Leonie and Buff, Christine and Heitmann, Carina Y. and Hofmann, David and Bruchmann, Maximilian and Becker, Michael P. I. and Herrmann, Martin J. and Straube, Thomas}, title = {Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients}, series = {NeuroImage: Clinical}, volume = {22}, journal = {NeuroImage: Clinical}, doi = {10.1016/j.nicl.2019.101735}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228071}, year = {2019}, abstract = {Anticipation of potentially threatening social situations is a key process in social anxiety disorder (SAD). In other anxiety disorders, recent research of neural correlates of anticipation of temporally unpredictable threat suggests a temporally dissociable involvement of amygdala and bed nucleus of the stria terminalis (BNST) with phasic amygdala responses and sustained BNST activation. However, the temporal profile of amygdala and BNST responses during temporal unpredictability of threat has not been investigated in patients suffering from SAD. We used functional magnetic resonance imaging (fMRI) to investigate neural activation in the central nucleus of the amygdala (CeA) and the BNST during anticipation of temporally unpredictable aversive (video camera observation) relative to neutral (no camera observation) events in SAD patients compared to healthy controls (HC). For the analysis of fMRI data, we applied two regressors (phasic/sustained) within the same model to detect temporally dissociable brain responses. The aversive condition induced increased anxiety in patients compared to HC. SAD patients compared to HC showed increased phasic activation in the CeA and the BNST for anticipation of aversive relative to neutral events. SAD patients as well as HC showed sustained activity alterations in the BNST for aversive relative to neutral anticipation. No differential activity during sustained threat anticipation in SAD patients compared to HC was found. Taken together, our study reveals both CeA and BNST involvement during threat anticipation in SAD patients. The present results point towards potentially SAD-specific threat processing marked by elevated phasic but not sustained CeA and BNST responses when compared to HC.}, language = {en} } @article{GodelPhamKeleetal.2019, author = {Godel, Tim and Pham, Mirko and Kele, Henrich and Kronlage, Moritz and Schwarz, Daniel and Brun{\´e}e, Merle and Heiland, Sabine and Bendszus, Martin and B{\"a}umer, Philipp}, title = {Diffusion tensor imaging in anterior interosseous nerve syndrome - functional MR Neurography on a fascicular level}, series = {NeuroImage: Clinical}, volume = {21}, journal = {NeuroImage: Clinical}, doi = {10.1016/j.nicl.2019.101659}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233061}, year = {2019}, abstract = {Purpose By applying diffusor tensor imaging (DTI) in patients with anterior interosseous nerve syndrome (AINS), this proof of principle study aims to quantify the extent of structural damage of a peripheral nerve at the anatomical level of individual fascicles. Methods In this institutional review board approved prospective study 13 patients with spontaneous AINS were examined at 3 Tesla including a transversal T2-weighted turbo-spin-echo and a spin-echo echo-planar-imaging pulse sequence of the upper arm level. Calculations of quantitative DTI parameters including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for median nerve lesion and non-lesion fascicles as well as ulnar and radial nerve were obtained. DTI values were compared to each other and to a previously published dataset of 58 healthy controls using one-way Analysis of Variance with Bonferroni correction and p-values <.05 were considered significant. Receiver operating characteristic (ROC) curves were performed to assess diagnostic accuracy. Results FA of median nerve lesion fascicles was decreased compared to median nerve non-lesion fascicles, ulnar nerve and radial nerve while MD, RD, and AD was increased (p < .001 for all parameters). Compared to median nerve values of healthy controls, lesion fascicles showed a significant decrease in FA while MD, RD, and AD was increased (p < .001 for all parameters). FA of median nerve non-lesion fascicles showed a weak significant decrease compared to healthy controls (p < .01) while there was no difference in MD, RD, and AD. ROC analyses revealed an excellent diagnostic accuracy of FA, MD and RD in the discrimination of median nerve lesion and non-lesion fascicles in AINS patients as well as in the discrimination of lesion fascicles and normative median nerve values of healthy controls. Conclusion By applying this functional MR Neurography technique in patients with AINS, this proof of principle study demonstrates that diffusion tensor imaging is feasible to quantify structural nerve injury at the anatomical level of individual fascicles.}, language = {en} } @article{GorlovaPavlovAnthonyetal.2019, author = {Gorlova, Anna and Pavlov, Dmitrii and Anthony, Daniel C. and Ponomarev, Eugene D. and Sambon, Margaux and Proshin, Andrey and Shafarevich, Igor and Babaevskaya, Diana and Lesch, Klaus-Peter and Bettendorff, Lucien and Strekalova, Tatyana}, title = {Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice}, series = {Neuropharmacology}, volume = {156}, journal = {Neuropharmacology}, doi = {10.1016/j.neuropharm.2019.02.025}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227439}, year = {2019}, abstract = {The negative societal impacts associated with the increasing prevalence of violence and aggression is increasing, and, with this rise, is the need to understand the molecular and cellular changes that underpin ultrasound-induced aggressive behavior. In mice, stress-induced aggression is known to alter AMPA receptor subunit expression, plasticity markers, and oxidative stress within the brain. Here, we induced aggression in BALB/c mice using chronic ultrasound exposure and examined the impact of the psychoactive anti-oxidant compounds thiamine (vitamin B1), and its derivative benfotiamine, on AMPA receptor subunit expression, established plasticity markers, and oxidative stress. The administration of thiamine or benfotiamine (200 mg/kg/day) in drinking water decreased aggressive behavior following 3-weeks of ultrasound exposure and benfotiamine, reduced floating behavior in the swim test. The vehicle-treated ultrasound-exposed mice exhibited increases in protein carbonyl and total glutathione, altered AMPA receptor subunits expression, and decreased expression of plasticity markers. These ultrasound-induced effects were ameliorated by thiamine and benfotiamine treatment; in particular both antioxidants were able to reverse ultrasound-induced changes in GluA1 and GluA2 subunit expression, and, within the prefrontal cortex, significantly reversed the changes in protein carbonyl and polysialylated form of neural cell adhesion molecule (PSA-NCAM) expression levels. Benfotiamine was usually more efficacious than thiamine. Thus, the thiamine compounds were able to counteract ultrasound-induced aggression, which was accompanied by the normalization of markers that have been showed to be associated with ultrasound-induced aggression. These commonly used, orally-active compounds may have considerable potential for use in the control of aggression within the community. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.}, language = {en} } @article{VerheijenStevensGentieretal.2018, author = {Verheijen, Bert M. and Stevens, Jo A. A. and Gentier, Romina J. G. and van't Hekke, Christian D. and van den Hove, Daniel L. A. and Hermes, Denise J. H. P. and Steinbusch, Harry W. M. and Ruijter, Jan M. and Grimm, Marcus O. W. and Haupenthal, Viola J. and Annaert, Wim and Hartmann, Tobias and van Leeuwen, Fred W.}, title = {Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model}, series = {Neurobiology of Aging}, volume = {72}, journal = {Neurobiology of Aging}, doi = {10.1016/j.neurobiolaging.2018.08.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233185}, pages = {62-71}, year = {2018}, abstract = {Amyloid-β (Aβ) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated Aβ peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several Aβ-associated factors. Efficient clearance of Aβ from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Aβ pathology in vivo, transgenic APPSwe/PS1ΔE9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Aβ plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and γ-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of β-APP-CTF, which is a γ-secretase substrate. Although UBB+1 reduced Aβ pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals.}, language = {en} } @article{HedrichMuellerBeckeretal.2018, author = {Hedrich, Rainer and Mueller, Thomas D. and Becker, Dirk and Marten, Irene}, title = {Structure and Function of TPC1 Vacuole SV Channel Gains Shape}, series = {Molecular Plant}, volume = {11}, journal = {Molecular Plant}, doi = {10.1016/j.molp.2018.03.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228046}, pages = {764-775}, year = {2018}, abstract = {Plants and animals in endosomes operate TPC1/SV-type cation channels. All plants harbor at least one TPC1 gene. Although the encoded SV channel was firstly discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site-directed mutation approaches, enabling structure-function analyses of TPC1/SV channels to shed new light on earlier findings. Fou2 plants carrying a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta.}, language = {en} } @article{MuehlemannZdziebloFriedrichetal.2018, author = {M{\"u}hlemann, Markus and Zdzieblo, Daniela and Friedrich, Alexandra and Berger, Constantin and Otto, Christoph and Walles, Heike and Koepsell, Hermann and Metzger, Marco}, title = {Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet}, series = {Molecular Metabolism}, volume = {13}, journal = {Molecular Metabolism}, doi = {10.1016/j.molmet.2018.05.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224230}, pages = {67-76}, year = {2018}, abstract = {Objectives Glycemic control by medical treatment represents one therapeutic strategy for diabetic patients. The Na+-d-glucose cotransporter 1 (SGLT1) is currently of high interest in this context. SGLT1 is known to mediate glucose absorption and incretin secretion in the small intestine. Recently, inhibition of SGLT1 function was shown to improve postprandial hyperglycemia. In view of the lately demonstrated SGLT1 expression in pancreatic islets, we investigated if loss of SGLT1 affects islet morphology and function. Methods Effects associated with the loss of SGLT1 on pancreatic islet (cyto) morphology and function were investigated by analyzing islets of a SGLT1 knockout mouse model, that were fed a glucose-deficient, fat-enriched diet (SGLT1-/--GDFE) to circumvent the glucose-galactose malabsorption syndrome. To distinguish diet- and Sglt1-/--dependent effects, wildtype mice on either standard chow (WT-SC) or the glucose-free, fat-enriched diet (WT-GDFE) were used as controls. Feeding a glucose-deficient, fat-enriched diet further required the analysis of intestinal SGLT1 expression and function under diet-conditions. Results Consistent with literature, our data provide evidence that small intestinal SGLT1 mRNA expression and function is regulated by nutrition. In contrast, pancreatic SGLT1 mRNA levels were not affected by the applied diet, suggesting different regulatory mechanisms for SGLT1 in diverse tissues. Morphological changes such as increased islet sizes and cell numbers associated with changes in proliferation and apoptosis and alterations of the β- and α-cell population are specifically observed for pancreatic islets of SGLT1-/--GDFE mice. Glucose stimulation revealed no insulin response in SGLT1-/--GDFE mice while WT-GDFE mice displayed only a minor increase of blood insulin. Irregular glucagon responses were observed for both, SGLT1-/--GDFE and WT-GDFE mice. Further, both animal groups showed a sustained release of GLP-1 compared to WT-SC controls. Conclusion Loss or impairment of SGLT1 results in abnormal pancreatic islet (cyto)morphology and disturbed islet function regarding the insulin or glucagon release capacity from β- or α-cells, respectively. Consequently, our findings propose a new, additional role for SGLT1 maintaining proper islet structure and function.}, language = {en} } @article{BaluapuriHofstetterDudvarskiStankovicetal.2019, author = {Baluapuri, Apoorva and Hofstetter, Julia and Dudvarski Stankovic, Nevenka and Endres, Theresa and Bhandare, Pranjali and Vos, Seychelle Monique and Adhikari, Bikash and Schwarz, Jessica Denise and Narain, Ashwin and Vogt, Markus and Wang, Shuang-Yan and D{\"u}ster, Robert and Jung, Lisa Anna and Vanselow, Jens Thorsten and Wiegering, Armin and Geyer, Matthias and Maric, Hans Michael and Gallant, Peter and Walz, Susanne and Schlosser, Andreas and Cramer, Patrick and Eilers, Martin and Wolf, Elmar}, title = {MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation}, series = {Molecular Cell}, volume = {74}, journal = {Molecular Cell}, doi = {10.1016/j.molcel.2019.02.031}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221438}, pages = {674-687}, year = {2019}, abstract = {The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.}, language = {en} } @article{BugaiQuaresmaFriedeletal.2019, author = {Bugai, Andrii and Quaresma, Alexandre J. C. and Friedel, Caroline C. and Lenasi, Tina and D{\"u}ster, Robert and Sibley, Christopher R. and Fujinaga, Koh and Kukanja, Petra and Hennig, Thomas and Blasius, Melanie and Geyer, Matthias and Ule, Jernej and D{\"o}lken, Lars and Barborič, Matjaž}, title = {P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress}, series = {Molecular Cell}, volume = {74}, journal = {Molecular Cell}, doi = {10.1016/j.molcel.2019.01.033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221726}, pages = {254-267}, year = {2019}, abstract = {DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). This is mediated by activation of p38MAPK, which triggers enhanced binding of RBM7 with core subunits of 7SK snRNP. In turn, P-TEFb relocates to chromatin to induce transcription of short units, including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with the axis of RBM7 and P-TEFb provokes cellular hypersensitivity to DNA-damage-inducing agents due to activation of apoptosis. Our work uncovers the importance of stress-dependent stimulation of Pol II pause release, which enables a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult.}, language = {en} } @article{ŽutićMatosAbiagueScharfetal.2019, author = {Žutić, Igor and Matos-Abiague, Alex and Scharf, Benedikt and Dery, Hanan and Belashchenko, Kirill}, title = {Proximitized materials}, series = {Materials Today}, volume = {22}, journal = {Materials Today}, doi = {10.1016/j.mattod.2018.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233972}, pages = {85-107}, year = {2019}, abstract = {Advances in scaling down heterostructures and having an improved interface quality together with atomically thin two-dimensional materials suggest a novel approach to systematically design materials. A given material can be transformed through proximity effects whereby it acquires properties of its neighbors, for example, becoming superconducting, magnetic, topologically nontrivial, or with an enhanced spin-orbit coupling. Such proximity effects not only complement the conventional methods of designing materials by doping or functionalization but also can overcome their various limitations. In proximitized materials, it is possible to realize properties that are not present in any constituent region of the considered heterostructure. While the focus is on magnetic and spin-orbit proximity effects with their applications in spintronics, the outlined principles also provide a broader framework for employing other proximity effects to tailor materials and realize novel phenomena.}, language = {en} } @article{McCollGrollJungstetal.2018, author = {McColl, Erin and Groll, J{\"u}rgen and Jungst, Tomasz and Dalton, Paul D.}, title = {Design and fabrication of melt electrowritten tubes using intuitive software}, series = {Materials and Design}, volume = {155}, journal = {Materials and Design}, doi = {10.1016/j.matdes.2018.05.036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223891}, pages = {46-58}, year = {2018}, abstract = {This study approaches the accurate continuous direct-writing onto a cylindrical collector from a mathematical perspective, taking into account the winding angle, cylinder diameter and length required for the final 3D printed tube. Using an additive manufacturing process termed melt electrowriting (MEW), porous tubes intended for tissue engineering applications are fabricated from medical-grade poly(ε-caprolactone) (PCL), validating the mathematically-derived method. For the fabricated tubes in this study, the pore size, winding angle and printed length can all be planned in advance and manufactured as designed. The physical dimensions of the tubes matched theoretical predictions and mechanical testing performed demonstrated that variations in the tubular morphology have a direct impact on their strength. MEWTubes, the web-based application developed and described here, is a particularly useful tool for planning the complex continuous direct writing path required for MEW onto a rotating, cylindrical build surface.}, language = {en} } @article{FazziniLaminaFendtetal.2019, author = {Fazzini, Federica and Lamina, Claudia and Fendt, Liane and Schultheiss, Ulla T. and Kotsis, Fruzsina and Hicks, Andrew A. and Meiselbach, Heike and Weissensteiner, Hansi and Forer, Lukas and Krane, Vera and Eckardt, Kai-Uwe and K{\"o}ttgen, Anna and Kronenberg, Florian}, title = {Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease}, series = {Kidney International}, volume = {96}, journal = {Kidney International}, organization = {GCKD Investigators}, doi = {10.1016/j.kint.2019.04.021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227662}, pages = {480-488}, year = {2019}, abstract = {Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95\% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95\% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95\% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95\% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.}, language = {en} } @phdthesis{Fuhl2024, author = {Fuhl, Lucas}, title = {Photolumineszenzmikroskopie und -spektroskopie endohedraler Farbstoffe in Bornitridnanor{\"o}hren}, doi = {10.25972/OPUS-37115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371150}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Im Rahmen der vorliegenden Dissertation wurde untersucht, wie die Einkapselung organischer Farbstoffmolek{\"u}le in Bornitridnanor{\"o}hren (BNNTs) die photophysikalischen Eigenschaften der Fluorophore beeinflusst. Als Farbstoffe wurden hierbei alpha-Quaterthiophen (4T), alpha-Sexithiophen (6T), alpha-Octithiophen (8T) sowie Nilrot (NR) ausgew{\"a}hlt. Die eingesetzten BNNTs besitzen einen nominellen Durchmesser von \(5 \pm 2\)nm. F{\"u}r die Charakterisierung der reinen Farbstoffe und der hybriden Systeme aus Farbstoff und Nanor{\"o}hre kam ein Laboraufbau zum Einsatz, der neben Absorptions- und Photolumineszenz (PL)-Spektroskopie auch PL-Mikroskopie erm{\"o}glicht. Zus{\"a}tzlich l{\"a}sst sich damit auch eine zeitaufgel{\"o}ste Untersuchung der PL (engl. time correlated single photon counting, TCSPC) im Ensemble und an einzelnen, separierten Nano-Objekten (mit Farbstoff gef{\"u}llte BNNTs) umsetzen. In Kapitel 5 wurden zun{\"a}chst die freien Farbstoffe in L{\"o}sung charakterisiert. Es hat sich gezeigt, dass sowohl 4T als auch NR im verwendeten L{\"o}semittel Dimethylformamid (DMF) l{\"o}slich sind, wohingegen 6T und 8T hier eine geringere L{\"o}slichkeit zeigen. Die unterschiedlichen Verl{\"a}ufe der konzentrationsabh{\"a}ngigen PL-Spektren f{\"u}r 4T und 6T in DMF lassen sich vermutlich auf diesen L{\"o}slichkeitsunterschied zur{\"u}ckf{\"u}hren. Zudem wurden Extinktionskoeffizienten f{\"u}r 4T und NR mittels konzentrationsabh{\"a}ngiger Absorptionsspektren bestimmt und es zeigte sich eine gute {\"U}bereinstimmung mit der Literatur. F{\"u}r 6T und 8T war eine Bestimmung aufgrund der geringen L{\"o}slichkeit nicht m{\"o}glich, weshalb auf Literaturwerte zur{\"u}ckgegriffen wurde oder diese extrapoliert wurden (8T). In Kapitel 6 erfolgte die detaillierte Charakterisierung der mit Oligothiophenen gef{\"u}llten BNNTs. Die Bef{\"u}llung wurde dabei im Wesentlichen nach einem von C. Allard publizierten Verfahren durchgef{\"u}hrt und auf die zus{\"a}tzlichen Fluorophore 4T, 8T und NR {\"u}bertragen. F{\"u}r Messungen mittels UV-Vis-Spektroskopie in L{\"o}sung bzw. Dispersion hat sich beim Farbstoff 6T gezeigt, dass sich das Absorptionsmaximum von 407nm (freies 6T) hin zu 506nm (6T@BNNT) verschiebt. Ursache hierf{\"u}r ist vermutlich die Bildung von J-Aggregaten im Inneren der R{\"o}hren. Die entsprechenden PL-Spektren von freiem 6T und dem Hybridsystem zeigen dabei keine signifikanten Unterschiede. F{\"u}r konzentrationsabh{\"a}ngige PL-Spektren von 6T@BNNT ergibt sich (anders als bei freiem 6T in DMF) keine {\"A}nderung des Verlaufs der Kurven, was als ein Indiz f{\"u}r eine erfolgreiche Einkapselung gedeutet werden kann. Durch Kombination von Rasterkraft- und PL-Mikroskopie konnten die Außendurchmesser von einzelnen 6T@BNNT Objekten ermittelt und in direkten Zusammenhang mit deren photophysikalischen Eigenschaften gebracht werden. Bei einer Analyse der Polarisation des Emissionslichtes von 6T@BNNT in Abh{\"a}ngigkeit des Außendurchmessers ließ sich jedoch keine klare Korrelation zwischen Struktur und Emissionscharakteristiken erkennen. Diese Beobachtung l{\"a}sst sich vermutlich dadurch erkl{\"a}ren, dass mit Hilfe der Rasterkraftmikroskopie lediglich der Außendurchmesser der (teils mehrwandigen) BNNTs bestimmt werden kann. Die entscheidende Gr{\"o}ße an dieser Stelle ist allerdings der innere Durchmesser der BNNTs, welcher die Ausrichtung und damit auch die Polarisation der Farbstoffmolek{\"u}le beeinflusst. Ein Vergleich des mittleren maximalen Polarisationsgrades der jeweiligen Hybridsysteme hat gezeigt, dass 4T@BNNT den geringsten und 6T@BNNT mit den h{\"o}chsten Wert aufweist. Dies best{\"a}tigt die Annahme, dass mit zunehmender Molek{\"u}ll{\"a}nge die Polarisation, aufgrund des h{\"o}heren Templat-Effektes der R{\"o}hre, zunimmt. 8T@BNNT liegt zwischen den beiden anderen Werten, was dieser Annahme widerspricht. Der mittlere Verkippungswinkel der eingekapselten Farbstoffmolek{\"u}le gegen{\"u}ber der R{\"o}hrenachse liegt f{\"u}r 4T@BNNT bei etwa 16° und ist damit etwas gr{\"o}ßer als derjenige von 6T@BNNT. Somit zeigt sich auch hier, dass k{\"u}rzere Molek{\"u}le mehr sterische Freiheitsgerade im Innern der R{\"o}hren besitzen. F{\"u}r 8T@BNNT liegt der Winkel bei ca. 28° und widerspricht abermals der Annahme. TCSPC-Messungen an freien Oligothiophen-Farbstoffen sowie an den hybriden Systemen zeigten, dass die Fluoreszenzlebensdauer \(\tau\) f{\"u}r 4T und 6T (jeweils in DMF) infolge der Einkapselung deutlich zunimmt wenn die Hybridsysteme ebenfalls in DMF dispergiert sind. Die ermittelten Werte f{\"u}r \(\tau\) der separierten Nanoobjekte lagen f{\"u}r 4T@BNNT und 6T@BNNT unterhalb der entsprechenden in DMF. F{\"u}r 8T bzw. 8T@BNNT ergab sich eine deutlich k{\"u}rzerer Lebensdauer der separierten Nanoobjekte im Vergleich zum freien Farbstoff in kolloidaler Suspension. Ein erster Ansatz, um den zugrundeliegende Mechanismus aufzukl{\"a}ren, bestand darin, die TCSPC-Spektren (f{\"u}r 6T in DMF und 6T@BNNT in DMF) hinsichtlich der einzelnen Zerfallskan{\"a}le zu analysieren. Die erhaltenen Ergebnisse deuteten darauf hin, dass bei freiem 6T in DMF andere Zerfallskan{\"a}le dominieren als beim Hybridsystem 6T@BNNT (in DMF). Eine Korrelation der Fluorezenslebensdauer von 6T@BNNT vom {\"a}ußeren Durchmesser der Nanor{\"o}hren zeigte keinen eindeutigen Zusammenhang. Die Charakterisierung von Nilrot bzw. NR@BNNT (analog zu den Oligothiophenen) erfolgte in Kapitel 4. Auch hier zeigte sich eine Verschiebung des PL-Spektrums des Fluorophores durch die Einkapselung in die BNNTs. Allerdings ist das PL-Spektrum des Hybridsystems (NR@BNNT) um etwa 20nm hypsochrom verschoben. Nilrot ist in der Literatur zudem als Nanosonde zur Ermittlung der Permittivit{\"a}t des L{\"o}semittels bzw. der Umgebung bekannt. Dies erlaubte eine Absch{\"a}tzung der relativen Permittiv{\"a}t im Inneren der BNNTs. Der ermittelte Wert von ca. 4 f{\"u}r ein isoliertes NR@BNNT Objekt deutet auf eine relativ unpolare Umgebung im R{\"o}hreninneren hin. Zum Vergleich dazu, liegt der Wert von freiem NR in DMF bei 47, was die relativ hohe Polarit{\"a}t von DMF best{\"a}tigt. Der ermittelte Wert f{\"u}r die mittlere maximale Polarisation lag leicht {\"u}ber dem der hybriden Systeme aus Oligothiophenen und Nanor{\"o}hren. F{\"u}r die Auslenkung der NR-Molek{\"u}le gegen{\"u}ber der R{\"o}hrenachse ergab sich ein Winkel von etwa 16°, was im Bereich der Werte von 4T@BNNT und 6T@BNNT liegt. Die Messung der zeitaufgel{\"o}sten Fluoreszenz von freiem und eingekapseltem Nilrot hat ergeben, dass auch in diesem Fall eine Verk{\"u}rzung der Lebensdauer (von 4091 ps auf 812 ps) erfolgte. Eine solche Verk{\"u}rzung der Lebensdauer von Chromophoren wird in der Literatur unter anderem mit der Bildung von J-Aggregaten in Zusammenhang gebracht.}, subject = {Fluoreszenzmikroskopie}, language = {de} } @phdthesis{Adolf2024, author = {Adolf, Jonas Michael}, title = {Die Zusammenarbeit zwischen der station{\"a}ren beziehungsweise teilstation{\"a}ren psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen}, doi = {10.25972/OPUS-37109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371098}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuit{\"a}t in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)station{\"a}ren und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und - falls m{\"o}glich - erste M{\"o}glichkeiten zur Verbesserung der derzeitigen Versorgungskontinuit{\"a}t aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich f{\"u}r Medizinische Psychologie und Psychotherapie im Zentrum f{\"u}r psychische Gesundheit des Universit{\"a}tsklinikums W{\"u}rzburg wurde hierzu ein Fragebogen entwickelt und acht ausgew{\"a}hlten psychotherapeutischen Fachgesellschaften beziehungsweise Psychotherapeutenkammern mit der Bitte um Weiterleitung an deren Mitglieder zugesandt. In der vorliegenden Studie wurden - neben einer Globalbeurteilung - im Speziellen die Teil-aspekte des Austauschs, der entsprechenden Rahmenbedingungen und die Bereitstellung des poststation{\"a}ren ambulanten Psychotherapieplatzes betrachtet. Die Studienergebnisse bilden den derzeitigen Status Quo der psychotherapeutischen Versorgungslage aus Sicht der niedergelassenen Psychotherapeut:innen ab und weisen im Zuge dessen auf einige Defizite in den untersuchten Teilaspekten hin. Die aufgestellten Nebenfragestellungen zeigen gleichsam aber auch Ansatzunkte f{\"u}r L{\"o}sungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es - zur Erm{\"o}glichung einer ad{\"a}quaten kontinuierlichen psychotherapeutischen Versorgung - eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. F{\"u}r ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)station{\"a}ren Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten M{\"o}glichkeiten der vorliegenden Arbeit gilt es große repr{\"a}sentative und nationale Studien anzustreben. Hierzu w{\"a}re die Etablierung zentral verwalteter Register zur B{\"u}ndelung der bisherigen und zuk{\"u}nftigen Forschungsarbeiten im Bereich der Psychotherapie w{\"u}nschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und k{\"o}nnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen.}, subject = {Psychotherapie}, language = {de} } @phdthesis{Schuhmair2024, author = {Schuhmair, Leah Sophia}, title = {Etablierung eines in-situ-Immunfluoreszenzf{\"a}rbeverfahrens zur dreidimensionalen Darstellung und Quantifizierung der Immunzellinfiltration in experimentellen Tumoren}, doi = {10.25972/OPUS-37094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370945}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Brustkrebs ist die h{\"a}ufigste diagnostizierte Krebserkrankung weltweit. Trotz der vielf{\"a}ltigen Behandlungsm{\"o}glichkeiten endet die Diagnose Brustkrebs in vielen F{\"a}llen noch immer t{\"o}dlich. Aus diesem Grund ist die Entwicklung neuer Therapieans{\"a}tze wichtig. Ein Therapieansatz, der in den letzten zehn Jahren immer mehr an Bedeutung gewonnen hat, ist die Immuntherapie. Allerdings konnte sie bei Brustkrebs noch keine großen Erfolge erzielen. Ursache hierf{\"u}r ist die geringe Immunzellinfiltration in Brusttumoren. Um Brustkrebs f{\"u}r Immuntherapie empf{\"a}nglicher zu machen, m{\"u}ssten Immuntherapeutika in Kombination mit Medikamenten angewendet werden, die die Immunzellinfiltration steigern. Um die Wirksamkeit solcher Medikamente in pr{\"a}klinischen Studien zu testen, braucht es eine Methode, mit der man die T-Zellverteilung innerhalb des Tumors darstellen kann. F{\"u}r umfassendes Verst{\"a}ndnis ist dreidimensionale Darstellung der Zellen im Tumor notwendig, da es einen großen Unterschied macht, ob sich die T-Zellen im Tumorstroma oder in unmittelbarer N{\"a}he zu den Tumorzellen befinden. Die starke Fibrotisierung der Extrazellul{\"a}ren Matrix, die typisch f{\"u}r Brusttumoren ist, erschwert nicht nur die Immunzellinfiltration, sondern auch die Diffusion der fluoreszierenden Antik{\"o}rper ins Gewebe. Im Zuge dieser Arbeit wurde eine Methode entwickelt, um im dreidimensionalen CD4 und CD8-positive T-Zellen in Brusttumoren darzustellen. Dies gelang mittels Immunfluoreszenzf{\"a}rbung und anschließender dreidimensionaler Aufnahme mithilfe optischer Sektionierung am Lichtblattmikroskop. Erreicht wurde dies durch deutliche Erh{\"o}hung der Inkubationszeiten, aggressive Permeabilisierung des Gewebes, Testen unterschiedlicher Antik{\"o}rper bzw. Antik{\"o}rperkombinationen und Entf{\"a}rbung sowie Kl{\"a}rung des Tumorgewebes. Dar{\"u}ber hinaus konnten erste Schritte in der nachtr{\"a}glichen Bearbeitung der Aufnahmen inklusive Rekonstruktion der Zellen gemacht werden. F{\"u}r die Anwendung des Verfahrens in Studien zur Medikamentenwirksamkeit ist noch weitere Optimierung notwendig.}, subject = {Immunfluoreszenz}, language = {de} } @phdthesis{Wanner2024, author = {Wanner, Maren}, title = {L{\"a}ngsschnittanalyse von Stimmparametern bei gesunden S{\"a}uglingen im zweiten Lebenshalbjahr}, doi = {10.25972/OPUS-37096}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370962}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In der vorliegenden Arbeit wurde die Melodiestrukturentwicklung im zweiten Lebenshalbjahr, exemplarisch an zehn gesunden S{\"a}uglingen mit deutscher Umgebungssprache, untersucht. Zusammen mit den zuvor erhobenen und vorliegenden Ergebnissen der ersten sechs Lebensmonate (Kottmann, 2023) war erstmalig eine systematische L{\"a}ngsschnittanalyse {\"u}ber das gesamte erste Lebensjahr m{\"o}glich. Mithilfe des Lautanalyseprogramms CDAP wurden f{\"u}r die vorliegende Arbeit 4686 fr{\"u}hkindliche Lautaufahmen bez{\"u}glich ihres Melodiekonturverlaufs sowie ihrer auditiv und visuell wahrnehmbaren Feinstrukturmerkmale detailliert analysiert und ausgewertet. Der Datensatz spiegelt repr{\"a}sentativ das typische Lautrepertoire von S{\"a}uglingen im zweiten Lebenshalbjahr mit den hier untersuchten Komfort-Vokalisationstypen wider: {\"U}bergangslaute, marginale und kanonische Babbellaute. In {\"U}bereinstimmung mit dem von Wermke und Mende postulierten MD-Modell, das eine vokalisationstyp-{\"u}bergreifende Komplexit{\"a}tszunahme fr{\"u}hkindlicher Laut{\"a}ußerungen beschreibt, konnten erstmals die regelhaften Entwicklungsverl{\"a}ufe im zweiten Lebenshalbjahr gezeigt und ausf{\"u}hrlich benannt werden. Dabei scheint die Zunahme der Komplexit{\"a}t vor allem im Zusammenhang mit artikulatorischen Reifeprozessen zu stehen. In der Melodie selbst fiel diesbez{\"u}glich vor allem der Einbau von Segmentierungen auf. Diese innermelodischen Unterbrechungen k{\"o}nnen wiederum als Vorl{\"a}ufer linguistischer Strukturen, wie beispielsweise Silben, angesehen werden. Der {\"U}bergang von einfachen zu fortgeschritteneren Vokalisationen, bis hin zu den ersten W{\"o}rtern, ist fließend. Zuk{\"u}nftig w{\"a}re f{\"u}r weitere empirische Untersuchungen interessant, inwiefern sich der Grundfrequenzverlauf zunehmend zur suprasegmentalen Intonationskurve entwickelt, was sich bereits in den durchgef{\"u}hrten Analysen angedeutet hat. Die kontinuierlich wachsende Kontrolle des S{\"a}uglings {\"u}ber den Vokaltrakt mit zunehmend gezielter Reproduktion erlernter Lautstrukturen wird durch die Ergebnisse der vorliegenden Arbeit belegt. Sie liefert einen wichtigen Beitrag zum Verst{\"a}ndnis der Sprachentwicklung von S{\"a}uglingen und erm{\"o}glicht durch die Erkenntnisse der physiologisch ablaufenden Prozesse eine vorsprachliche Diagnostik, eine fr{\"u}hzeitige Intervention und F{\"o}rderung der Sprache. Vor allem der Beginn des Babbelns scheint hierbei eine wichtige Evaluationsgr{\"o}ße zu sein.}, subject = {Sprachentwicklung}, language = {de} } @phdthesis{Liu2024, author = {Liu, Yang}, title = {Predictions for Composite Higgs Models Using Gauge/Gravity Duality}, doi = {10.25972/OPUS-37083}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370833}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {This thesis is dedicated to construct a non-abelian holographic dynamical minimal composite Higgs model. We first build a non-abelian bottom-up AdS/YM model that can explain the QCD meson spectrum well. The model is made non-abelian by considering non-abelian DBI action in the top-down model. We then change the dual theory from the QCD to the minimal composite Higgs model U (4)/Sp(4). By adding a second explicit U (4) → Sp(4) breaking through the NJL interaction at the boundary, we managed to construct a composite Higgs phase and a technicolor phase in this model. The transition between the two phases is also realized, which is controlled by the NJL coupling. This thesis is based on the works [1, 2].}, subject = {Higgs-Modell}, language = {en} } @phdthesis{Mueller2024, author = {M{\"u}ller, Nicole}, title = {Modellierung klonaler Evolution beim Multiplen Myelom}, doi = {10.25972/OPUS-37081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370818}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde ein modulares Zelllinienmodell zur Visualisierung klonaler Evolutionsmechanismen etabliert. Hierf{\"u}r wurden unterschiedlich fluoreszierende Proteine (LSSmKate2, EGFP, mTagBFP2) durch Anwendung eines Sleeping Beauty basierten Vektorsystems in unterschiedliche Sublinien der Myelom Zelllinie L363 eingebracht. Diese vier Sublinien beinhalten jeweils eine von drei aus prim{\"a}ren Patientenproben gewonnenen Mutationen in IKZF1 (A152T, E170D, R439H) oder den IKZF1 WT. Die Anwendung von immunmodulatorischen Medikamenten (IMiDs) f{\"u}hrt zu einer Ubiquitinierung des Transkriptionsfaktors IKZF1 durch die E3-Ubiquitin-Protein-Ligase (CRBN-CUL4). Durch Mutationen in IKZF1 kommt es zu St{\"o}rungen in diesem Prozess und damit zu einer {\"U}berexpression von IKZF1. Dies wirkt sich wachstumsf{\"o}rdert auf die Myelomzellen aus. Die Auswirkungen der einzelnen Mutationen in IKZF1 ist aufgrund dessen ein klinisch relevantes Forschungsthema. In dieser Arbeit wurden jeweils zwei Sublinien mit Zellen des IKZF1 WT und Zellen mit einer IKZF1 Mutation mit jeweils unterschiedlich fluoreszierenden Proteinen markiert. Diese wurden gemeinsam unter Behandlung mit verschiedenen Konzentrationen von Lenalidomid inkubiert. Somit konnte das Selektionsverhalten mittels Durchflusszytometrie-Auswertungen visualisiert werden. Es konnte gezeigt werden, dass die IKZF1 Mutation A152T einen deutlichen Selektionsvorteil f{\"u}r die Myelomzellen darstellt. Bei den IKZF1 Mutationen E170D und R439H konnte kein Selektionsvorteil gegen{\"u}ber dem IKZF1 WT beobachtet werden.}, subject = {Lenalidomid}, language = {de} } @phdthesis{Rode2024, author = {Rode, Stefan}, title = {Automated resummation of electroweak Sudakov logarithms in diboson production}, doi = {10.25972/OPUS-37106}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371060}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {The present thesis is concerned with the automated computation of integrated and differential cross sections of diboson production in proton-proton and electron-positron collisions at very high energies, including a resummation of electroweak Sudakov logarithms to all orders in the fine-structure constant using soft-collinear effective theory. The search for new physics at future colliders such as the FCC-hh or the CLIC requires precise predictions for scattering cross sections from the theoretical high-energy physics com- munity. Electroweak Sudakov logarithms, which currently limit the accuracy of predictions in the high-energy tails of differential distributions for LHC-like energies, are known to destroy the convergence behaviour of the fixed-order perturbative series, once sufficiently high energies are considered. To resum these large corrections, soft-collinear effective theory has been applied to simple processes, which permits analytic calculations. Within this work, we present an automated computation within a Monte Carlo integration framework, thus facilitating the computation of fully differential cross section to complicated processes. This requires the use of the Catani- Seymour subtraction algorithm to treat the occurring infrared divergences. The machinery is applied to all diboson processes with intermediate weak gauge bosons, including the photon- induced W+ W- -production channel. To this end we carefully study the validity of the necessary assumptions such as the double- pole approximation and estimate the order of magnitude of neglected effects. Especially the non-doubly-resonant contributions turn out to be sizeable in several interesting phase-space regions. For lepton collisions at 3 TeV we obtain the integrated cross sections of W-pair and Z-pair production to be shifted by more than 20\% with respect to the Born value, owing to the resum- mation of the leading-logarithmic corrections These effects are partly cancelled by subleading effects. For proton-proton collisions at √ s = 100 TeV we observe sizeable resummation effects in the high-energy tails, while the integrated cross sections are dominated by interactions, for which soft-collinear effective theory is not applicable.}, language = {en} } @phdthesis{Aljasem2024, author = {Aljasem, Anwar}, title = {Der Einfluss des Hepatocyte growth factors auf die PD-L1-Expression in Kopf-Hals-Karzinomen: Die Bedeutung des MAPK-, AKT- und STAT3-Signalwegs}, doi = {10.25972/OPUS-37035}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370358}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die zielgerichtete Therapie und die Immuncheckpoint-Inhibitoren haben die Tumortherapie revolutioniert. W{\"a}hrend erstere die Tumorzellen gezielt angreift, verhindern letztere die Hemmung des Immunsystems durch Immuncheckpoints, um eine robuste Immunantwort zu erreichen. Zus{\"a}tzlich ist das Nebenwirkungsprofil bei direktem Vergleich mit der konventionellen Chemotherapie g{\"u}nstiger. Beim HNSCC werden beide Ans{\"a}tze angewendet. Cetuximab ist ein monoklonaler Antik{\"o}rper, der sich gegen EGFR, welcher bei HNSCC {\"u}berexprimiert ist, richtet. Nivolumab und Pembrolizumab richten sich gegen das Immuncheckpoint-Protein PD-1. Nach wie vor sind die Resistenzen, sowohl die initialen als auch die erworbenen, die gr{\"o}ßte zu {\"u}berwindende Herausforderung. Aufbauend auf dem Ergebnis vorangegangener Arbeiten, die zeigen konnten, dass HGF {\"u}ber c-MET die Expression des Immuncheckpointliganden PD-L1 steigert, setzt sich diese Arbeit weiter mit den intrazellul{\"a}ren nachgeschalteten Signalwegen nach c-MET Aktivierung auseinander. Dies ist von besonderem Interesse, weil diese Signalwege ebenfalls f{\"u}r die Resistenzentwicklung verantwortlich sein k{\"o}nnen, zeitgleich k{\"o}nnen diese im Rahmen der zielgerichteten Therapie gezielt inhibiert werden. Um den HGF-Einfluss auf die intrazellul{\"a}ren Signalwege zu pr{\"u}fen, wurden vier etablierte HNSCC-Zelllinien herangezogen. Im ersten Teil der Arbeit wurden die 4 HNSCC-abgeleitete Zelllinien mit HGF stimuliert und mittels Western Blot der PD-L1-Anstieg und die Phosphorylierungs{\"a}nderung der Schl{\"u}sselproteine der einzelnen Signalwege nachgewiesen. Daraus ergab sich, dass HGF die MAPK- und PIK3/AKT-Signalwege aktiviert. W{\"a}hrend eine kombinierte Blockade des MAPK-Signalwegs den PD-L1-Anstieg vollst{\"a}ndig verhindern konnte, hemmte die PIK3/AKT-Blockade den PD-L1-Anstieg nur partiell. Im zweiten Teil wurde mit siRNA der haupts{\"a}chlich f{\"u}r den PD-L1-Anstieg zust{\"a}ndige MAPK-Signalweg unterbunden, was mittels quantitativer PCR auf der mRNA-Ebene nachgewiesen werden konnte. Mittels Western Blot konnte entsprechend gezeigt werden, dass der PD-L1-Anstieg trotz HGF-Stimulation bei nicht funktionsf{\"a}higem MAPK-Signalweg eingeschr{\"a}nkt war. Weiter wurde der Effekt mit dem Medikament Trametinib, das im Rahmen der zielgerichteten Therapie bei malignem Melanom und NSCLC f{\"u}r die MAPK-Signalweg-Hemmung zugelassen ist, evaluiert. Sowohl im Western Blot als auch in der Durchflusszytometrie konnte best{\"a}tigt werden, dass Trametinib den HGF-induzierten Anstieg von PD-L1 signifikant blockiert. Dar{\"u}ber hinaus konnte im Rahmen der Western Blot-Versuche gezeigt werden, dass die Signalwege und die PD-L1-Expression in den Zelllinien unterschiedlich aktiv bzw. hoch waren. Unter den vier Zelllinien zeigte die FaDu-Zelllinie eine erh{\"o}hte PI3K/AKT-Aktivit{\"a}t, Detroit562 und SCC9 eine erh{\"o}hte MAPK-Aktivit{\"a}t. Die PD-L1- Expression war in der SCC9-Zelllinie am h{\"o}chsten. Die Arbeit zeigt eine einheitliche Reaktion der HNSCC-Zelllinien auf den Wachstumsfaktor HGF, welcher im Tumormilieu von HNSCC oft in hoher Konzentration vorhanden ist. Neben dem EGFR-Antik{\"o}rper (Cetuximab) kann eine kombinierte Hemmung entweder von c-MET oder von den nachgeschalteten Signalwegen MAPK und PI3K/AKT bei Resistenzen, Progression oder Unvertr{\"a}glichkeiten eine M{\"o}glichkeit f{\"u}r eine wirksamere Therapie von HNSCC darstellen. Ein Screening der Signalwege und deren Aktivierungsmechanismen k{\"o}nnte bei Resistenzen oder bei einem Rezidiv/Progress dazu beitragen, gezielt die alternative Aktivierung zu hemmen und m{\"o}glicherweise die Wirksamkeit einer Immuncheckpointblockade zu verbessern.}, subject = {Hepatozyten-Wachstumsfaktor}, language = {de} } @phdthesis{Lechermeier2024, author = {Lechermeier, Carina}, title = {Neuroanatomical and functional evaluation of ADHD candidate genes in the model organism zebrafish (\(Danio\) \(rerio\))}, doi = {10.25972/OPUS-37108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-371084}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent developmental disorders, affecting 5.9\% children and adolescents and 2.5\% adults worldwide. The core characteristics are age-inappropriate levels of hyperactivity, impulsivity and inattention, often accompanied by co-morbidities such as mood and conduct disorders as wells as learning deficits. In the majority of cases, ADHD is caused by an interplay of accumulated genetic and environmental risk factors. Twin studies report a very high heritability of 70-80\%, however, common genetic variants in the population only explain a third of the heritability. The rest of the genetic predisposition is composed of rare copy number variations (CNVs) and gene x environment interactions including epigenetic alterations. Through genome wide association (GWAS) and linkage studies a number of likely candidate genes were identified. A handful of them play a role in dopamine or noradrenaline neurotransmitter systems, simultaneously those systems are the main targets of common drug treatment approaches. However, for the majority of candidates the biological function in relation to ADHD is unknown. It is crucial to identify those functions in order to gain a deeper understanding of the pathomechanism and genetic networks potentially responsible for the disorder. This work focuses on the three candidate genes GFOD1, SLC2A3 and LBX1 and their role in the healthy organism as well as in case of ADHD. The neuroanatomy was regarded through expression analysis and various behavioural assays of activity were performed to link alterations on the transcript level to phenotypes associated with the neurodevelopmental disorder. Zebrafish orthologues of the human risk genes were identified and extensive temporal and spacial expression characterisation performed via RNA in situ hybridisation. Through morpholino derived knock-down and mRNA overexpression zebrafish models with subsequent behavioural analysis, both hyper- and hypoactive phenotypes were discovered. Additional expression analysis through double in situ hybridisation revealed a co-localisation during zebrafish neurodevelopment of each gfod1 and slc2a3a together with gad1b, a marker for GABAergic neurons. Interestingly, both risk genes have previously been associated with glucose homeostasis and energy metabolism, which when disrupted could lead to alterations in signal transduction and neuron survival. Likewise, Lbx1 plays a pivotal role in GABAergic versus glutamatergic neuron specification during spinal cord and hindbrain development in mice and chicken. Preliminary results of this work suggest a similar role in zebrafish. Taken together, those findings on the one hand represent a sturdy basis to con- tinue studies of the function of the genes and on the other hand open up the opportunity to investigate novel aspects of ADHD research by exploring the role of the GABAergic neurotransmitter system or the connection between energy metabolism and psychiatric disorders.}, subject = {Aufmerksamkeitsdefizit-Syndrom}, language = {en} } @article{ZhangYeGburecketal.2018, author = {Zhang, Zishuai and Ye, Siyu and Gbureck, Uwe and Barralet, Jake E. and Merle, G{\´e}raldine}, title = {Cavitation Mediated 3D Microstructured Architectures from Nanocarbon}, series = {Advanced Functional Materials}, volume = {28}, journal = {Advanced Functional Materials}, doi = {10.1002/adfm.201706832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233926}, year = {2018}, abstract = {Here, the formation of high surface area microscale assemblies of nanocarbon through phosphate and ultrasound cavitation treatment is reported. Despite high conductivity and large surface area, potential health and safety concerns limit the use of nanocarbon and add challenges to handling. Previously, it is shown that phosphate ultrasonic bonding is ineffective for organic materials but in this study, it is found that by a preliminary oxidizing treatment, several carbons can be readily assembled from xerogels. Assembling nanocarbon into microparticles can usually require a binder or surfactants, which can reduce surface area or conductivity and generate a low microsphere yield. Carbon nanotube microspheres are nitrogen-doped and flower-like nanostructured Pt deposited on their surface, and finally showcased as efficient cathode electrocatalysts for the oxygen reduction reaction (half-wave potential 0.78 V vs reversible hydrogen electrode) and methanol oxidation (417 mA mg-1). In particular, no significant degradation of the catalysts is detected after 12 000 cycles (26.6 h). These results indicate the potential of this multimaterial assembly method and open a new way to improve handling of nanoscale materials.}, language = {en} } @article{McMasterHoefnerHrynevichetal.2019, author = {McMaster, Rebecca and Hoefner, Christiane and Hrynevich, Andrei and Blum, Carina and Wiesner, Miriam and Wittmann, Katharina and Dargaville, Tim R. and Bauer-Kreisel, Petra and Groll, J{\"u}rgen and Dalton, Paul D. and Blunk, Torsten}, title = {Tailored Melt Electrowritten Scaffolds for the Generation of Sheet-Like Tissue Constructs from Multicellular Spheroids}, series = {Advanced Healthcare Materials}, volume = {8}, journal = {Advanced Healthcare Materials}, doi = {10.1002/adhm.201801326}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223921}, year = {2019}, abstract = {Melt electrowriting (MEW) is an additive manufacturing technology that is recently used to fabricate voluminous scaffolds for biomedical applications. In this study, MEW is adapted for the seeding of multicellular spheroids, which permits the easy handling as a single sheet-like tissue-scaffold construct. Spheroids are made from adipose-derived stromal cells (ASCs). Poly(ε-caprolactone) is processed via MEW into scaffolds with box-structured pores, readily tailorable to spheroid size, using 13-15 µm diameter fibers. Two 7-8 µm diameter "catching fibers" near the bottom of the scaffold are threaded through each pore (360 and 380 µm) to prevent loss of spheroids during seeding. Cell viability remains high during the two week culture period, while the differentiation of ASCs into the adipogenic lineage is induced. Subsequent sectioning and staining of the spheroid-scaffold construct can be readily performed and accumulated lipid droplets are observed, while upregulation of molecular markers associated with successful differentiation is demonstrated. Tailoring MEW scaffolds with pores allows the simultaneous seeding of high numbers of spheroids at a time into a construct that can be handled in culture and may be readily transferred to other sites for use as implants or tissue models.}, language = {en} } @article{SelcukTokluBeykanetal.2018, author = {Selcuk, Nalan Alan and Toklu, Turkay and Beykan, Seval and Karaaslan, Serife Ipek}, title = {Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer}, series = {Journal of Applied Clinical Medical Physics}, volume = {19}, journal = {Journal of Applied Clinical Medical Physics}, doi = {10.1002/acm2.12350}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235882}, pages = {134-140}, year = {2018}, abstract = {In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole-body counts were collected at 2, 24, 72, and 120 h after I-131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I-131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th-hour uptake and time-integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion-based dosimetry.}, language = {en} } @article{GoettlichKunzZappetal.2018, author = {G{\"o}ttlich, Claudia and Kunz, Meik and Zapp, Cornelia and Nietzer, Sarah L. and Walles, Heike and Dandekar, Thomas and Dandekar, Gudrun}, title = {A combined tissue-engineered/in silico signature tool patient stratification in lung cancer}, series = {Molecular Oncology}, volume = {12}, journal = {Molecular Oncology}, doi = {10.1002/1878-0261.12323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233137}, pages = {1264-1285}, year = {2018}, abstract = {Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this, we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations, we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: It correctly shows a strong drug response upon gefitinib (Gef) treatment in a cell line harboring an EGFR-activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549). In contrast, 2D testing implies wrongly KRAS as a biomarker for HSP90 inhibitor treatment, although this fails in clinical studies. Signaling analysis by phospho-arrays showed similar effects of EGFR inhibition by Gef in HCC827 cells, under both 2D and 3D conditions. Western blot analysis confirmed that for 3D conditions, HSP90 inhibitor treatment implies different p53 regulation and decreased MET inhibition in HCC827 and H441 cells. Using in vitro data (western, phospho-kinase array, proliferation, and apoptosis), we generated cell line-specific in silico topologies and condition-specific (2D, 3D) simulations of signaling correctly mirroring in vitro treatment responses. Networks predict drug targets considering key interactions and individual cell line mutations using the Human Protein Reference Database and the COSMIC database. A signature of potential biomarkers and matching drugs improve stratification and treatment in KRAS-mutated tumors. In silico screening and dynamic simulation of drug actions resulted in individual therapeutic suggestions, that is, targeting HIF1A in H441 and LKB1 in A549 cells. In conclusion, our in vitro tumor tissue model combined with an in silico tool improves drug effect prediction and patient stratification. Our tool is used in our comprehensive cancer center and is made now publicly available for targeted therapy decisions.}, language = {en} } @article{StromeckiTatariCoudiereMorrisonetal.2018, author = {Stromecki, Margaret and Tatari, Nazanin and Coudi{\`e}re Morrison, Ludivine and Kaur, Ravinder and Zagozewski, Jamie and Palidwor, Gareth and Ramaswamy, Vijay and Skowron, Patryk and W{\"o}lfl, Matthias and Milde, Till and Del Bigio, Marc R. and Taylor, Michael D. and Werbowetski-Ogilvie, Tamra E.}, title = {Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma}, series = {Molecular Oncology}, volume = {12}, journal = {Molecular Oncology}, doi = {10.1002/1878-0261.12177}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240089}, pages = {495-513}, year = {2018}, abstract = {Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo. To determine how OTX2 contributes to these processes, we employed complementary bioinformatic approaches to characterize the OTX2 regulatory network and identified novel relationships between OTX2 and genes associated with neuronal differentiation and axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX2 levels were negatively correlated with semaphorin (SEMA) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX2 knockdown with some being potential direct OTX2 targets. Importantly, this negative correlation was also observed in patient samples, with lower expression of SEMA4D associated with poor outcome specifically in Group 4 tumors. Functional proof-of-principle studies demonstrated that increased levels of select SEMA pathway genes are associated with decreased self-renewal and growth in vitro and in vivo and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX2 KD phenotype. Our study provides mechanistic insight into the networks controlled by OTX2 in MB stem/progenitor cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors in MB.}, language = {en} } @article{StoreyStaplinHaynesetal.2018, author = {Storey, Benjamin C. and Staplin, Natalie and Haynes, Richard and Reith, Christina and Emberson, Jonathan and Herrington, William G. and Wheeler, David C. and Walker, Robert and Fellstr{\"o}m, Bengt and Wanner, Christoph and Landray, Martin J. and Baigent, Colin}, title = {Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation}, series = {Kidney International}, volume = {93}, journal = {Kidney International}, organization = {The SHARP Collaborative Group}, doi = {10.1016/j.kint.2017.09.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240067}, pages = {1000-1007}, year = {2018}, abstract = {Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95\% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.}, language = {en} } @article{HoeniglOraschFaserletal.2019, author = {Hoenigl, Martin and Orasch, Thomas and Faserl, Klaus and Prattes, Juergen and Loeffler, Juergen and Springer, Jan and Gsaller, Fabio and Reischies, Frederike and Duettmann, Wiebke and Raggam, Reinhard B. and Lindner, Herbert and Haas, Hubertus}, title = {Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis}, series = {Journal of Infection}, volume = {78}, journal = {Journal of Infection}, doi = {10.1016/j.jinf.2018.09.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320939}, pages = {150-157}, year = {2019}, abstract = {Objectives Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA. Methods We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples. Results TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient. Conclusion For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis.}, language = {en} } @article{EstesAnsteeAriasLosteetal.2018, author = {Estes, Chris and Anstee, Quentin M. and Arias-Loste, Maria Teresa and Bantel, Heike and Bellentani, Stefano and Caballeria, Joan and Colombo, Massimo and Craxi, Antonio and Crespo, Javier and Day, Christopher P. and Eguchi, Yuichiro and Geier, Andreas and Kondili, Loreta A. and Kroy, Daniela C. and Lazarus, Jeffrey V. and Loomba, Rohit and Manns, Michael P. and Marchesini, Giulio and Nakajima, Atsushi and Negro, Francesco and Petta, Salvatore and Ratziu, Vlad and Romero-Gomez, Manuel and Sanyal, Arun and Schattenberg, J{\"o}rn M. and Tacke, Frank and Tanaka, Junko and Trautwein, Christian and Wei, Lai and Zeuzem, Stefan and Ravazi, Homie}, title = {Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030}, series = {Journal of Hepatology}, volume = {69}, journal = {Journal of Hepatology}, doi = {10.1016/j.jhep.2018.05.036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227286}, pages = {896-904}, year = {2018}, abstract = {Background \& Aims Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. Methods A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. Results If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30\%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56\%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. Conclusions NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Lay summary Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.}, language = {en} } @article{TappenbeckSchroederNiebergallRothetal.2019, author = {Tappenbeck, Nils and Schr{\"o}der, Hannes M. and Niebergall-Roth, Elke and Hassinger, Fathema and Dehio, Ulf and Dieter, Kathrin and Kraft, Korinna and Kerstan, Andreas and Esterlechner, Jasmina and Frank, Natasha Y. and Scharffetter-Kochanek, Karin and Murphy, George F. and Orgill, Dennis P. and Beck, Joachim and Frank, Markus H. and Ganss, Christoph and Kluth, Mark A.}, title = {In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials}, series = {Cytotherapy}, volume = {21}, journal = {Cytotherapy}, doi = {10.1016/j.jcyt.2018.12.005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240456}, pages = {546-560}, year = {2019}, abstract = {Background aims Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5+ MSCs) represent a promising candidate for stem cell-based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5+ MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice-conforming, MSC-based advanced-therapy medicinal product. Methods To support the development of ABCB5+ MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice-compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction. Results (i) Subcutaneous application of 1 × 107 ABCB5+ MSCs/animal and intravenous application of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5+ MSCs at doses ranging from 1 × 105 to 1 × 107 cells/animal and three biweekly intravenous injections of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 106 ABCB5+ MSCs/animal to immunocompromised mice was locally well tolerated. Discussion The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5+ MSCs.}, language = {en} } @article{WurmStarkZhuetal.2019, author = {Wurm, Michael and Stark, Thomas and Zhu, Xiao Xiang and Weigand, Matthias and Taubenb{\"o}ck, Hannes}, title = {Semantic segmentation of slums in satellite images using transfer learning on fully convolutional neural networks}, series = {ISPRS Journal of Photogrammetry and Remote Sensing}, volume = {150}, journal = {ISPRS Journal of Photogrammetry and Remote Sensing}, doi = {10.1016/j.isprsjprs.2019.02.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233799}, pages = {59-69}, year = {2019}, abstract = {Unprecedented urbanization in particular in countries of the global south result in informal urban development processes, especially in mega cities. With an estimated 1 billion slum dwellers globally, the United Nations have made the fight against poverty the number one sustainable development goal. To provide better infrastructure and thus a better life to slum dwellers, detailed information on the spatial location and size of slums is of crucial importance. In the past, remote sensing has proven to be an extremely valuable and effective tool for mapping slums. The nature of used mapping approaches by machine learning, however, made it necessary to invest a lot of effort in training the models. Recent advances in deep learning allow for transferring trained fully convolutional networks (FCN) from one data set to another. Thus, in our study we aim at analyzing transfer learning capabilities of FCNs to slum mapping in various satellite images. A model trained on very high resolution optical satellite imagery from QuickBird is transferred to Sentinel-2 and TerraSAR-X data. While free-of-charge Sentinel-2 data is widely available, its comparably lower resolution makes slum mapping a challenging task. TerraSAR-X data on the other hand, has a higher resolution and is considered a powerful data source for intra-urban structure analysis. Due to the different image characteristics of SAR compared to optical data, however, transferring the model could not improve the performance of semantic segmentation but we observe very high accuracies for mapped slums in the optical data: QuickBird image obtains 86-88\% (positive prediction value and sensitivity) and a significant increase for Sentinel-2 applying transfer learning can be observed (from 38 to 55\% and from 79 to 85\% for PPV and sensitivity, respectively). Using transfer learning proofs extremely valuable in retrieving information on small-scaled urban structures such as slum patches even in satellite images of decametric resolution.}, language = {en} } @article{CzimmererDanielHorvathetal.2018, author = {Czimmerer, Zsolt and Daniel, Bence and Horvath, Attila and R{\"u}ckerl, Dominik and Nagy, Gergely and Kiss, Mate and Peloquin, Matthew and Budai, Marietta M. and Cuaranta-Monroy, Ixchelt and Simandi, Zoltan and Steiner, Laszlo and Nagy Jr., Bela and Poliska, Szilard and Banko, Csaba and Bacso, Zsolt and Schulman, Ira G. and Sauer, Sascha and Deleuze, Jean-Francois and Allen, Judith E. and Benko, Szilvia and Nagy, Laszlo}, title = {The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages}, series = {Immunity}, volume = {48}, journal = {Immunity}, doi = {10.1016/j.immuni.2017.12.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223380}, pages = {75-90}, year = {2018}, abstract = {The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the molecular determinants of repression. Here we show that IL-4-activated STAT6 transcription factor is required for the direct transcriptional repression of a large number of genes during in vitro and in vivo alternative macrophage polarization. Repression results in decreased lineage-determining transcription factor, p300, and RNA polymerase II binding followed by reduced enhancer RNA expression, H3K27 acetylation, and chromatin accessibility. The repressor function of STAT6 is HDAC3 dependent on a subset of IL-4-repressed genes. In addition, STAT6-repressed enhancers show extensive overlap with the NF-κB p65 cistrome and exhibit decreased responsiveness to lipopolysaccharide after IL-4 stimulus on a subset of genes. As a consequence, macrophages exhibit diminished inflammasome activation, decreased IL-1β production, and pyroptosis. Thus, the IL-4-STAT6 signaling pathway establishes an alternative polarization-specific epigenenomic signature resulting in dampened macrophage responsiveness to inflammatory stimuli.}, language = {en} } @article{TruebeHertleinMrochenetal.2019, author = {Tr{\"u}be, Patricia and Hertlein, Tobias and Mrochen, Daniel M. and Schulz, Daniel and Jorde, Ilka and Krause, Bettina and Zeun, Julia and Fischer, Stefan and Wolf, Silver A. and Walther, Birgit and Semmler, Torsten and Br{\"o}ker, Barbara M. and Ulrich, Rainer G. and Ohlsen, Knut and Holtfreter, Silva}, title = {Bringing together what belongs together: Optimizing murine infection models by using mouse-adapted Staphylococcus aureus strains}, series = {International Journal of Medical Microbiology}, volume = {309}, journal = {International Journal of Medical Microbiology}, doi = {10.1016/j.ijmm.2018.10.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229081}, pages = {26-38}, year = {2019}, abstract = {Staphylococcus (S.) aureus is a leading cause of bacterial infection world-wide, and currently no vaccine is available for humans. Vaccine development relies heavily on clinically relevant infection models. However, the suitability of mice for S. aureus infection models has often been questioned, because experimental infection of mice with human-adapted S. aureus requires very high infection doses. Moreover, mice were not considered to be natural hosts of S. aureus. The latter has been disproven by our recent findings, showing that both laboratory mice, as well as wild small mammals including mice, voles, and shrews, are naturally colonized with S. aureus. Here, we investigated whether mouse-and vole-derived S. aureus strains show an enhanced virulence in mice as compared to the human-adapted strain Newman. Using a step-wise approach based on the bacterial genotype and in vitro assays for host adaptation, we selected the most promising candidates for murine infection models out of a total of 254 S. aureus isolates from laboratory mice as well as wild rodents and shrews. Four strains representing the clonal complexes (CC) 8, 49, and 88 (n = 2) were selected and compared to the human-adapted S. aureus strain Newman (CC8) in murine pneumonia and bacteremia models. Notably, a bank vole-derived CC49 strain, named DIP, was highly virulent in BALB/c mice in pneumonia and bacteremia models, whereas the other murine and vole strains showed virulence similar to or lower than that of Newman. At one tenth of the standard infection dose DIP induced disease severity, bacterial load and host cytokine and chemokine responses in the murine bacteremia model similar to that of Newman. In the pneumonia model, DIP was also more virulent than Newman but the effect was less pronounced. Whole genome sequencing data analysis identified a pore-forming toxin gene, lukF-PV(P83)/lukM, in DIP but not in the other tested S. aureus isolates. To conclude, the mouse-adapted S. aureus strain DIP allows a significant reduction of the inoculation dose in mice and is hence a promising tool to develop clinically more relevant infection models.}, language = {en} } @article{HeimannPenackHeinzetal.2019, author = {Heimann, Sebastian M. and Penack, Olaf and Heinz, Werner J. and Rachow, Tobias and Egerer, Gerlinde and Kessel, Johanna and Claßen, Annika Y. and Vehreschild, J{\"o}rg Janne}, title = {Intravenous and tablet formulation of posaconazole in antifungal therapy and prophylaxis: A retrospective, non-interventional, multicenter analysis of hematological patients treated in tertiary-care hospitals}, series = {International Journal of Infectious Diseases}, volume = {83}, journal = {International Journal of Infectious Diseases}, doi = {10.1016/j.ijid.2019.04.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319567}, pages = {130-138}, year = {2019}, abstract = {Objectives Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 - 03/2016 were observed. Median age was 58 years (range: 19 - 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76\%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573-1,498 μg/L) and 904 μg/L (IQR 728-1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6\%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86\%. The median overall duration of POS therapy was 18 days (IQR: 7 - 23 days). Fourteen patients (48\%) had progressive IFD under POS therapy, of these five patients (36\%) died related to or likely related to IFD. Conclusions Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.}, language = {en} } @article{DietzJohnsonMartinezMartinezetal.2019, author = {Dietz, Maximilian and Johnson, Alice and Mart{\´i}nez-Mart{\´i}nez, Antonio and Weller, Andrew S.}, title = {The [Rh(Xantphos)]+ catalyzed hydroboration of diphenylacetylene using trimethylamine-borane}, series = {Inorganica Chimica Acta}, volume = {491}, journal = {Inorganica Chimica Acta}, doi = {10.1016/j.ica.2019.03.032}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225352}, pages = {9-13}, year = {2019}, abstract = {The rhodium(I) complex [Rh(κ3-P,O,P-Xantphos)(η2-PhC≡CPh)][BArF4] (ArF = 3,5-(CF3)2C6H4) is an effective catalyst for the cis-selective hydroboration of the alkyne diphenylacetylene using the amine-borane H3B·NMe3. Detailed mechanistic studies, that include initial rate measurements, full simulation of temporal profiles for a variety of catalyst and substrate concentrations, and speciation experiments, suggest a mechanism that involves initial coordination of alkyne and a saturation kinetics regime for amine-borane binding. The solid-state molecular structure of a model complex that probes the proposed resting state is also reported, [Rh(κ3-P,O,P-Xantphos)(NCMe)(η2-PhC≡CPh)][BArF4].}, language = {en} } @article{SeitzvanEngelsdorpLeonhardt2019, author = {Seitz, Nicola and vanEngelsdorp, Dennis and Leonhardt, Sara D.}, title = {Conserving bees in destroyed landscapes: The potentials of reclaimed sand mines}, series = {Global Ecology and Conservation}, volume = {19}, journal = {Global Ecology and Conservation}, doi = {10.1016/j.gecco.2019.e00642}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235877}, year = {2019}, abstract = {Sand mines represent anthropogenically impacted habitats found worldwide, which bear potential for bee conservation. Although floral resources can be limited at these habitats, vegetation free patches of open sandy soils and embankments may offer good nesting possibilities for sand restricted and other bees. We compared bee communities as found in three reclaimed sand mines and at adjacent roadside meadows in Maryland, USA, over two years. Both sand mines and roadsides hosted diverse bee communities with 111 and 88 bee species, respectively. Bee abundances as well as richness and Shannon diversity of bee species were higher in sand mines than at roadsides and negatively correlated with the percentage of vegetational ground cover. Species composition also differed significantly between habitats. Sand mines hosted a higher proportion of ground nesters, more uncommon and more 'sand loving' bees similar to natural sandy areas of Maryland. Despite the destruction of the original pre-mining habitat, sand mines thus appear to represent a unique habitat for wild bees, particularly when natural vegetation and open sand spots are encouraged. Considering habitat loss, the lack of natural disturbance regimes, and ongoing declines of wild bees, sand mines could add promising opportunities for bee conservation which has hitherto mainly focused on agricultural and urban habitats.}, language = {en} } @article{vandePeppelAanenBiedermann2018, author = {van de Peppel, L. J. J. and Aanen, D. K. and Biedermann, P. H. W.}, title = {Low intraspecific genetic diversity indicates asexuality and vertical transmission in the fungal cultivars of ambrosia beetles}, series = {Fungal Ecology}, volume = {32}, journal = {Fungal Ecology}, doi = {10.1016/j.funeco.2017.11.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232161}, pages = {57-64}, year = {2018}, abstract = {Ambrosia beetles farm ascomycetous fungi in tunnels within wood. These ambrosia fungi are regarded asexual, although population genetic proof is missing. Here we explored the intraspecific genetic diversity of Ambrosiella grosmanniae and Ambrosiella hartigii (Ascomycota: Microascales), the mutualists of the beetles Xylosandrus germanus and Anisandrus dispar. By sequencing five markers (ITS, LSU, TEF1α, RPB2, β-tubulin) from several fungal strains, we show that X. germanus cultivates the same two clones of A. grosmanniae in the USA and in Europe, whereas A. dispar is associated with a single A. hartigii clone across Europe. This low genetic diversity is consistent with predominantly asexual vertical transmission of Ambrosiella cultivars between beetle generations. This clonal agriculture is a remarkable case of convergence with fungus-farming ants, given that both groups have a completely different ecology and evolutionary history.}, language = {en} } @article{GrebinykGrebinykPrylutskaetal.2018, author = {Grebinyk, Anna and Grebinyk, Sergii and Prylutska, Svitlana and Ritter, Uwe and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus}, title = {C60 fullerene accumulation in human leukemic cells and perspectives of LED-mediated photodynamic therapy}, series = {Free Radical Biology and Medicine}, volume = {124}, journal = {Free Radical Biology and Medicine}, doi = {10.1016/j.freeradbiomed.2018.06.022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228245}, pages = {319-327}, year = {2018}, abstract = {Recent progress in nanobiotechnology has attracted interest to a biomedical application of the carbon nanostructure C60 fullerene since it possesses a unique structure and versatile biological activity. C60 fullerene potential application in the frame of cancer photodynamic therapy (PDT) relies on rapid development of new light sources as well as on better understanding of the fullerene interaction with cells. The aim of this study was to analyze C60 fullerene effects on human leukemic cells (CCRF-CEM) in combination with high power single chip light-emitting diodes (LEDs) light irradiation of different wavelengths: ultraviolet (UV, 365 nm), violet (405 nm), green (515 nm) and red (632 nm). The time-dependent accumulation of fullerene C60 in CCRF-CEM cells up to 250 ng/106 cells at 24 h with predominant localization within mitochondria was demonstrated with immunocytochemical staining and liquid chromatography mass spectrometry. In a cell viability assay we studied photoexcitation of the accumulated C60 nanostructures with ultraviolet or violet LEDs and could prove that significant phototoxic effects did arise. A less pronounced C60 fullerene phototoxic effect was observed after irradiation with green, and no effect was detected with red light. A C60 fullerene photoactivation with violet light induced substantial ROS generation and apoptotic cell death, confirmed by caspase3/7 activation and plasma membrane phosphatidylserine externalization. Our work proved C60 fullerene ability to induce apoptosis of leukemic cells after photoexcitation with high power single chip 405 nm LED as a light source. This underlined the potential for application of C60 nanostructure as a photosensitizer for anticancer therapy.}, language = {en} } @article{MuellerJungWinteretal.2018, author = {Mueller, Dolores and Jung, Kathrin and Winter, Manuel and Rogoll, Dorothee and Melcher, Ralph and Kulozik, Ulrich and Schwarz, Karin and Richling, Elke}, title = {Encapsulation of anthocyanins from bilberries - Effects on bioavailability and intestinal accessibility in humans}, series = {Food Chemistry}, volume = {248}, journal = {Food Chemistry}, doi = {10.1016/j.foodchem.2017.12.058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224247}, pages = {217-224}, year = {2018}, abstract = {Anthocyanins are flavonoids that have been suggested to provide beneficial health effects. The biological activity of anthocyanins is influenced by their pharmacokinetic properties, but anthocyanins are associated with limited bioavailability in humans. In the presented study, we investigated how the encapsulation of bilberry extract (BE), a source of anthocyanins, with either whey protein or citrus pectin influences the bioavailability and intestinal accessibility of anthocyanins in humans. We performed an intervention study that analyzed anthocyanins and their degradation products in the urine, plasma, and ileal effluent of healthy volunteers and ileostomists (subjects without an intact colon). We were able to show, that whey protein encapsulation modulated short-term bioavailability and that citrus pectin encapsulation increased intestinal accessibility during passage through the small intestine and modulated the formation of the degradation product phloroglucinol aldehyde (PGAL) in human plasma.}, language = {en} } @article{FrankeMicheliniAshersonetal.2018, author = {Franke, Barbara and Michelini, Giorgia and Asherson, Philip and Banaschewski, Tobias and Bilbow, Andrea and Buitelaar, Jan K. and Cormand, Bru and Faraone, Stephen V. and Ginsberg, Ylva and Haavik, Jan and Kuntsi, Jonna and Larsson, Henrik and Lesch, Klaus-Peter and Ramos-Quiroga, J. Antoni and R{\´e}thelyi, J{\´a}nos M. and Ribases, Marta and Reif, Andreas}, title = {Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan}, series = {European Neuropsychopharmacology}, volume = {28}, journal = {European Neuropsychopharmacology}, doi = {10.1016/j.euroneuro.2018.08.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228407}, pages = {1059-1088}, year = {2018}, abstract = {Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.}, language = {en} } @article{HofrichterDollHabibietal.2019, author = {Hofrichter, Michaela A. H. and Doll, Julia and Habibi, Haleh and Enayati, Samaneh and Mehrjardi, Mohammad Yahya Vahidi and M{\"u}ller, Tobias and Dittrich, Marcus and Haaf, Thomas and Vona, Barbara}, title = {Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss}, series = {European Journal of Medical Genetics}, volume = {62}, journal = {European Journal of Medical Genetics}, doi = {10.1016/j.ejmg.2019.103724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322008}, year = {2019}, abstract = {Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697-3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL.}, language = {en} } @article{ElliotGermainHilzetal.2019, author = {Elliot, Perry M. and Germain, Dominique P. and Hilz, Max J. and Spada, Marco and Wanner, Christoph and Falissard, Bruno}, title = {Why systematic literature reviews in Fabry disease should include all published evidence}, series = {European Journal of Medical Genetics}, volume = {62}, journal = {European Journal of Medical Genetics}, doi = {10.1016/j.ejmg.2019.103702}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226654}, year = {2019}, abstract = {Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.}, language = {en} } @article{SondermannUtikalEnketal.2019, author = {Sondermann, Wiebke and Utikal, Jochen Sven and Enk, Alexander H. and Schadendorf, Dirk and Klode, Joachim and Hauschild, Axel and Weichenthal, Michael and French, Lars E. and Berking, Carola and Schilling, Bastian and Haferkamp, Sebastian and Fr{\"o}hling, Stefan and von Kalle, Christof and Brinker, Titus J.}, title = {Prediction of melanoma evolution in melanocytic nevi via artificial intelligence: A call for prospective data}, series = {European Journal of Cancer}, volume = {119}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2019.07.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239263}, pages = {30-34}, year = {2019}, abstract = {Recent research revealed the superiority of artificial intelligence over dermatologists to diagnose melanoma from images. However, 30-50\% of all melanomas and more than half of those in young patients evolve from initially benign lesions. Despite its high relevance for melanoma screening, neither clinicians nor computers are yet able to reliably predict a nevus' oncologic transformation. The cause of this lies in the static nature of lesion presentation in the current standard of care, both for clinicians and algorithms. The status quo makes it difficult to train algorithms (and clinicians) to precisely assess the likelihood of a benign skin lesion to transform into melanoma. In addition, it inhibits the precision of current algorithms since 'evolution' image features may not be part of their decision. The current literature reveals certain types of melanocytic nevi (i.e. 'spitzoid' or 'dysplastic' nevi) and criteria (i.e. visible vasculature) that, in general, appear to have a higher chance to transform into melanoma. However, owing to the cumulative nature of oncogenic mutations in melanoma, a more fine-grained early morphologic footprint is likely to be detectable by an algorithm. In this perspective article, the concept of melanoma prediction is further explored by the discussion of the evolution of melanoma, the concept for training of such a nevi classifier and the implications of early melanoma prediction for clinical practice. In conclusion, the authors believe that artificial intelligence trained on prospective image data could be transformative for skin cancer diagnostics by (a) predicting melanoma before it occurs (i.e. pre-in situ) and (b) further enhancing the accuracy of current melanoma classifiers. Necessary prospective images for this research are obtained via free mole-monitoring mobile apps.}, language = {en} } @article{ChenLuChenetal.2017, author = {Chen, Wei-Hua and Lu, Guanting and Chen, Xiao and Zhao, Xing-Ming and Bork, Peer}, title = {OGEE v2: an update of the online gene essentiality database with special focus on differentially essential genes in human cancer cell lines}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkw1013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181334}, pages = {D940-D944}, year = {2017}, abstract = {OGEE is an Online GEne Essentiality database. To enhance our understanding of the essentiality of genes, in OGEE we collected experimentally tested essential and non-essential genes, as well as associated gene properties known to contribute to gene essentiality. We focus on large-scale experiments, and complement our data with text-mining results. We organized tested genes into data sets according to their sources, and tagged those with variable essentiality statuses across data sets as conditionally essential genes, intending to highlight the complex interplay between gene functions and environments/experimental perturbations. Developments since the last public release include increased number of species and gene essentiality data sets, inclusion of non-coding essential sequences and genes with intermediate essentiality statuses. In addition, we included 16 essentiality data sets from cancer cell lines, corresponding to 9 human cancers; with OGEE, users can easily explore the shared and differentially essential genes within and between cancer types. These genes, especially those derived from cell lines that are similar to tumor samples, could reveal the oncogenic drivers, paralogous gene expression pattern and chromosomal structure of the corresponding cancer types, and can be further screened to identify targets for cancer therapy and/or new drug development. OGEE is freely available at http://ogee.medgenius.info.}, language = {en} } @article{GarainShoyamaGinderetal.2024, author = {Garain, Swadhin and Shoyama, Kazutaka and Ginder, Lea-Marleen and S{\´a}rosi, Menyh{\´a}rt and W{\"u}rthner, Frank}, title = {The delayed box: biphenyl bisimide cyclophane, a supramolecular nano-environment for the efficient generation of delayed fluorescence}, series = {Journal of the American Chemical Society}, volume = {146}, journal = {Journal of the American Chemical Society}, number = {31}, issn = {0002-7863}, doi = {10.1021/jacs.4c07730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370385}, pages = {22056-22063}, year = {2024}, abstract = {Activating delayed fluorescence emission in a dilute solution via a non-covalent approach is a formidable challenge. In this report, we propose a strategy for efficient delayed fluorescence generation in dilute solution using a non-covalent approach via supramolecularly engineered cyclophane-based nanoenvironments that provide sufficient binding strength to π-conjugated guests and that can stabilize triplet excitons by reducing vibrational dissipation and lowering the singlet-triplet energy gap for efficient delayed fluorescence emission. Toward this goal, a novel biphenyl bisimide-derived cyclophane is introduced as an electron-deficient and efficient triplet-generating host. Upon encapsulation of various carbazole-derived guests inside the nanocavity of this cyclophane, emissive charge transfer (CT) states close to the triplet energy level of the biphenyl bisimide are generated. The experimental results of host-guest studies manifest high association constants up to 10\(^4\) M\(^{-1}\) as the prerequisite for inclusion complex formation, the generation of emissive CT states, and triplet-state stabilization in a diluted solution state. By means of different carbazole guest molecules, we could realize tunable delayed fluorescence emission in this carbazole-encapsulated biphenyl bisimide cyclophane in methylcyclohexane/carbon tetrachloride solutions with a quantum yield (QY) of up to 15.6\%. Crystal structure analyses and solid-state photophysical studies validate the conclusions from our solution studies and provide insights into the delayed fluorescence emission mechanism.}, language = {en} } @article{BrinkerHeklerEnketal.2019, author = {Brinker, Titus J. and Hekler, Achim and Enk, Alexander H. and Berking, Carola and Haferkamp, Sebastian and Hauschild, Axel and Weichenthal, Michael and Klode, Joachim and Schadendorf, Dirk and Holland-Letz, Tim and von Kalle, Christof and Fr{\"o}hling, Stefan and Schilling, Bastian and Utikal, Jochen S.}, title = {Deep neural networks are superior to dermatologists in melanoma image classification}, series = {European Journal of Cancer}, volume = {119}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2019.05.023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220539}, pages = {11-17}, year = {2019}, abstract = {Background Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date. Methods For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes. Findings The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2\% (95\% confidence interval [CI]: 62.6\%-71.7\%) and 62.2\% (95\% CI: 57.6\%-66.9\%). In comparison, the trained CNN achieved a higher sensitivity of 82.3\% (95\% CI: 78.3\%-85.7\%) and a higher specificity of 77.9\% (95\% CI: 73.8\%-81.8\%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups. Interpretation For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001).}, language = {en} } @article{BrinkerHeklerHauschildetal.2019, author = {Brinker, Titus J. and Hekler, Achim and Hauschild, Axel and Berking, Carola and Schilling, Bastian and Enk, Alexander H. and Haferkamp, Sebastian and Karoglan, Ante and von Kalle, Christof and Weichenthal, Michael and Sattler, Elke and Schadendorf, Dirk and Gaiser, Maria R. and Klode, Joachim and Utikal, Jochen S.}, title = {Comparing artificial intelligence algorithms to 157 German dermatologists: the melanoma classification benchmark}, series = {European Journal of Cancer}, volume = {111}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2018.12.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220569}, pages = {30-37}, year = {2019}, abstract = {Background Several recent publications have demonstrated the use of convolutional neural networks to classify images of melanoma at par with board-certified dermatologists. However, the non-availability of a public human benchmark restricts the comparability of the performance of these algorithms and thereby the technical progress in this field. Methods An electronic questionnaire was sent to dermatologists at 12 German university hospitals. Each questionnaire comprised 100 dermoscopic and 100 clinical images (80 nevi images and 20 biopsy-verified melanoma images, each), all open-source. The questionnaire recorded factors such as the years of experience in dermatology, performed skin checks, age, sex and the rank within the university hospital or the status as resident physician. For each image, the dermatologists were asked to provide a management decision (treat/biopsy lesion or reassure the patient). Main outcome measures were sensitivity, specificity and the receiver operating characteristics (ROC). Results Total 157 dermatologists assessed all 100 dermoscopic images with an overall sensitivity of 74.1\%, specificity of 60.0\% and an ROC of 0.67 (range = 0.538-0.769); 145 dermatologists assessed all 100 clinical images with an overall sensitivity of 89.4\%, specificity of 64.4\% and an ROC of 0.769 (range = 0.613-0.9). Results between test-sets were significantly different (P < 0.05) confirming the need for a standardised benchmark. Conclusions We present the first public melanoma classification benchmark for both non-dermoscopic and dermoscopic images for comparing artificial intelligence algorithms with diagnostic performance of 145 or 157 dermatologists. Melanoma Classification Benchmark should be considered as a reference standard for white-skinned Western populations in the field of binary algorithmic melanoma classification.}, language = {en} } @article{LinkPaouneskouVelkovaetal.2018, author = {Link, Jana and Paouneskou, Dimitra and Velkova, Maria and Daryabeigi, Anahita and Laos, Triin and Labella, Sara and Barroso, Consuelo and Pacheco Pi{\~n}ol, Sarai and Montoya, Alex and Kramer, Holger and Woglar, Alexander and Baudrimont, Antoine and Markert, Sebastian Mathias and Stigloher, Christian and Martinez-Perez, Enrique and Dammermann, Alexander and Alsheimer, Manfred and Zetka, Monique and Jantsch, Verena}, title = {Transient and Partial Nuclear Lamina Disruption Promotes Chromosome Movement in Early Meiotic Prophase}, series = {Developmental Cell}, volume = {45}, journal = {Developmental Cell}, doi = {10.1016/j.devcel.2018.03.018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236901}, pages = {212-225}, year = {2018}, abstract = {Meiotic chromosome movement is important for the pairwise alignment of homologous chromosomes, which is required for correct chromosome segregation. Movement is driven by cytoplasmic forces, transmitted to chromosome ends by nuclear membrane-spanning proteins. In animal cells, lamins form a prominent scaffold at the nuclear periphery, yet the role lamins play in meiotic chromosome movement is unclear. We show that chromosome movement correlates with reduced lamin association with the nuclear rim, which requires lamin phosphorylation at sites analogous to those that open lamina network crosslinks in mitosis. Failure to remodel the lamina results in delayed meiotic entry, altered chromatin organization, unpaired or interlocked chromosomes, and slowed chromosome movement. The remodeling kinases are delivered to lamins via chromosome ends coupled to the nuclear envelope, potentially enabling crosstalk between the lamina and chromosomal events. Thus, opening the lamina network plays a role in modulating contacts between chromosomes and the nuclear periphery during meiosis.}, language = {en} } @article{TesfamariamJakobWoeckeletal.2019, author = {Tesfamariam, Y. and Jakob, T. and W{\"o}ckel, A. and Adams, A. and Weigl, A. and Monsef, I. and Kuhr, K. and Skoetz, N.}, title = {Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: A systematic review and network meta-analysis}, series = {Critical Reviews in Oncology / Hematology}, volume = {137}, journal = {Critical Reviews in Oncology / Hematology}, doi = {10.1016/j.critrevonc.2019.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240827}, pages = {1-8}, year = {2019}, abstract = {Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95\%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95\%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95\%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.}, language = {en} } @article{MooijvanWijkBeusenetal.2019, author = {Mooij, Wolf M and van Wijk, Dianneke and Beusen, Arthur HW and Brederveld, Robert J and Chang, Manqi and Cobben, Marleen MP and DeAngelis, Don L and Downing, Andrea S and Green, Pamela and Gsell, Alena S and Huttunen, Inese and Janse, Jan H and Janssen, Annette BG and Hengeveld, Geerten M and Kong, Xiangzhen and Kramer, Lilith and Kuiper, Jan J and Langan, Simon J and Nolet, Bart A and Nuijten, Rascha JM and Strokal, Maryna and Troost, Tineke A and van Dam, Anne A and Teurlincx, Sven}, title = {Modeling water quality in the Anthropocene: directions for the next-generation aquatic ecosystem models}, series = {Current Opinion in Environmental Sustainability}, volume = {36}, journal = {Current Opinion in Environmental Sustainability}, doi = {10.1016/j.cosust.2018.10.012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224173}, pages = {85-95}, year = {2019}, abstract = {"Everything changes and nothing stands still" (Heraclitus). Here we review three major improvements to freshwater aquatic ecosystem models — and ecological models in general — as water quality scenario analysis tools towards a sustainable future. To tackle the rapid and deeply connected dynamics characteristic of the Anthropocene, we argue for the inclusion of eco-evolutionary, novel ecosystem and social-ecological dynamics. These dynamics arise from adaptive responses in organisms and ecosystems to global environmental change and act at different integration levels and different time scales. We provide reasons and means to incorporate each improvement into aquatic ecosystem models. Throughout this study we refer to Lake Victoria as a microcosm of the evolving novel social-ecological systems of the Anthropocene. The Lake Victoria case clearly shows how interlinked eco-evolutionary, novel ecosystem and social-ecological dynamics are, and demonstrates the need for transdisciplinary research approaches towards global sustainability.}, language = {en} } @article{KieferTrumppSchaitzetal.2019, author = {Kiefer, Markus and Trumpp, Natalie M. and Schaitz, Caroline and Reuss, Heiko and Kunde, Wilfried}, title = {Attentional modulation of masked semantic priming by visible and masked task cues}, series = {Cognition}, volume = {187}, journal = {Cognition}, doi = {10.1016/j.cognition.2019.02.013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325751}, pages = {62-77}, year = {2019}, abstract = {In contrast to classical theories of cognitive control, recent evidence suggests that cognitive control and unconscious automatic processing influence each other. First, masked semantic priming, an index of unconscious automatic processing, depends on attention to semantics induced by a previously executed task. Second, cognitive control operations (e.g., implementation of task sets indicating how to process a particular stimulus) can be activated by masked task cues, presented outside awareness. In this study, we combined both lines of research. We investigated in three experiments whether induction tasks and presentation of visible or masked task cues, which signal subsequent semantic or perceptual tasks but do not require induction task execution, comparably modulate masked semantic priming. In line with previous research, priming was consistently larger following execution of a semantic rather than a perceptual induction task. However, we observed in experiment 1 (masked letter cues) a reversed priming pattern following task cues (larger priming following cues signaling perceptual tasks) compared to induction tasks. Experiment 2 (visible letter cues) and experiment 3 (visible color cues) showed that this reversed priming pattern depended only on apriori associations between task cues and task elements (task set dominance), but neither on awareness nor on the verbal or non-verbal format of the cues. These results indicate that task cues have the power to modulate subsequent masked semantic priming through attentional mechanisms. Task-set dominance conceivably affects the time course of task set activation and inhibition in response to task cues and thus the direction of their modulatory effects on priming.}, language = {en} } @article{GerberKoenigFendtetal.2019, author = {Gerber, Bertram and K{\"o}nig, Christian and Fendt, Markus and Andreatta, Marta and Romanos, Marcel and Pauli, Paul and Yarali, Ayse}, title = {Timing-dependent valence reversal: a principle of reinforcement processing and its possible implications}, series = {Current Opinion in Behavioral Sciences}, volume = {26}, journal = {Current Opinion in Behavioral Sciences}, doi = {10.1016/j.cobeha.2018.12.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232933}, pages = {114-120}, year = {2019}, abstract = {Punishment feels bad, but relief upon its termination feels good. As a consequence of such timing-dependent valence reversal, memories of opposite valence can result from associating stimulus A with, for example, the occurrence of punishment (A-) versus punishment termination (-A): A- training results in aversive memory, but -A training in appetitive memory (corresponding effects exist for reward occurrence and termination). Whereas learning through the occurrence of punishment is well studied, much less is known about learning through its termination. Current research investigates how dopaminergic system function contributes to these processes in Drosophila, rats and humans. We argue that dopamine-related psychopathology may entail distortions in learning through punishment termination, and that this may contribute, for example, to non-suicidal self-injury or post-traumatic stress disorder.}, language = {en} } @article{ColungaHayworthKressetal.2019, author = {Colunga, Thomas and Hayworth, Miranda and Kreß, Sebastian and Reynolds, David M. and Chen, Luoman and Nazor, Kristopher L. and Baur, Johannes and Singh, Amar M. and Loring, Jeanne F. and Metzger, Marco and Dalton, Stephen}, title = {Human Pluripotent Stem Cell-Derived Multipotent Vascular Progenitors of the Mesothelium Lineage Have Utility in Tissue Engineering and Repair}, series = {Cell Reports}, volume = {26}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2019.02.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223217}, pages = {2566-2579}, year = {2019}, abstract = {In this report we describe a human pluripotent stem cell-derived vascular progenitor (MesoT) cell of the mesothelium lineage. MesoT cells are multipotent and generate smooth muscle cells, endothelial cells, and pericytes and self-assemble into vessel-like networks in vitro. MesoT cells transplanted into mechanically damaged neonatal mouse heart migrate into the injured tissue and contribute to nascent coronary vessels in the repair zone. When seeded onto decellularized vascular scaffolds, MesoT cells differentiate into the major vascular lineages and self-assemble into vasculature capable of supporting peripheral blood flow following transplantation. These findings demonstrate in vivo functionality and the potential utility of MesoT cells in vascular engineering applications.}, language = {en} } @article{ChhatbarDetjeGrabskietal.2018, author = {Chhatbar, Chintan and Detje, Claudia N. and Grabski, Elena and Borst, Katharina and Spanier, Julia and Ghita, Luca and Elliott, David A. and Jord{\~a}o, Marta Joana Costa and Mueller, Nora and Sutton, James and Prajeeth, Chittappen K. and Gudi, Viktoria and Klein, Michael A. and Prinz, Marco and Bradke, Frank and Stangel, Martin and Kalinke, Ulrich}, title = {Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis}, series = {Cell Reports}, volume = {25}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2018.09.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222456}, pages = {118-129}, year = {2018}, abstract = {In sterile neuroinflammation, a pathological role is proposed for microglia, whereas in viral encephalitis, their function is not entirely clear. Many viruses exploit the odorant system and enter the CNS via the olfactory bulb (OB). Upon intranasal vesicular stomatitis virus instillation, we show an accumulation of activated microglia and monocytes in the OB. Depletion of microglia during encephalitis results in enhanced virus spread and increased lethality. Activation, proliferation, and accumulation of microglia are regulated by type I IFN receptor signaling of neurons and astrocytes, but not of microglia. Morphological analysis of myeloid cells shows that type I IFN receptor signaling of neurons has a stronger impact on the activation of myeloid cells than of astrocytes. Thus, in the infected CNS, the cross talk among neurons, astrocytes, and microglia is critical for full microglia activation and protection from lethal encephalitis.}, language = {en} } @article{KuschBornscheinLorethetal.2018, author = {Kusch, Valentin and Bornschein, Grit and Loreth, Desiree and Bank, Julia and Jordan, Johannes and Baur, David and Watanabe, Masahiko and Kulik, Akos and Heckmann, Manfred and Eilers, Jens and Schmidt, Hartmut}, title = {Munc13-3 Is Required for the Developmental Localization of Ca2+ Channels to Active Zones and the Nanopositioning of Cav2.1 Near Release Sensors}, series = {Cell Reports}, volume = {22}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2018.02.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233468}, pages = {1965-1973}, year = {2018}, abstract = {Spatial relationships between Cav channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Cav2.1 and Cav2.2 channels, alters the localization of Cav2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+-channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling. We found that a normally occurring developmental shift from release being dominated by Ca2+ influx through Cav2.1 and Cav2.2 channels with domain overlap and loose coupling (microdomains) to a nanodomain Cav2.1 to sensor coupling is impaired in Munc13-3-deficient synapses. Thus, at AZs lacking Munc13-3, release remained triggered by Cav2.1 and Cav2.2 microdomains, suggesting a critical role of Munc13-3 in the formation of release sites with calcium channel nanodomains.}, language = {en} } @article{BecherAndresPonsRomanovetal.2018, author = {Becher, Isabelle and Andr{\´e}s-Pons, Amparo and Romanov, Natalie and Stein, Frank and Schramm, Maike and Baudin, Florence and Helm, Dominic and Kurzawa, Nils and Mateus, Andr{\´e} and Mackmull, Marie-Therese and Typas, Athanasios and M{\"u}ller, Christoph W. and Bork, Peer and Beck, Martin and Savitski, Mikhail M.}, title = {Pervasive Protein Thermal Stability Variation during the Cell Cycle}, series = {Cell}, volume = {173}, journal = {Cell}, doi = {10.1016/j.cell.2018.03.053}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221565}, pages = {1495-1507}, year = {2018}, abstract = {Quantitative mass spectrometry has established proteome-wide regulation of protein abundance and post-translational modifications in various biological processes. Here, we used quantitative mass spectrometry to systematically analyze the thermal stability and solubility of proteins on a proteome-wide scale during the eukaryotic cell cycle. We demonstrate pervasive variation of these biophysical parameters with most changes occurring in mitosis and G1. Various cellular pathways and components vary in thermal stability, such as cell-cycle factors, polymerases, and chromatin remodelers. We demonstrate that protein thermal stability serves as a proxy for enzyme activity, DNA binding, and complex formation in situ. Strikingly, a large cohort of intrinsically disordered and mitotically phosphorylated proteins is stabilized and solubilized in mitosis, suggesting a fundamental remodeling of the biophysical environment of the mitotic cell. Our data represent a rich resource for cell, structural, and systems biologists interested in proteome regulation during biological transitions.}, language = {en} } @article{FazeliStetterLisacketal.2018, author = {Fazeli, Gholamreza and Stetter, Maurice and Lisack, Jaime N. and Wehman, Ann M.}, title = {C. elegans Blastomeres Clear the Corpse of the Second Polar Body by LC3-Associated Phagocytosis}, series = {Cell Reports}, volume = {23}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2018.04.043}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227651}, pages = {2070-2082}, year = {2018}, abstract = {To understand how undifferentiated pluripotent cells cope with cell corpses, we examined the clearance of polar bodies born during female meiosis. We found that polar bodies lose membrane integrity and expose phosphatidylserine in Caenorhabditis elegans. Polar body signaling recruits engulfment receptors to the plasma membrane of embryonic blastomeres using the PI3K VPS-34, RAB-5 GTPase and the sorting nexin SNX-6. The second polar body is then phagocytosed using receptor-mediated engulfment pathways dependent on the Rac1 ortholog CED-10 but undergoes non-apoptotic programmed cell death independent of engulfment. RAB-7 GTPase is required for lysosome recruitment to the polar body phagosome, while LC3 lipidation is required for degradation of the corpse membrane after lysosome fusion. The polar body phagolysosome vesiculates in an mTOR- and ARL-8-dependent manner, which assists its timely degradation. Thus, we established a genetic model to study clearance by LC3-associated phagocytosis and reveal insights into the mechanisms of phagosome maturation and degradation.}, language = {en} } @article{LieseSchoenvanderLindenetal.2019, author = {Liese, J. G. and Schoen, C. and van der Linden, M. and Lehmann, L. and Goettler, D. and Keller, S. and Maier, A. and Segerer, F. and Rose, M. A. and Streng, A.}, title = {Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study}, series = {Clinical Microbiology and Infection}, volume = {25}, journal = {Clinical Microbiology and Infection}, doi = {10.1016/j.cmi.2018.10.020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236866}, pages = {857-864}, year = {2019}, abstract = {Objectives Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants. Methods Children <18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting >7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae. Results The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34\%), 541 bacteria (>40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87\%); these were most frequently Streptococcus pneumoniae (41\%), Streptococcus pyogenes (19\%) and Staphylococcus aureus (6\%). Serotype 3 accounted for 45\% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95\%CI 12-16) and 18 (95\%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95\%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95\%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95\%CI 1.5-3.2) by 2016/17 (p 0.205). Conclusions In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance.}, language = {en} } @article{EisenhoferPeitzschKadenetal.2019, author = {Eisenhofer, Graeme and Peitzsch, Mirko and Kaden, Denise and Langton, Katharina and Mangelis, Anastasios and Pamporaki, Christina and Masjkur, Jimmy and Geroula, Aikaterini and Kurlbaum, Max and Deutschbein, Timo and Beuschlein, Felix and Prejbisz, Aleksander and Bornstein, Stefan R. and Lenders, Jacques W. M.}, title = {Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine}, series = {Clinica Chimica Acta}, volume = {490}, journal = {Clinica Chimica Acta}, doi = {10.1016/j.cca.2018.12.019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226598}, pages = {46-54}, year = {2019}, abstract = {Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites.}, language = {en} } @article{CasarottoTurcoComanduccietal.2019, author = {Casarotto, Silvia and Turco, Francesco and Comanducci, Angela and Perretti, Alessio and Marotta, Giorgio and Pezzoli, Gianni and Rosanova, Mario and Isaias, Ioannis U.}, title = {Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage}, series = {Brain Stimulation}, volume = {12}, journal = {Brain Stimulation}, doi = {10.1016/j.brs.2018.10.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222261}, pages = {152-160}, year = {2019}, abstract = {Background Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). Objective We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. Methods In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. Results We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. Conclusions These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.}, language = {en} } @article{BarkhuizenvanMechelenVermeeretal.2019, author = {Barkhuizen, Melinda and van Mechelen, Ralph and Vermeer, Marijne and Chedraui, Peter and Paes, Dean and van den Hove, Daniel L. A. and Vaes, Bart and Mays, Robert W. and Steinbusch, Harry W. M. and Robertson, Nicola J. and Kramer, Boris W. and Gavilanes, Antonio W. D.}, title = {Systemic multipotent adult progenitor cells improve long-term neurodevelopmental outcomes after preterm hypoxic-ischemic encephalopathy}, series = {Behavioural Brain Research}, volume = {362}, journal = {Behavioural Brain Research}, doi = {10.1016/j.bbr.2019.01.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221506}, pages = {77-81}, year = {2019}, abstract = {There is an urgent need for therapies that could reduce the disease burden of preterm hypoxic-ischemic encephalopathy. Here, we evaluate the long-term effects of multipotent adult progenitor cells (MAPC) on long-term behavioral outcomes in a preterm rat model of perinatal asphyxia. Rats of both sexes were treated with two doses of MAPCs within 24 h after the insult. Locomotor, cognitive and psychiatric impairments were evaluated starting at 1.5 (juvenile) and 6 months (adult). Hypoxia-ischemia affected locomotion, cognition, and anxiety in a sex-dependent manner, with higher vulnerability observed in males. The MAPC therapy partially attenuated deficits in object recognition memory in females of all tested ages, and in the adult males. The hypoxic insult caused delayed hyperactivity in adult males, which was corrected by MAPC therapy. These results suggest that MAPCs may have long-term benefits for neurodevelopmental outcome after preterm birth and global hypoxia-ischemia, which warrants further preclinical exploration.}, language = {en} } @article{SteinKantarjianGoekbugetetal.2019, author = {Stein, Anthony S. and Kantarjian, Hagop and G{\"o}kbuget, Nicola and Bargou, Ralf and Litzow, Mark R. and Rambaldi, Alessandro and Ribera, Josep-Maria and Zhang, Alicia and Zimmerman, Zachary and Zugmaier, Gerhard and Topp, Max S.}, title = {Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation}, series = {Biology of Blood and Marrow Transplantation}, volume = {25}, journal = {Biology of Blood and Marrow Transplantation}, doi = {10.1016/j.bbmt.2019.04.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239510}, pages = {1498-1504}, year = {2019}, abstract = {Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43\% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36\% at 1 year and 18\% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31\%) and 28 patients (44\%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.}, language = {en} } @article{Gohla2019, author = {Gohla, Antje}, title = {Do metabolic HAD phosphatases moonlight as protein phosphatases?}, series = {BBA - Molecular Cell Research}, volume = {1866}, journal = {BBA - Molecular Cell Research}, doi = {10.1016/j.bbamcr.2018.07.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233168}, pages = {153-166}, year = {2019}, abstract = {Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.}, language = {en} } @article{JeanclosAlbersenRamosetal.2019, author = {Jeanclos, Elisabeth and Albersen, Monique and Ramos, R{\´u}ben J. J. and Raab, Annette and Wilhelm, Christian and Hommers, Leif and Lesch, Klaus-Peter and Verhoeven-Duif, Nanda M. and Gohla, Antje}, title = {Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice}, series = {BBA - Molecular Basis of Disease}, volume = {1865}, journal = {BBA - Molecular Basis of Disease}, doi = {10.1016/j.bbadis.2018.08.018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323396}, pages = {193-205}, year = {2019}, abstract = {Pyridoxal 5′-phosphate (PLP) is an essential cofactor in the catalysis of ~140 different enzymatic reactions. A pharmacological elevation of cellular PLP concentrations is of interest in neuropsychiatric diseases, but whole-body consequences of higher intracellular PLP levels are unknown. To address this question, we have generated mice allowing a conditional ablation of the PLP phosphatase PDXP. Ubiquitous PDXP deletion increased PLP levels in brain, skeletal muscle and red blood cells up to 3-fold compared to control mice, demonstrating that PDXP acts as a major regulator of cellular PLP concentrations in vivo. Neurotransmitter analysis revealed that the concentrations of dopamine, serotonin, epinephrine and glutamate were unchanged in the brains of PDXP knockout mice. However, the levels of γ-aminobutyric acid (GABA) increased by ~20\%, demonstrating that elevated PLP levels can drive additional GABA production. Behavioral phenotyping of PDXP knockout mice revealed improved spatial learning and memory, and a mild anxiety-like behavior. Consistent with elevated GABA levels in the brain, PDXP loss in neural cells decreased performance in motor tests, whereas PDXP-deficiency in skeletal muscle increased grip strength. Our findings suggest that PDXP is involved in the fine-tuning of GABA biosynthesis. Pharmacological inhibition of PDXP might correct the excitatory/inhibitory imbalance in some neuropsychiatric diseases.}, language = {en} } @article{HochleitnerChenBlumetal.2018, author = {Hochleitner, Gernot and Chen, Fei and Blum, Carina and Dalton, Paul D. and Amsden, Brian and Groll, J{\"u}rgen}, title = {Melt electrowriting below the critical translation speed to fabricate crimped elastomer scaffolds with non-linear extension behaviour mimicking that of ligaments and tendons}, series = {Acta Biomaterialia}, volume = {72}, journal = {Acta Biomaterialia}, doi = {10.1016/j.actbio.2018.03.023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320846}, pages = {110-120}, year = {2018}, abstract = {Abstract Ligaments and tendons are comprised of aligned, crimped collagen fibrils that provide tissue-specific mechanical properties with non-linear extension behaviour, exhibiting low stress at initial strain (toe region behaviour). To approximate this behaviour, we report fibrous scaffolds with sinusoidal patterns by melt electrowriting (MEW) below the critical translation speed (CTS) by exploitation of the natural flow behaviour of the polymer melt. More specifically, we synthesised photopolymerizable poly(L-lactide-co-ε-caprolactone-co-acryloyl carbonate) (p(LLA-co-ε-CL-co-AC)) and poly(ε-caprolactone-co-acryloyl carbonate) (p(ε-CL-co-AC)) by ring-opening polymerization (ROP). Single fibre (f{\O} = 26.8 ± 1.9 µm) tensile testing revealed a customisable toe region with Young's Moduli ranging from E = 29 ± 17 MPa for the most crimped structures to E = 314 ± 157 MPa for straight fibres. This toe region extended to scaffolds containing multiple fibres, while the sinusoidal pattern could be influenced by printing speed. The synthesized polymers were cytocompatible and exhibited a tensile strength of σ = 26 ± 7 MPa after 104 cycles of preloading at 10\% strain while retaining the distinct toe region commonly observed in native ligaments and tendon tissue. Statement of Significance Damaged tendons and ligaments are serious and frequently occurring injuries worldwide. Recent therapies, including autologous grafts, still have severe disadvantages leading to a demand for synthetic alternatives. Materials envisioned to induce tendon and ligament regeneration should be degradable, cytocompatible and mimic the ultrastructural and mechanical properties of the native tissue. Specifically, we utilised photo-cross-linkable polymers for additive manufacturing (AM) with MEW. In this way, we were able to direct-write cytocompatible fibres of a few micrometres thickness into crimp-structured elastomer scaffolds that mimic the non-linear biomechanical behaviour of tendon and ligament tissue.}, language = {en} } @phdthesis{Zhu2024, author = {Zhu, Yan}, title = {Small RNA-associated RNA-binding proteins in \(Fusobacterium\) \(nucleatum\)}, doi = {10.25972/OPUS-37073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370731}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Fusobacterium nucleatum is an emerging cancer-associated bacterium belonging to the Fusobacteriota phylum, which is evolutionary distant from all model bacteria. Recent analysis generated global fusobacterial RNA maps, which enabled the discovery of 24 small noncoding RNAs (sRNAs) in F. nucleatum. Notably, the σE-dependent sRNA FoxI and FoxJ act as a posttranscriptional regulator of several cell envelope proteins. The σE-dependent sRNAs in Escherichia coli and Salmonella require the RNA chaperone Hfq for their functions. Intriguingly, F. nucleatum seems to have no homologs of the three common RNA-binding proteins (RBPs) CsrA, Hfq and ProQ. However, it remains unclear if other families of RBPs act in concert with FoxI, FoxJ and other fusobacterial sRNAs. This work has successfully established a 14-mer capture tagged-sRNA affinity purification procedure initially using 6S RNA as a proof-of-concept. Applying this method to 19 different F. nucleatum sRNAs led to a comprehensive mapping of sRNA-binding proteins in this bacterium. This screen identified a total of 75 proteins significantly enriched across all sRNAs and prominent in ribosomal proteins, uncharacterized proteins and enzymes associated with metabolism. This work further focused on the homologs of two KH domain proteins KhpA and KhpB, which were recently recognized as global RBPs in various Gram-positive bacteria such as Streptococcus pneumoniae, Clostridioides difficile, and Enterococcus faecalis. Comparative analyses revealed conserved domain composition and gene synteny of KhpA and KhpB across F. nucleatum, S. pneumoniae, C. difficle and E. faecalis, indicating conserved roles of these proteins in bacteria. Further protein-protein interaction assays and global RNA targets profiling demonstrated that KhpA and KhpB form dimers and act together as broad RBPs, binding to sRNAs, mRNAs and tRNAs in F. nucleatum. Further functional characterizations unveiled that KhpA/B are required for the growth of F. nucleatum under nutrient limitation conditions and impact cell morphology. Additionally, the two RBPs also influence global gene expression in F. nucleatum affecting various bacterial physiological processes, including ethanolamine utilization. In summary, this work established a sRNA-centric approach for screening sRNA-binding proteins in F. nucleatum. Further, the assay could be applied in other non-model organisms and is feasible to screen multiple sRNA baits in parallel for sRNA-interactors. By applying this procedure to nearly all known fusobacterial sRNAs, this work generated an extensive map of sRNA-interacting proteins in F. nucleatum. Molecular and genetic studies identified that KhpA/B act as major RBPs and gene regulators in F. nucleatum, representing important first steps in elucidating key players of post-transcriptional control at the root of the bacterial phylogenetic tree.}, subject = {Proteine}, language = {en} } @article{OPUS4-37080, title = {Interview mit Prof. Dr. Marina Ortrud Hertrampf}, series = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, volume = {9}, journal = {promptus - W{\"u}rzburger Beitr{\"a}ge zur Romanistik}, editor = {Hesselbach, Robert}, issn = {2510-2613}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370808}, pages = {7-13}, year = {2023}, abstract = {Interview mit Prof. Dr. Marina Ortrud Hertrampf}, language = {de} }