TY - JOUR T1 - Dijet azimuthal correlations and conditional yields in \({pp}\) and \(p\) + Pb collisions at √S-NN=5.02 TeV with the ATLAS detector JF - Physical Review C N2 - This paper presents a measurement of forward-forward and forward-central dijet azimuthal angular correlations and conditional yields in proton-proton (pp) and proton-lead (p + Pb) collisions as a probe of the nuclear gluon density in regions where the fraction of the average momentum per nucleon carried by the parton entering the hard scattering is low. In these regions, gluon saturation can modify the rapidly increasing parton distribution function of the gluon. The analysis utilizes 25 pb(-1) of pp data and 360 mu b(-1) of p + Pb data, both at root S-NN = 5.02 TeV, collected in 2015 and 2016, respectively, with the ATLAS detector at the Large Hadron Collider. The measurement is performed in the center-of-mass frame of the nucleon-nucleon system in the rapidity range between -4.0 and 4.0 using the two highest transverse-momentum jets in each event, with the highest transverse-momentum jet restricted to the forward rapidity range. No significant broadening of azimuthal angular correlations is observed for forward-forward or forward-central dijets in p + Pb compared to pp collisions. For forward-forward jet pairs in the proton-going direction, the ratio of conditional yields in p + Pb collisions to those in pp collisions is suppressed by approximately 20%, with no significant dependence on the transverse momentum of the dijet system. No modification of conditional yields is observed for forward-central dijets. KW - Nuclear Modification KW - Cross-Sections KW - Jet Prodution KW - Proton-Lead KW - Saturation KW - Rapidity KW - Hard scattering KW - Particle correlations & fluctuations KW - Quark & gluon jets KW - Relativistic heavy-ion collisions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313823 VL - 100 IS - 3 ER - TY - JOUR A1 - Müller, Jörg A1 - Noss, Reed F. A1 - Thorn, Simon A1 - Bässler, Claus A1 - Leverkus, Alexandro B. A1 - Lindenmayer, David T1 - Increasing disturbance demands new policies to conserve intact forest JF - Conservation Letters N2 - Ongoing controversy over logging the ancient Białowieża Forest in Poland symbolizes a global problem for policies and management of the increasing proportion of the earth's intact forest that is subject to postdisturbance logging. We review the extent of, and motivations for, postdisturbance logging in protected and unprotected forests globally. An unprecedented level of logging in protected areas and other places where green-tree harvest would not normally occur is driven by economic interests and a desire for pest control. To avoid failure of global initiatives dedicated to reducing the loss of species, five key policy reforms are necessary: (1) salvage logging must be banned from protected areas; (2) forest planning should address altered disturbance regimes for all intact forests to ensure that significant areas remain undisturbed by logging; (3) new kinds of integrated analyses are needed to assess the potential economic benefits of salvage logging against its ecological, economic, and social costs; (4) global and regional maps of natural disturbance regimes should be created to guide better spatiotemporal planning of protected areas and undisturbed forests outside reserves; and (5) improved education and communication programs are needed to correct widely held misconceptions about natural disturbances. KW - anthropogenic disturbance KW - forestry KW - FSC KW - natural disturbance KW - protected area management KW - sanitary logging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224256 VL - 12 ER - TY - JOUR A1 - Ingendoh-Tsakmakidis, Alexandra A1 - Mikolai, Carina A1 - Winkel, Andreas A1 - Szafrański, Szymon P. A1 - Flak, Christine S. A1 - Rossi, Angela A1 - Walles, Heike A1 - Stiesch, Meike T1 - Commensal and pathogenic biofilms differently modulate peri-implant oral mucosa in an organotypic model JF - Cellular Microbiology N2 - The impact of oral commensal and pathogenic bacteria on peri-implant mucosa is not well understood, despite the high prevalence of peri-implant infections. Hence, we investigated responses of the peri-implant mucosa to Streptococcus oralis or Aggregatibacter actinomycetemcomitans biofilms using a novel in vitro peri-implant mucosa-biofilm model. Our 3D model combined three components, organotypic oral mucosa, implant material, and oral biofilm, with structural assembly close to native situation. S. oralis induced a protective stress response in the peri-implant mucosa through upregulation of heat shock protein (HSP70) genes. Attenuated inflammatory response was indicated by reduced cytokine levels of interleukin-6 (IL-6), interleukin-8 (CXCL8), and monocyte chemoattractant protein-1 (CCL2). The inflammatory balance was preserved through increased levels of tumor necrosis factor-alpha (TNF-α). A. actinomycetemcomitans induced downregulation of genes important for cell survival and host inflammatory response. The reduced cytokine levels of chemokine ligand 1 (CXCL1), CXCL8, and CCL2 also indicated a diminished inflammatory response. The induced immune balance by S. oralis may support oral health, whereas the reduced inflammatory response to A. actinomycetemcomitans may provide colonisation advantage and facilitate later tissue invasion. The comprehensive characterisation of peri-implant mucosa-biofilm interactions using our 3D model can provide new knowledge to improve strategies for prevention and therapy of peri-implant disease. KW - Aggregatibacter actinomycetemcomitans KW - dental implants KW - host modulation KW - organotypic oral mucosa KW - Streptococcus oralis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323077 VL - 21 ER - TY - JOUR A1 - Van Assche, Nele A1 - Fickl, Stefan A1 - Francisco, Helena A1 - Gurzawska, Katarzyna A1 - Milinkovic, Iva A1 - Navarro, Jose M. A1 - Torsello, Ferruccio A1 - Thoma, Daniel S. T1 - Guidelines for development of Implant Dentistry in the next 10 years regarding innovation, education, certification, and associations JF - Clinical Oral Implants Research N2 - Background During the third Summer Camp of European Association of Osseointegration (EAO), 40 junior representatives from various European societies and associations were brought together to discuss and explore the following topics in Implant Dentistry in the next 10 years: (I) certification, (II) societies and associations, (III) continuing education, and (IV) innovations. Aims The aims of all working groups were to identify and outline the present situation in the area of the selected topic and to propose improvements and innovations to be implemented in the following 10 years. Materials and methods Four different groups were assigned randomly to one of the four working units. The method to discuss the selected topics was World Cafè. The summaries of four topics were then given to all participants for peer review. Results and conclusions All four groups presented the conclusions and guidelines accordingly: (I) The recognition for Implant Dentistry and accreditation of training programs would lead to an improvement of the quality of care to the benefit of the patients; (II) Dental associations and societies have to continuously improve communication to meet needs of dental students, professionals, and patients (III) European Dental Board should be installed and become responsible for continue dental education; (IV) dental engineering, peri-implant diseases, and digital workflow in dentistry currently have limited tools that do not guarantee predictable results. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232150 VL - 29 ER - TY - JOUR A1 - Zeiner, Pia S. A1 - Preusse, Corinna A1 - Golebiewska, Anna A1 - Zinke, Jenny A1 - Iriondo, Ane A1 - Muller, Arnaud A1 - Kaoma, Tony A1 - Filipski, Katharina A1 - Müller-Eschner, Monika A1 - Bernatz, Simon A1 - Blank, Anna-Eva A1 - Baumgarten, Peter A1 - Ilina, Elena A1 - Grote, Anne A1 - Hansmann, Martin L. A1 - Verhoff, Marcel A. A1 - Franz, Kea A1 - Feuerhake, Friedrich A1 - Steinbach, Joachim P. A1 - Wischhusen, Jörg A1 - Stenzel, Werner A1 - Niclou, Simone P. A1 - Harter, Patrick N. A1 - Mittelbronn, Michel T1 - Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas JF - Brain Pathology N2 - While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs. KW - glioma KW - glioma-associated microglia and macrophages; KW - immune polarization KW - tumor microenvironment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233897 VL - 29 ER - TY - JOUR A1 - Jandke, Solveig A1 - Garz, Cornelia A1 - Schwanke, Daniel A1 - Sendtner, Michael A1 - Heinze, Hans-Jochen A1 - Carare, Roxana O. A1 - Schreiber, Stefanie T1 - The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats JF - Brain Pathology N2 - We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17–44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain. KW - cerebral amyloid angiopathy KW - cerebral small vessel disease KW - hypertensive arteriopathy KW - intravital imaging KW - spontaneously hypertensive stroke-prone rat Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323279 VL - 28 ER - TY - JOUR A1 - Bahram, Mohammad A1 - Anslan, Sten A1 - Hildebrand, Falk A1 - Bork, Peer A1 - Tedersoo, Leho T1 - Newly designed 16S rRNA metabarcoding primers amplify diverse and novel archaeal taxa from the environment JF - Environmental Microbiology Reports N2 - High-throughput studies of microbial communities suggest that Archaea are a widespread component of microbial diversity in various ecosystems. However, proper quantification of archaeal diversity and community ecology remains limited, as sequence coverage of Archaea is usually low owing to the inability of available prokaryotic primers to efficiently amplify archaeal compared to bacterial rRNA genes. To improve identification and quantification of Archaea, we designed and validated the utility of several primer pairs to efficiently amplify archaeal 16S rRNA genes based on up-to-date reference genes. We demonstrate that several of these primer pairs amplify phylogenetically diverse Archaea with high sequencing coverage, outperforming commonly used primers. Based on comparing the resulting long 16S rRNA gene fragments with public databases from all habitats, we found several novel family- to phylum-level archaeal taxa from topsoil and surface water. Our results suggest that archaeal diversity has been largely overlooked due to the limitations of available primers, and that improved primer pairs enable to estimate archaeal diversity more accurately. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221380 VL - 11 ER - TY - JOUR A1 - Moll, Julia A1 - Kellner, Harald A1 - Leonhardt, Sabrina A1 - Stengel, Elisa A1 - Dahl, Andreas A1 - Bässler, Claus A1 - Buscot, François A1 - Hofrichter, Martin A1 - Hoppe, Björn T1 - Bacteria inhabiting deadwood of 13 tree species are heterogeneously distributed between sapwood and heartwood JF - Environmental Microbiology N2 - Deadwood represents an important structural component of forest ecosystems, where it provides diverse niches for saproxylic biota. Although wood-inhabiting prokaryotes are involved in its degradation, knowledge about their diversity and the drivers of community structure is scarce. To explore the effect of deadwood substrate on microbial distribution, the present study focuses on the microbial communities of deadwood logs from 13 different tree species investigated using an amplicon based deep-sequencing analysis. Sapwood and heartwood communities were analysed separately and linked to various relevant wood physico-chemical parameters. Overall, Proteobacteria, Acidobacteria and Actinobacteria represented the most dominant phyla. Microbial OTU richness and community structure differed significantly between tree species and between sapwood and heartwood. These differences were more pronounced for heartwood than for sapwood. The pH value and water content were the most important drivers in both wood compartments. Overall, investigating numerous tree species and two compartments provided a remarkably comprehensive view of microbial diversity in deadwood. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224168 VL - 20 ER - TY - JOUR A1 - Hilmers, Torben A1 - Friess, Nicolas A1 - Bässler, Claus A1 - Heurich, Marco A1 - Brandl, Roland A1 - Pretzsch, Hans A1 - Seidl, Rupert A1 - Müller, Jörg T1 - Biodiversity along temperate forest succession JF - Journal of Applied Ecology N2 - 1. The successional dynamics of forests—from canopy openings to regeneration, maturation, and decay—influence the amount and heterogeneity of resources available for forest-dwelling organisms. Conservation has largely focused only on selected stages of forest succession (e.g., late-seral stages). However, to develop comprehensive conservation strategies and to understand the impact of forest management on biodiversity, a quantitative understanding of how different trophic groups vary over the course of succession is needed. 2. We classified mixed mountain forests in Central Europe into nine successional stages using airborne LiDAR. We analysed α- and β-diversity of six trophic groups encompassing approximately 3,000 species from three kingdoms. We quantified the effect of successional stage on the number of species with and without controlling for species abundances and tested whether the data fit the more-individuals hypothesis or the habitat heterogeneity hypothesis. Furthermore, we analysed the similarity of assemblages along successional development. 3. The abundance of producers, first-order consumers, and saprotrophic species showed a U-shaped response to forest succession. The number of species of producer and consumer groups generally followed this U-shaped pattern. In contrast to our expectation, the number of saprotrophic species did not change along succession. When we controlled for the effect of abundance, the number of producer and saproxylic beetle species increased linearly with forest succession, whereas the U-shaped response of the number of consumer species persisted. The analysis of assemblages indicated a large contribution of succession-mediated β-diversity to regional γ-diversity. 4. Synthesis and applications. Depending on the species group, our data supported both the more-individuals hypothesis and the habitat heterogeneity hypothesis. Our results highlight the strong influence of forest succession on biodiversity and underline the importance of controlling for successional dynamics when assessing biodiversity change in response to external drivers such as climate change. The successional stages with highest diversity (early and late successional stages) are currently strongly underrepresented in the forests of Central Europe. We thus recommend that conservation strategies aim at a more balanced representation of all successional stages. KW - biodiversity KW - forest dynamics KW - forest succession KW - habitat heterogeneity KW - LiDAR KW - species density KW - temperate forests KW - β-diversity Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320632 VL - 55 ER - TY - JOUR A1 - Kwok, Chee Keong A1 - Ueda, Yuichiro A1 - Kadari, Asifiqbal A1 - Günther, Katharina A1 - Ergün, Süleyman A1 - Heron, Antoine A1 - Schnitzler, Aletta C. A1 - Rook, Martha A1 - Edenhofer, Frank T1 - Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single-use bioreactors JF - Journal of Tissue Engineering and Regenerative Medicine N2 - The production of human induced pluripotent stem cells (hiPSCs) in quantities that are relevant for cell-based therapies and cell-loaded implants through standard adherent culture is hardly achievable and lacks process scalability. A promising approach to overcoming these hurdles is the culture of hiPSCs in suspension. In this study, stirred suspension culture vessels were investigated for their suitability in the expansion of two hiPSC lines inoculated as a single cell suspension, with a free scalability between volumes of 50 and 2400 ml. The simple and robust two-step process reported here first generates hiPSC aggregates of 324 ± 71 μm diameter in 7 days in 125 ml spinner flasks (100 ml volume). These are subsequently dissociated into a single cell suspension for inoculation in 3000 ml bioreactors (1000 ml volume), finally yielding hiPSC aggregates of 198 ± 58 μm after 7 additional days. In both spinner flasks and bioreactors, hiPSCs can be cultured as aggregates for more than 40 days in suspension, maintain an undifferentiated state as confirmed by the expression of pluripotency markers TRA-1-60, TRA-1-81, SSEA-4, OCT4, and SOX2, can differentiate into cells of all three germ layers, and can be directed to differentiate into specific lineages such as cardiomyocytes. Up to a 16-fold increase in hiPSC quantity at the 100 ml volume was achieved, corresponding to a fold increase per day of 2.28; at the 1000 ml scale, an additional 10-fold increase was achieved. Taken together, 16 × 106 hiPSCs were expanded into 2 × 109 hiPSCs in 14 days for a fold increase per day of 8.93. This quantity of hiPSCs readily meets the requirements of cell-based therapies and brings their clinical potential closer to fruition. KW - bioprocessing KW - human pluripotent stem cells KW - process optimization KW - single-use bioreactors KW - stirred suspension culture KW - scalable culture system Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234545 VL - 12 ER - TY - JOUR A1 - Hrynevich, Andrei A1 - Elçi, Bilge Ş. A1 - Haigh, Jodie N. A1 - McMaster, Rebecca A1 - Youssef, Almoatazbellah A1 - Blum, Carina A1 - Blunk, Torsten A1 - Hochleitner, Gernot A1 - Groll, Jürgen A1 - Dalton, Paul D. T1 - Dimension-Based Design of Melt Electrowritten Scaffolds JF - Small N2 - The electrohydrodynamic stabilization of direct-written fluid jets is explored to design and manufacture tissue engineering scaffolds based on their desired fiber dimensions. It is demonstrated that melt electrowriting can fabricate a full spectrum of various fibers with discrete diameters (2–50 µm) using a single nozzle. This change in fiber diameter is digitally controlled by combining the mass flow rate to the nozzle with collector speed variations without changing the applied voltage. The greatest spectrum of fiber diameters was achieved by the simultaneous alteration of those parameters during printing. The highest placement accuracy could be achieved when maintaining the collector speed slightly above the critical translation speed. This permits the fabrication of medical-grade poly(ε-caprolactone) into complex multimodal and multiphasic scaffolds, using a single nozzle in a single print. This ability to control fiber diameter during printing opens new design opportunities for accurate scaffold fabrication for biomedical applications. KW - biofabrication KW - electrohydrodynamic KW - melt electrospinning writing KW - scaffold design KW - tissue engineering Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322677 VL - 14 ER - TY - JOUR A1 - de Ruijter, Mylène A1 - Hrynevich, Andrei A1 - Haigh, Jodie N. A1 - Hochleitner, Gernot A1 - Castilho, Miguel A1 - Groll, Jürgen A1 - Malda, Jos A1 - Dalton, Paul D. T1 - Out-of-Plane 3D-Printed Microfibers Improve the Shear Properties of Hydrogel Composites JF - Small N2 - One challenge in biofabrication is to fabricate a matrix that is soft enough to elicit optimal cell behavior while possessing the strength required to withstand the mechanical load that the matrix is subjected to once implanted in the body. Here, melt electrowriting (MEW) is used to direct-write poly(ε-caprolactone) fibers “out-of-plane” by design. These out-of-plane fibers are specifically intended to stabilize an existing structure and subsequently improve the shear modulus of hydrogel–fiber composites. The stabilizing fibers (diameter = 13.3 ± 0.3 µm) are sinusoidally direct-written over an existing MEW wall-like structure (330 µm height). The printed constructs are embedded in different hydrogels (5, 10, and 15 wt% polyacrylamide; 65% poly(2-hydroxyethyl methacrylate) (pHEMA)) and a frequency sweep test (0.05–500 rad s−1, 0.01% strain, n = 5) is performed to measure the complex shear modulus. For the rheological measurements, stabilizing fibers are deposited with a radial-architecture prior to embedding to correspond to the direction of the stabilizing fibers with the loading of the rheometer. Stabilizing fibers increase the complex shear modulus irrespective of the percentage of gel or crosslinking density. The capacity of MEW to produce well-defined out-of-plane fibers and the ability to increase the shear properties of fiber-reinforced hydrogel composites are highlighted. KW - biofabrication KW - fiber reinforcement KW - hydrogels KW - mechanical properties KW - melt electrowriting Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223666 VL - 14 ER - TY - JOUR A1 - Greber, Johannes A1 - Polat, Bülent A1 - Flentje, Michael A1 - Bratengeier, Klaus T1 - Properties of the anisotropy of dose contributions: A planning study on prostate cases JF - Medical Physics N2 - Purpose To characterize the static properties of the anisotropy of dose contributions for different treatment techniques on real patient data (prostate cases). From this, we aim to define a class of treatment techniques with invariant anisotropy distribution carrying information of target coverage and organ-at-risk (OAR) sparing. The anisotropy presumably is a helpful quantity for plan adaptation problems. Methods The anisotropy field is analyzed for different intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques for a total of ten planning CTs of prostate cases. Primary irradiation directions ranged from 5 to 15. The uniqueness of anisotropy was explored: In particular, the anisotropy distribution inside the planning treatment volume (PTV) and in its vicinity was investigated. Furthermore, deviations of the anisotropy under beam rotations were explored by direct plan comparison as an indicating the susceptibility of each planned technique to changes in the geometric plan configuration. In addition, plan comparisons enabled the categorization of treatment techniques in terms of their anisotropy distribution. Results The anisotropy profile inside the PTV and in the transition between OAR and PTV is independent of the treatment technique as long as a sufficient number of beams contribute to the dose distribution. Techniques with multiple beams constitute a class of almost identical and technique-independent anisotropy distribution. For this class of techniques, substructures of the anisotropy are particularly pronounced in the PTV, thus offering good options for applying adaptation rules. Additionally, the techniques forming the mentioned class fortunately allow a better OAR sparing at constant PTV coverage. Besides the characterization of the distribution, a pairwise plan comparison reveals each technique's susceptibility to deviations which decreases for an increasing number of primary irradiation directions. Conclusions Techniques using many irradiation directions form a class of almost identical anisotropy distributions which are assumed to provide a basis for improved adaptation procedures. Encouragingly, these techniques deliver quite invariant anisotropy distributions with respect to rotations correlated with good plan qualities than techniques using few gantry angles. The following will be the next steps toward anisotropy-based adaptation: first, the quantification of anisotropy regarding organ deformations; and second, establishing the interrelation between the anisotropy and beam shaping. KW - adaptation KW - IMRT KW - radiotherapy KW - VMAT Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228237 VL - 46 ER - TY - JOUR A1 - Mirza, Myriam A1 - Vainshtein, Anna A1 - DiRonza, Alberto A1 - Chandrachud, Uma A1 - Haslett, Luke J. A1 - Palmieri, Michela A1 - Storch, Stephan A1 - Groh, Janos A1 - Dobzinski, Niv A1 - Napolitano, Gennaro A1 - Schmidtke, Carolin A1 - Kerkovich, Danielle M. T1 - The CLN3 gene and protein: What we know JF - Molecular Genetics & Genomic Medicine N2 - Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long-held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works. KW - Batten KW - CLN3 KW - JNCL KW - juvenile Batten KW - neuronal ceroid lipofuscinosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224138 VL - 7 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Brand, Eva A1 - Burlina, Alessandro A1 - Cecchi, Franco A1 - Garman, Scott C. A1 - Kempf, Judy A1 - Laney, Dawn A. A1 - Linhart, Aleš A1 - Maródi, László A1 - Nicholls, Kathy A1 - Ortiz, Alberto A1 - Pieruzzi, Federico A1 - Shankar, Suma P. A1 - Waldek, Stephen A1 - Wanner, Christoph A1 - Jovanovic, Ana T1 - Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study JF - Molecular Genetics & Genomic Medicine N2 - Background The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25–34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55–64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65–74 years), and rarely in females (3%). Conclusion p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males. KW - cardiac variant KW - Fabry disease KW - GLA KW - p.Asn215Ser KW - p.N215S KW - phenotype Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232976 VL - 6 ER - TY - JOUR A1 - Arlotti, Mattia A1 - Palmisano, Chiara A1 - Minafra, Brigida A1 - Todisco, Massimiliano A1 - Pacchetti, Claudio A1 - Canessa, Andrea A1 - Pozzi, Nicoló G. A1 - Cilia, Roberto A1 - Prenassi, Marco A1 - Marceglia, Sara A1 - Priori, Alberto A1 - Rampini, Paolo A1 - Barbieri, Sergio A1 - Servello, Domenico A1 - Volkmann, Jens A1 - Pezzoli, Gianni A1 - Isaias, Ioannis U. T1 - Monitoring subthalamic oscillations for 24 hours in a freely moving Parkinson's disease patient JF - Movement Disorders N2 - No abstract available Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221249 VL - 34 ER - TY - JOUR A1 - Steigerwald, Frank A1 - Timmermann, Lars A1 - Kühn, Andrea A1 - Schnitzler, Alfons A1 - Reich, Martin M. A1 - Kirsch, Anna Dalal A1 - Barbe, Michael Thomas A1 - Visser-Vandewalle, Veerle A1 - Hübl, Julius A1 - van Riesen, Christoph A1 - Groiss, Stefan Jun A1 - Moldovan, Alexia-Sabine A1 - Lin, Sherry A1 - Carcieri, Stephen A1 - Manola, Ljubomir A1 - Volkmann, Jens T1 - Pulse duration settings in subthalamic stimulation for Parkinson's disease JF - Movement Disorders N2 - Background Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinson's disease (PD) are rarely tested in double-blind conditions. Evidence-based recommendations on optimal stimulator settings are needed. Results from the CUSTOM-DBS study are reported, comparing 2 pulse durations. Methods A total of 15 patients were programmed using a pulse width of 30 µs (test) or 60 µs (control). Efficacy and side-effect thresholds and unified PD rating scale (UPDRS) III were measured in meds-off (primary outcome). The therapeutic window was the difference between patients’ efficacy and side effect thresholds. Results The therapeutic window was significantly larger at 30 µs than 60 µs (P = ·0009) and the efficacy (UPDRS III score) was noninferior (P = .00008). Interpretation Subthalamic neurostimulation at 30 µs versus 60 µs pulse width is equally effective on PD motor signs, is more energy efficient, and has less likelihood of stimulation-related side effects. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. KW - deep brain stimulation KW - Parkinson's disease; KW - pulse width KW - stimulation parameters KW - subthalamic Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239402 VL - 33 ER - TY - JOUR A1 - Calderon, Dayana A1 - Peña, Luis A1 - Suarez, Angélica A1 - Villamil, Carolina A1 - Ramirez-Rojas, Adan A1 - Anzola, Juan M. A1 - García-Betancur, Juan C. A1 - Cepeda, Martha L. A1 - Uribe, Daniel A1 - Del Portillo, Patricia A1 - Mongui, Alvaro T1 - Recovery and functional validation of hidden soil enzymes in metagenomic libraries JF - MicrobiologyOpen N2 - The vast microbial diversity on the planet represents an invaluable source for identifying novel activities with potential industrial and therapeutic application. In this regard, metagenomics has emerged as a group of strategies that have significantly facilitated the analysis of DNA from multiple environments and has expanded the limits of known microbial diversity. However, the functional characterization of enzymes, metabolites, and products encoded by diverse microbial genomes is limited by the inefficient heterologous expression of foreign genes. We have implemented a pipeline that combines NGS and Sanger sequencing as a way to identify fosmids within metagenomic libraries. This strategy facilitated the identification of putative proteins, subcloning of targeted genes and preliminary characterization of selected proteins. Overall, the in silico approach followed by the experimental validation allowed us to efficiently recover the activity of previously hidden enzymes derived from agricultural soil samples. Therefore, the methodology workflow described herein can be applied to recover activities encoded by environmental DNA from multiple sources. KW - environmental microbiology KW - functional genomics KW - metagenomics KW - microbial genomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222016 VL - 8 ER - TY - JOUR A1 - Hettich, Georg A1 - Schierjott, Ronja A. A1 - Ramm, Heiko A1 - Graichen, Heiko A1 - Jansson, Volkmar A1 - Rudert, Maximilian A1 - Traina, Francesco A1 - Grupp, Thomas M. T1 - Method for quantitative assessment of acetabular bone defects JF - Journal of Orthopaedic Research N2 - The objective of the study was to suggest a novel quantitative assessment of acetabular bone defects based on a statistical shape model, validate the method, and present preliminary results. Two exemplary CT-data sets with acetabular bone defects were segmented to obtain a solid model of each defect pelvis. The pathological areas around the acetabulum were excluded and a statistical shape model was fitted to the remaining healthy bone structures. The excluded areas were extrapolated such that a solid model of the native pelvis per specimen resulted (i.e., each pelvis without defect). The validity of the reconstruction was tested by a leave-one-out study. Validation results showed median reconstruction errors of 3.0 mm for center of rotation, 1.7 mm for acetabulum diameter, 2.1° for inclination, 2.5° for anteversion, and 3.3 mm3 for bone volume around the acetabulum. By applying Boolean operations on the solid models of defect and native pelvis, bone loss and bone formation in four different sectors were assessed. For both analyzed specimens, bone loss and bone formation per sector were calculated and were consistent with the visual impression. In specimen_1 bone loss was predominant in the medial wall (10.8 ml; 79%), in specimen_2 in the posterior column (15.6 ml; 46%). This study showed the feasibility of a quantitative assessment of acetabular bone defects using a statistical shape model-based reconstruction method. Validation results showed acceptable reconstruction accuracy, also when less healthy bone remains. The method could potentially be used for implant development, pre-clinical testing, pre-operative planning, and intra-operative navigation. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 9999:1–9, 2018. KW - acetabular bone defects KW - quantification KW - statistical shape model KW - volume analysis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320226 VL - 37 ER - TY - JOUR A1 - Kaspar-Ott, Irena A1 - Hertig, Elke A1 - Kaspar, Severin A1 - Pollinger, Felix A1 - Ring, Christoph A1 - Paeth, Heiko A1 - Jacobeit, Jucundus T1 - Weights for general circulation models from CMIP3/CMIP5 in a statistical downscaling framework and the impact on future Mediterranean precipitation JF - The International Journal of Climatology N2 - This study investigates the projected precipitation changes of the 21st century in the Mediterranean area with a model ensemble of all available CMIP3 and CMIP5 data based on four different scenarios. The large spread of simulated precipitation change signals underlines the need of an evaluation of the individual general circulation models in order to give higher weights to better and lower weights to worse performing models. The models' spread comprises part of the internal climate variability, but is also due to the differing skills of the circulation models. The uncertainty resulting from the latter is the aim of our weighting approach. Each weight is based on the skill to simulate key predictor variables in context of large and medium scale atmospheric circulation patterns within a statistical downscaling framework for the Mediterranean precipitation. Therefore, geopotential heights, sea level pressure, atmospheric layer thickness, horizontal wind components and humidity data at several atmospheric levels are considered. The novelty of this metric consists in avoiding the use of the precipitation data by itself for the weighting process, as state-of-the-art models still have major deficits in simulating precipitation. The application of the weights on the downscaled precipitation changes leads to more reliable and precise change signals in some Mediterranean sub-regions and seasons. The model weights differ between sub-regions and seasons, however, a clear sequence from better to worse models for the representation of precipitation in the Mediterranean area becomes apparent. KW - CMIP3 KW - CMIP5 KW - Mediterranean area KW - precipitation KW - statistical downscaling KW - weights Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325628 VL - 39 ER - TY - JOUR A1 - Mazon, Melody A1 - Larouche, Valérie A1 - St-Louis, Maryse A1 - Schindler, Detlev A1 - Carreau, Madeleine T1 - Elevated blood levels of Dickkopf-1 are associated with acute infections JF - Immunity, Inflammation and Disease N2 - Introduction Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/β-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. Methods Plasma samples were collected from 58 children admitted to the Centre Mère-Enfant Soleil du Centre Hospitalier de Québec-Université Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the Héma-Québec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. Results Patients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections. Conclusion These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses. KW - blood plasma KW - Dickkopf-1 KW - ELISA KW - Fanconi anemia KW - infections Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222171 VL - 6 ER - TY - JOUR A1 - Bavendiek, Udo A1 - Berliner, Dominik A1 - Aguirre Dávila, Lukas A1 - Schwab, Johannes A1 - Maier, Lars A1 - Philipp, Sebastian A. A1 - Rieth, Andreas A1 - Westenfeld, Ralf A1 - Piorkowski, Christopher A1 - Weber, Kristina A1 - Hänselmann, Anja A1 - Oldhafer, Maximiliane A1 - Schallhorn, Sven A1 - von der Leyen, Heiko A1 - Schröder, Christoph A1 - Veltmann, Christian A1 - Störk, Stefan A1 - Böhm, Michael A1 - Koch, Armin A1 - Bauersachs, Johann T1 - Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study JF - European Journal of Heart Failure N2 - Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment. KW - heart failure KW - cardiac glycosides KW - digitalis KW - digitoxin KW - clinical trial Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221548 VL - 21 ER - TY - JOUR A1 - de Boer, Rudolf A. A1 - De Keulenaer, Gilles A1 - Bauersachs, Johann A1 - Brutsaert, Dirk A1 - Cleland, John G. A1 - Diez, Javier A1 - Du, Xiao-Jun A1 - Ford, Paul A1 - Heinzel, Frank R. A1 - Lipson, Kenneth E. A1 - McDonagh, Theresa A1 - Lopez-Andres, Natalia A1 - Lunde, Ida G. A1 - Lyon, Alexander R. A1 - Pollesello, Piero A1 - Prasad, Sanjay K. A1 - Tocchetti, Carlo G. A1 - Mayr, Manuel A1 - Sluijter, Joost P. G. A1 - Thum, Thomas A1 - Tschöpe, Carsten A1 - Zannad, Faiez A1 - Zimmermann, Wolfram-Hubertus A1 - Ruschitzka, Frank A1 - Filippatos, Gerasimos A1 - Lindsey, Merry L. A1 - Maack, Christoph A1 - Heymans, Stephane T1 - Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology JF - European Journal of Heart Failure N2 - Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research. KW - fibrosis KW - heart failure KW - biomarkers KW - fibroblast KW - matrix KW - prognosis KW - imaging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223613 VL - 21 ER - TY - JOUR A1 - Frantz, Stefan A1 - Falcao-Pires, Ines A1 - Balligand, Jean-Luc A1 - Bauersachs, Johann A1 - Brutsaert, Dirk A1 - Ciccarelli, Michele A1 - Dawson, Dana A1 - de Windt, Leon J. A1 - Giacca, Mauro A1 - Hamdani, Nazha A1 - Hilfiker-Kleiner, Denise A1 - Hirsch, Emilio A1 - Leite-Moreira, Adelino A1 - Mayr, Manuel A1 - Thum, Thomas A1 - Tocchetti, Carlo G. A1 - van der Velden, Jolanda A1 - Varricchi, Gilda A1 - Heymans, Stephane T1 - The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC JF - European Journal of Heart Failure N2 - Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies. KW - immune system KW - macrophage KW - T-cell KW - ischaemic cardiomyopathy KW - hypertensive cardiomyopathy KW - diabetic cardiomyopathy KW - toxic cardiomyopathy KW - viral cardiomyopathy KW - genetic cardiomyopathy KW - peripartum cardiomyopathy KW - autoimmune cardiomyopathy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229091 VL - 20 ER - TY - JOUR A1 - Nolte, Kathleen A1 - Hermann-Lingen, Christoph A1 - Platschek, Lars A1 - Holzendorf, Volker A1 - Pilz, Stefan A1 - Tomaschitz, Andreas A1 - Düngen, Hans-Dirk A1 - Angermann, Christiane E. A1 - Hasenfuß, Gerd A1 - Pieske, Burkert A1 - Wachter, Rolf A1 - Edelmann, Frank T1 - Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction JF - ESC Heart Failure N2 - Aims Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. Methods and results We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. Conclusions Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities. KW - vitamin D KW - diastolic dysfunction KW - heart failure KW - HFpEF KW - NT-proBNP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232303 VL - 6 ER - TY - JOUR A1 - König, Kerstin A1 - Zundel, Petra A1 - Krimmer, Elena A1 - König, Christian A1 - Pollmann, Marie A1 - Gottlieb, Yuval A1 - Steidle, Johannes L. M. T1 - Reproductive isolation due to prezygotic isolation and postzygotic cytoplasmic incompatibility in parasitoid wasps JF - Ecology and Evolution N2 - The reproductive barriers that prevent gene flow between closely related species are a major topic in evolutionary research. Insect clades with parasitoid lifestyle are among the most species-rich insects and new species are constantly described, indicating that speciation occurs frequently in this group. However, there are only very few studies on speciation in parasitoids. We studied reproductive barriers in two lineages of Lariophagus distinguendus (Chalcidoidea: Hymenoptera), a parasitoid wasp of pest beetle larvae that occur in human environments. One of the two lineages occurs in households preferably attacking larvae of the drugstore beetle Stegobium paniceum (“DB-lineage”), the other in grain stores with larvae of the granary weevil Sitophilus granarius as main host (“GW-lineage”). Between two populations of the DB-lineage, we identified slight sexual isolation as intraspecific barrier. Between populations from both lineages, we found almost complete sexual isolation caused by female mate choice, and postzygotic isolation, which is partially caused by cytoplasmic incompatibility induced by so far undescribed endosymbionts which are not Wolbachia or Cardinium. Because separation between the two lineages is almost complete, they should be considered as separate species according to the biological species concept. This demonstrates that cryptic species within parasitoid Hymenoptera also occur in Central Europe in close contact to humans. KW - cytoplasmic incompatibility KW - endosymbiotic bacteria KW - Lariophagus distinguendus KW - parasitoid wasps KW - sexual isolation KW - speciation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222796 VL - 9 ER - TY - JOUR A1 - Hartke, Juliane A1 - Sprenger, Philipp P. A1 - Sahm, Jacqueline A1 - Winterberg, Helena A1 - Orivel, Jérôme A1 - Baur, Hannes A1 - Beuerle, Till A1 - Schmitt, Thomas A1 - Feldmeyer, Barbara A1 - Menzel, Florian T1 - Cuticular hydrocarbons as potential mediators of cryptic species divergence in a mutualistic ant association JF - Ecology and Evolution N2 - Upon advances in sequencing techniques, more and more morphologically identical organisms are identified as cryptic species. Often, mutualistic interactions are proposed as drivers of diversification. Species of the neotropical parabiotic ant association between Crematogaster levior and Camponotus femoratus are known for highly diverse cuticular hydrocarbon (CHC) profiles, which in insects serve as desiccation barrier but also as communication cues. In the present study, we investigated the association of the ants’ CHC profiles with genotypes and morphological traits, and discovered cryptic species pairs in both genera. To assess putative niche differentiation between the cryptic species, we conducted an environmental association study that included various climate variables, canopy cover, and mutualistic plant species. Although mostly sympatric, the two Camponotus species seem to prefer different climate niches. However in the two Crematogaster species, we could not detect any differences in niche preference. The strong differentiation in the CHC profiles may thus suggest a possible role during speciation itself either by inducing assortative mating or by reinforcing sexual selection after the speciation event. We did not detect any further niche differences in the environmental parameters tested. Thus, it remains open how the cryptic species avoid competitive exclusion, with scope for further investigations. KW - environmental association KW - integrative taxonomy KW - niche differentiation KW - population structure KW - sexual selection KW - speciation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227857 VL - 9 ER - TY - JOUR A1 - Kendall, Liam K. A1 - Rader, Romina A1 - Gagic, Vesna A1 - Cariveau, Daniel P. A1 - Albrecht, Matthias A1 - Baldock, Katherine C. R. A1 - Freitas, Breno M. A1 - Hall, Mark A1 - Holzschuh, Andrea A1 - Molina, Francisco P. A1 - Morten, Joanne M. A1 - Pereira, Janaely S. A1 - Portman, Zachary M. A1 - Roberts, Stuart P. M. A1 - Rodriguez, Juanita A1 - Russo, Laura A1 - Sutter, Louis A1 - Vereecken, Nicolas J. A1 - Bartomeus, Ignasi T1 - Pollinator size and its consequences: Robust estimates of body size in pollinating insects JF - Ecology and Evolution N2 - Body size is an integral functional trait that underlies pollination-related ecological processes, yet it is often impractical to measure directly. Allometric scaling laws have been used to overcome this problem. However, most existing models rely upon small sample sizes, geographically restricted sampling and have limited applicability for non-bee taxa. Allometric models that consider biogeography, phylogenetic relatedness, and intraspecific variation are urgently required to ensure greater accuracy. We measured body size as dry weight and intertegular distance (ITD) of 391 bee species (4,035 specimens) and 103 hoverfly species (399 specimens) across four biogeographic regions: Australia, Europe, North America, and South America. We updated existing models within a Bayesian mixed-model framework to test the power of ITD to predict interspecific variation in pollinator dry weight in interaction with different co-variates: phylogeny or taxonomy, sexual dimorphism, and biogeographic region. In addition, we used ordinary least squares regression to assess intraspecific dry weight ~ ITD relationships for ten bees and five hoverfly species. Including co-variates led to more robust interspecific body size predictions for both bees and hoverflies relative to models with the ITD alone. In contrast, at the intraspecific level, our results demonstrate that the ITD is an inconsistent predictor of body size for bees and hoverflies. The use of allometric scaling laws to estimate body size is more suitable for interspecific comparative analyses than assessing intraspecific variation. Collectively, these models form the basis of the dynamic R package, “pollimetry,” which provides a comprehensive resource for allometric pollination research worldwide. KW - Apoidea KW - biogeography KW - body size KW - dry weight KW - pollimetry KW - pollination KW - predictive models KW - R package KW - Syrphidae Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325705 VL - 9 ER - TY - JOUR A1 - Hillaert, Jasmijn A1 - Hovestadt, Thomas A1 - Vandegehuchte, Martijn L. A1 - Bonte, Dries T1 - Size-dependent movement explains why bigger is better in fragmented landscapes JF - Ecology and Evolution N2 - Body size is a fundamental trait known to allometrically scale with metabolic rate and therefore a key determinant of individual development, life history, and consequently fitness. In spatially structured environments, movement is an equally important driver of fitness. Because movement is tightly coupled with body size, we expect habitat fragmentation to induce a strong selection pressure on size variation across and within species. Changes in body size distributions are then, in turn, expected to alter food web dynamics. However, no consensus has been reached on how spatial isolation and resource growth affect consumer body size distributions. Our aim was to investigate how these two factors shape the body size distribution of consumers under scenarios of size-dependent and size-independent consumer movement by applying a mechanistic, individual-based resource–consumer model. We also assessed the consequences of altered body size distributions for important ecosystem traits such as resource abundance and consumer stability. Finally, we determined those factors that explain most variation in size distributions. We demonstrate that decreasing connectivity and resource growth select for communities (or populations) consisting of larger species (or individuals) due to strong selection for the ability to move over longer distances if the movement is size-dependent. When including size-dependent movement, intermediate levels of connectivity result in increases in local size diversity. Due to this elevated functional diversity, resource uptake is maximized at the metapopulation or metacommunity level. At these intermediate levels of connectivity, size-dependent movement explains most of the observed variation in size distributions. Interestingly, local and spatial stability of consumer biomass is lowest when isolation and resource growth are high. Finally, we highlight that size-dependent movement is of vital importance for the survival of populations or communities within highly fragmented landscapes. Our results demonstrate that considering size-dependent movement is essential to understand how habitat fragmentation and resource growth shape body size distributions—and the resulting metapopulation or metacommunity dynamics—of consumers. KW - allometric scaling KW - body size distributions; KW - eco-evolutionary dynamics KW - habitat fragmentation KW - isolation KW - metabolic theory KW - optimal size KW - size-dependent movement Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320322 VL - 8 ER - TY - JOUR A1 - Stein, Katharina A1 - Stenchly, Kathrin A1 - Coulibaly, Drissa A1 - Pauly, Alain A1 - Dimobe, Kangbeni A1 - Steffan-Dewenter, Ingolf A1 - Konaté, Souleymane A1 - Goetze, Dethardt A1 - Porembski, Stefan A1 - Linsenmair, K. Eduard T1 - Impact of human disturbance on bee pollinator communities in savanna and agricultural sites in Burkina Faso, West Africa JF - Ecology and Evolution N2 - All over the world, pollinators are threatened by land-use change involving degradation of seminatural habitats or conversion into agricultural land. Such disturbance often leads to lowered pollinator abundance and/or diversity, which might reduce crop yield in adjacent agricultural areas. For West Africa, changes in bee communities across disturbance gradients from savanna to agricultural land are mainly unknown. In this study, we monitored for the impact of human disturbance on bee communities in savanna and crop fields. We chose three savanna areas of varying disturbance intensity (low, medium, and high) in the South Sudanian zone of Burkina Faso, based on land-use/land cover data via Landsat images, and selected nearby cotton and sesame fields. During 21 months covering two rainy and two dry seasons in 2014 and 2015, we captured bees using pan traps. Spatial and temporal patterns of bee species abundance, richness, evenness and community structure were assessed. In total, 35,469 bee specimens were caught on 12 savanna sites and 22 fields, comprising 97 species of 32 genera. Bee abundance was highest at intermediate disturbance in the rainy season. Species richness and evenness did not differ significantly. Bee communities at medium and highly disturbed savanna sites comprised only subsets of those at low disturbed sites. An across-habitat spillover of bees (mostly abundant social bee species) from savanna into crop fields was observed during the rainy season when crops are mass-flowering, whereas most savanna plants are not in bloom. Despite disturbance intensification, our findings suggest that wild bee communities can persist in anthropogenic landscapes and that some species even benefitted disproportionally. West African areas of crop production such as for cotton and sesame may serve as important food resources for bee species in times when resources in the savanna are scarce and receive at the same time considerable pollination service. KW - bee communities KW - cotton KW - sesame KW - species spillover KW - sub-Saharan Africa Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239999 VL - 8 ER - TY - JOUR A1 - Minden, Vanessa A1 - Schnetger, Bernhard A1 - Pufal, Gesine A1 - Leonhardt, Sara D. T1 - Antibiotic-induced effects on scaling relationships and on plant element contents in herbs and grasses JF - Ecology and Evolution N2 - Plant performance is correlated with element concentrations in plant tissue, which may be impacted by adverse chemical soil conditions. Antibiotics of veterinary origin can adversely affect plant performance. They are released to agricultural fields via grazing animals or manure, taken up by plants and may be stored, transformed or sequestered by plant metabolic processes. We studied the potential effects of three antibiotics (penicillin, sulfadiazine, and tetracycline) on plant element contents (macro- and microelements). Plant species included two herb species (Brassica napus and Capsella bursa-pastoris) and two grass species (Triticum aestivum and Apera spica-venti), representing two crop species and two noncrop species commonly found in field margins, respectively. Antibiotic concentrations were chosen as to reflect in vivo situations, that is, relatively low concentrations similar to those detected in soils. In a greenhouse experiment, plants were raised in soil spiked with antibiotics. After harvest, macro- and microelements in plant leaves, stems, and roots were determined (mg/g). Results indicate that antibiotics can affect element contents in plants. Penicillin exerted the greatest effect both on element contents and on scaling relationships of elements between plant organs. Roots responded strongest to antibiotics compared to stems and leaves. We conclude that antibiotics in the soil, even in low concentrations, lead to low-element homeostasis, altering the scaling relationships between roots and other plant organs, which may affect metabolic processes and ultimately the performance of a plant. KW - antibiotics KW - homeostasis KW - scaling relationships KW - standardized major axis regression KW - tissue nutrient contents Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224094 VL - 8 ER - TY - JOUR A1 - Angay, Oguzhan A1 - Friedrich, Mike A1 - Pinnecker, Jürgen A1 - Hintzsche, Henning A1 - Stopper, Helga A1 - Hempel, Klaus A1 - Heinze, Katrin G. T1 - Image-based modeling and scoring of Howell–Jolly Bodies in human erythrocytes JF - Cytometry Part A N2 - The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell–Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a “critical distance” dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit—a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. KW - fluorescence imaging KW - splenic function KW - Jolly bodies KW - image analysis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221140 VL - 93 ER - TY - JOUR A1 - Li, Ru-Jin A1 - Han, Muxin A1 - Tessarolo, Jacopo A1 - Holstein, Julian J. A1 - Lübben, Jens A1 - Dittrich, Birger A1 - Volkmann, Christian A1 - Finze, Maik A1 - Jenne, Carsten A1 - Clever, Guido H. T1 - Successive Photoswitching and Derivatization Effects in Photochromic Dithienylethene-Based Coordination Cages JF - ChemPhotoChem N2 - A new series of [Pd2(L)4] cages based on photochromic dithienylethene (DTE) ligands allowed us to gain insight into the successive photoswitching of multiple DTE moieties in a confined metallo-supramolecular assembly. Three new X-ray structures of [Pd2(o-L4)4], [Pd2(o-L1)2(c-L1)2] and [Pd2(c-L1)4] (o-L and c-L = open and closed forms of DTE ligands, respectively) were obtained. The structures deliver snapshots of three different combinations of DTE photoisomeric states within the cage, facilitating a comparison of the all-open with the all-closed, and most notably, an intermediate form where open and closed switches co-exist in the same cage. Moreover, a series of spherical anionic borate clusters was introduced in order to study their roles in the light-controllable host–guest chemistry. The binding guests show higher affinities with the flexible open cage [Pd2(o-L1)4] than with the rigid closed cage [Pd2(c-L1)4]. For the [B12F12]2− guest, thermodynamic data obtained from NMR experiments was compared to results from isothermal titration calorimetry (ITC). KW - coordination cages KW - dithienylethene KW - host-guest systems KW - photoswitches KW - supramolecular chemistry Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236815 VL - 3 ER - TY - JOUR A1 - Müntze, Jonas A1 - Nordbeck, Peter T1 - Response to “Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data” JF - Clinical Pharmacology & Therapeutics N2 - No abstract available Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231600 VL - 106 ER - TY - JOUR A1 - Duell, Johannes A1 - Lammers, Philip E. A1 - Djuretic, Ivana A1 - Chunyk, Allison G. A1 - Alekar, Shilpa A1 - Jacobs, Ira A1 - Gill, Saar T1 - Bispecific Antibodies in the Treatment of Hematologic Malignancies JF - Clinical Pharmacology & Therapeutics N2 - Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226392 VL - 106 ER - TY - THES A1 - Weis, Philipp T1 - Translationale Untersuchung zur Anwendung der durchflusszytometrischen Bestimmung \(Aspergillus\) \(fumigatus\) spezifischer T-Zellen in der Diagnostik von Aspergillosen T1 - Translational study on the application of flow cytometric detection of \(Aspergillus\) \(fumigatus\) specific T-cells in the diagnosis of aspergillosis N2 - Bei Patienten mit invasiver Aspergillose fanden sich gegenüber gesunden Probanden deutlich erhöhte Werte A. fumigatus spezifischer CD154+/CD4+ Zellen. Die Anwendbarkeit dieses Assays im klinischen Routinebetrieb und bei gegenüber A. fumigatus epxonierten Probanden und Patienten sollte in dieser translationalen Arbeit untersucht werden. Für den vorbeschriebenen Assay zur Bestimmung CD154+/CD4+ Zellen aus aufgereinigten PBMCs zeigt diese Arbeit eine signifikant reduzierte Detektionsrate nach Blutprobenlagerung von über 2 Stunden. In der Literatur beschriebene Verfahren zur verlängerten Lagerungszeit von heparinisierten Blutproben mittels vorhergehender Dilution und Agitation ermöglichen keine Verlängerung präanalytischer Lagerungszeiten über 6 Stunden. Die Kryokonservierung frisch aufbereiteter PBMCs bei −20 C vor Bestimmung A. fumigatus spezifischer T-Zellen wird als Versandmöglichkeit in einem multizentrischen Setting gezeigt. Um die klinische Anwendbarkeit zu verbessern, wird ein Vollblutprotokoll zur Detektion A. fumigatus spezifischer CD154+/CD4+ Zellen demonstriert, das die Verwendung von bettseitig mit Vollblut beimpften Blutmonovetten mit vorgelegtem A. fumigatus-Lysat ermöglicht. Die Anwendung des Assays zur Bestimmung A. fumigatus spezifischer T-Zellen wurde bei hämatoonkologischen Patienten vor und drei Monate nach Stammzelltransplantation untersucht. Insbesondere eine reduzierte Zellzahl der gemessenen Lymphozyten ist hier ein limitierender Faktor der erfolgreichen Messung. Aufgrund der generell nied- rigen Erfolgsrate von 20 % bzw. 54 % vor bzw. nach HSCT ist die Anwendbarkeit des Assays in diesem Kollektiv fraglich. Die Erhebung von Expositionsfaktoren gesunder Probanden gegenüber A. fumigatus ermöglicht die Einteilung in eine schwach und stark gegenüber A. fumigatus exponierte Gruppe mit signifikant erhöhtem Anteil A. fumigatus spezifischer CD154+/CD4+ Zellen. Hierzu trägt insbesondere das Vorliegen antigenspezifischer T-Gedächtniszellen als Korrelat einer langfristigen Exposition bei. Retrospektiv fand sich auch nach kurzfris- tiger beruflicher Exposition ein Anstieg CD154+/CD4+ spezifischer T-Zellen. Dies legt eine Verwendung CD154+/CD4+ spezifischer T-Zellen als Biomarker in Bereichen der umweltmedizinischen Abklärung von Schimmelpilzexposition oder der Diagnostik allergischer Erkrankungen nahe. N2 - In patients with invasive aspergillosis, significantly elevated levels of A. fumigatus specific CD154+/CD4+ cells were found compared to healthy subjects. This translational study aimed to investigate the applicability of this assay in clinical routine practice, as well as in subjects and patients exposed to A. fumigatus. For the previously described assay for determining CD154+/CD4+ cells from purified PBMCs, this study demonstrates a significantly reduced detection rate after blood sample storage for more than 2 hours. Methods described in the literature for extending the storage time of heparinized blood samples through prior dilution and agitation do not allow for pre-analytical storage times beyond 6 hours. Cryopreservation of freshly prepared PBMCs at −20°C before determining A. fumigatus-specific T-cells is presented as a shipping option in a multicenter setting. To improve clinical applicability, a whole-blood protocol for the detection of A. fumigatus-specific CD154+/CD4+ cells is demonstrated, enabling the use of blood monovettes preloaded with A. fumigatus lysate for bedside inoculation with whole blood. The application of the assay for determining A. fumigatus specific T-cells was examined in hemato-oncological patients before and three months after stem cell transplantation. A particularly limiting factor for successful measurement in this context is the reduced cell count of measured lymphocytes. Due to the generally low success rate of 20% before and 54% after HSCT, the applicability of the assay in this cohort is questionable. The assessment of A. fumigatus exposure factors in healthy subjects allows for classification into a group with weak and strong A. fumigatus exposure, with a significantly increased proportion of A. fumigatus specific CD154+/CD4+ cells. The presence of antigen-specific memory T-cells, as a correlate of long-term exposure, particularly contributes to this. Retrospectively, an increase in CD154+/CD4+ specific T-cells was also observed after short-term occupational exposure. This suggests that CD154+/CD4+ specific T-cells could be used as biomarkers in environmental medicine assessments of mold exposure or in the diagnosis of allergic diseases. KW - Aspergillus fumigatus KW - Durchflusscytometrie KW - Aspergillose KW - Immunologie KW - T-Zellimmunität KW - CD154 Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371145 ER - TY - THES A1 - Kußberger, Julia Bettina T1 - Protein - Biomarker zur Unterscheidung zwischen unipolarer und bipolarer Depression T1 - Protein - Biomarkers for Differentiating Between Unipolar and Bipolar Depression N2 - Die Diagnosestellung von unipolarer und bipolarer Depression basiert bis heute ausschließlich auf der Bewertung klinischer Symptome. Objektive biochemische Marker, wie sie bei zahlreichen somatischen Krankheiten zur Diagnosestellung angewendet werden, sind bisher nicht verfügbar. Da sich die beide Krankheitsbilder vor allem in der depressiven Episode stark ähneln, ist eine Unterscheidung in diesem Krankheitsstadium häufig nicht eindeutig möglich. Dies kann zu Fehldiagnosen, einer Verschlechterung des Krankheitsverlaufs, einer erhöhten Krankheitslast und höheren Gesundheitskosten führen. Periphere Biomarker wären daher wertvoll, um die klinische Diagnosestellung zu unterstützen und eine adäquate Behandlung frühzeitige zu ermöglichen. In einer vorherigen Studie der Arbeitsgruppe haben Proteom-Analysen bestimmte Proteine wie den Wachstumsfaktor PDGF-BB und das Thrombospondin TSP-1 identifiziert, die potenziell als Biomarker fungieren könnten. In der vorliegenden Studie wurde untersucht, ob sich die Konzentration von PDGF-BB und TSP-1 im Blut zwischen Patient*innen mit unipolarer bzw. bipolarer Depression signifikant unterscheidet. Es konnte gezeigt werden, dass PDGF-BB bei unipolaren Patientinnen signifikant niedriger ist als bei bipolaren Patientinnen und gesunden Kontrollpersonen. Zudem sank die PDGF-BB-Konzentration bei bipolaren Patientinnen während einer remittierten Episode im Vergleich zu einer depressiven Episode signifikant ab. Im Gegensatz dazu zeigte TSP-1 keine signifikanten Unterschiede zwischen den Patient*innengruppen und Kontrollpersonen. Die Arbeit konnte zeigen, dass PDGF-BB das Potenzial hat, als diagnostischer Biomarker für die Unterscheidung zwischen unipolarer und bipolarer Depression zu dienen, während TSP-1 in dieser Hinsicht nicht geeignet erscheint. Weitere Forschung ist jedoch notwendig, um die Rolle von PDGF-BB in der Pathogenese affektiver Erkrankungen besser zu verstehen und seinen Einsatz als Biomarker im klinischen Alltag zu validieren.   N2 - The diagnosis of unipolar and bipolar depression is still based on clinical symptoms. Objective biochemical markers, which are commonly used for diagnosing somatic diseases, are not yet available. Since both conditions, particularly during the depressive phase, exhibit very similar symptoms, distinguishing between them in this stage is often complicated. This can lead to misdiagnosis, a worsening of the disease course, increased disease burden, and higher healthcare costs. Peripheral biomarkers would therefore be of great value in supporting clinical diagnosis and enabling early and appropriate treatment. A previous study by our research group identified proteins such as the growth factor PDGF-BB and thrombospondin TSP-1 through proteomic analysis, which could potentially serve as biomarkers. In the present study, the concentrations of PDGF-BB and TSP-1 in the blood of patients with unipolar and bipolar depression were examined to determine if there were significant differences. The results showed that PDGF-BB levels were significantly lower in unipolar patients compared to bipolar patients and healthy controls. Additionally, PDGF-BB concentrations decreased significantly in bipolar patients during a remitted episode compared to a depressive episode. In contrast, TSP-1 did not show significant differences between the groups studied. The study suggests that PDGF-BB has the potential to serve as a diagnostic biomarker for differentiating between unipolar and bipolar depression, whereas TSP-1 appears less suitable in this context. However, further research is needed to better understand the role of PDGF-BB in the pathogenesis of affective disorders and to validate its clinical utility as a biomarker. KW - Differentialdiagnose KW - Depression KW - Biomarker KW - Affektive Erkrankungen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371109 ER - TY - THES A1 - Hinsch, Jan Per T1 - Die Geschichte der Metalllegierungen in der zahnärztlichen Prothetik und Technologie T1 - The History of Metal Alloys in Dental Prosthetics and Technology N2 - Die vorliegende Promotionsstudie leistet durch Gewinnung neuer Erkenntnisse zur zahnmedizinisch (technik-)historischen Forschung mittels der Erarbeitung und Darstellung einer chronologisch geordneten Entwicklungsgeschichte der zahnärztlich-prothetisch verwendeten Metalllegierungen sowie ihrer dentalen Technologie einen eigenständigen Forschungsbeitrag und trägt damit zu neuen Erkenntnissen in der zahnmedizinisch-historischen Forschung bei. Als problematisch stellte sich zu Beginn des 19. Jahrhunderts die Kunst des Legierens selbst heraus. So legierten und fertigten die Zahnärzte ihre Metalllegierungen bis zum Ende des 19. Jahrhunderts meistens noch selbst, bedienten sich an vorlegierten Dukatengoldlegierungen oder beauftragten Goldschmiede. Diverse nützliche Legierungskompositionen wurden schriftlich von Pionieren der Zahnheilkunde und den ersten, erfahrensten Prothetikern dieser Zeit in deren frühen Lehrbüchern und Veröffentlichungen festgehalten und damit der breiten Zahnärzteschaft zugänglich gemacht. Mit ihrem Engagement wurde der Weg von der Empirie nicht nur bis zur Verwissenschaftlichung der Zahnmedizin geebnet, sondern zugleich der Fortschritt der dentalen Materialwissenschaft und besonders der Verarbeitungstechnologie dentaler Metalllegierungen eingeläutet. Erst zu Beginn des 20. Jahrhunderts etablierte sich durch Forschung und Vernetzung von Chemie, Metallurgie, Industrie und Zahnmedizin eine sach- und fachkundige zahnärztliche Werkstoffkunde mit speziellen prothetisch geeigneten Metalllegierungen. Die verschiedenen Typenbezeichnungen Goldersatzlegierungen, Austauschlegierungen, Alternativlegierungen oder Aufbrennlegierungen waren in jeder Epoche einem tiefgreifenden Wandel unterworfen und charakteristisch für die jeweilige Zeit. Eine wichtige Erkenntnis aus dieser Studie ist, dass politisch-ökonomische Veränderungen, insbesondere schwankende Edelmetallpreise, Inflation, politische Beschränkungen aufgrund von (vor-)kriegswirtschaftlichen Sparmaßnahmen sowie Gesundheitsreformen und Kostendämpfungsgesetze einen erheblichen Einfluss auf die Zahnärzte und die zahnmedizinisch-prothetische Rehabilitation ihrer Patienten hatte. Die indikationsgerechte Metalllegierungsauswahl und die damit verbundenen optimalen Materialeigenschaften für Zahnersatz und Patienten stellten Zahnärzte damals wie heute vor eine Herausforderung. N2 - This doctoral study makes an independent research contribution by gaining new insights into the history of dentistry (technology) by developing and presenting a chronologically ordered development history of the metal alloys used in dental prosthetics and their dental technology, and thus contributes to new findings in dental historical research. At the beginning of the 19th century, the art of alloying itself proved to be problematic. Up until the end of the 19th century, dentists mostly alloyed and manufactured their metal alloys themselves, using pre-alloyed ducat gold alloys or commissioning goldsmiths. Various useful alloy compositions were recorded in writing by pioneers of dentistry and the first, most experienced prosthodontists of the time in their early textbooks and publications, thus making them accessible to the general dental community. Their commitment not only paved the way from empiricism to the scientification of dentistry, but also ushered in progress in dental materials science and particularly in the processing technology of dental metal alloys. It was not until the beginning of the 20th century that a professional and expert dental materials science with special metal alloys suitable for prosthetics was established through research and networking between chemistry, metallurgy, industry and dentistry. The various type designations gold replacement alloys, exchange alloys, alternative alloys or bonding alloys were subject to profound change in every era and were characteristic of the respective time. An important finding from this study is that political and economic changes, in particular fluctuating precious metal prices, inflation, political restrictions due to (pre-)war economic austerity measures as well as health reforms and cost containment laws had a significant impact on dentists and the dental and prosthetic rehabilitation of their patients. The selection of metal alloys appropriate to the indication and the associated optimal material properties for dentures and patients presented a challenge to dentists then and now. KW - Prothetik KW - Geschichte KW - Dentallegierung KW - Metalllegierungen KW - Dentaltechnologie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371285 ER - TY - THES A1 - Beck [geb. Liebetanz], Lina T1 - Die Rolle CD8\(^+\) T-Zellen in der Atherosklerose T1 - The role of CD8\(^+\) T cells in atherosclerosis N2 - Atherosklerose ist eine chronisch inflammatorische Erkrankung der Gefäßwände, bei der sowohl die angeborene als auch die erworbene Immunantwort beteiligt ist. Von Monozyten abstammende Makrophagen spielen eine Schlüsselrolle bei der Entstehung atherosklerotischer Läsionen. Durch die Aufnahme modifizierte Lipide (z.B. oxLDL) werden sie zu Schaumzellen, sezernieren inflammatorische Zytokine und befeuern somit die vaskuläre Entzündungsreaktion. Makrophagen können jedoch auch schützende Funktionen wahrnehmen, bspw. durch die antiinflammatorische Aufnahme apoptotischer Zellen, die Efferozytose. Um den Einfluss CD8+ T-Zellen auf Makrophagen zu bestimmen, wurde ein in vitro Model gewählt, in dem aktivierte CD8+ T-Zellen mit aus Knochenmark isolierten Makrophagen kokultiviert wurden. Zunächst konnte gezeigt werden, dass CD8+ T-Zellen die oxLDL Aufnahme und Schaumzellbildung der Makrophagen fördern, assoziiert mit der gesteigerten Expression des oxLDL Rezeptors CD36 und verminderten Expression des reversen Cholesterintransporters ABCA1. Zusätzlich reduzierten CD8+ T-Zellen die Phagozytose apoptotischer Zellen und die Sekretion des antiinflammatorischen Zytokins IL-10 als Antwort auf die Aufnahme apoptotischer Zellen, was auf eine verminderte Efferozytose hindeutet. Zudem förderten CD8+ T-Zellen die Expression des proinflammatorischen M1-Polarisationsmarker iNOS in Makrophagen und die Sekretion des proatherogenen Chemokins CCL2. Durch die Zugabe neutralisierender Antikörper in die in vitro Kultur konnte gezeigt werden, dass die aufgeführten Prozesse teilweise von den klassischen Effektorzytokinen der CD8+ T-Zellen, INFγ und TNFα, abhängen. Zusammenfassend zeigen unsere Daten, dass CD8+ T-Zellen die Ausbildung eines proatherogenen Phänotyps der Makrophagen, durch die Steigerung der Schaumzellbildung und Förderung der proinflammatorischen Makrophagenpolarisation, sowie die Inhibierung der antiinflammatorischen Efferozytosefunktion, bewirken. N2 - Atherosclerosis is a chronic inflammatory disease of the vessel wall involving innate and adaptive immune responses. Monocyte-derived macrophages play a key role in atherosclerotic lesion formation, by developing into foam cells upon modified lipid (e.g. oxLDL) ingestion and secreting inflammatory cytokines to further fuel vascular inflammation. However, macrophages also have protective functions such as the anti-inflammatory disposal of apoptotic cells by efferocytosis. To determine the influence of CD8+ T cells on macrophages, we used an in vitro model system where activated CD8+ T cells were co-cultured with bone marrow derived macrophages. We first demonstrated that CD8+ T cells promoted macrophage oxLDL uptake and foam cell formation associated with increased expression of the oxLDL receptor CD36, and decreased expression of the reverse cholesterol transporter ABCA1. CD8+ T cells also reduced macrophage apoptotic cell phagocytosis and anti-inflammatory IL-10 release in response to apoptotic cell engulfment, indicating diminished efferocytosis. Finally, CD8+ T cells promoted expression of the pro-inflammatory M1 polarization marker iNOS in macrophages, as well as secretion of the pro-atherogenic chemokine CCL2. These processes were partially dependent on the CD8+ T cell effector cytokines IFNγ and TNFα, as revealed by the addition of neutralizing antibodies in our in vitro co-culture system. In conclusion, our data shows that CD8+ T cells promote a pro-atherogenic phenotype in macrophages in vitro, increasing their foam cell formation and pro-inflammatory potential while inhibiting efferocytosis. KW - Immunität KW - CD8+ T-Zellen KW - Arteriosklerose KW - Atherosklerose Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371344 ER - TY - THES A1 - Makowski, Lisa Maria T1 - Erfahrungen von HausärztInnen mit der COVID-19-Pandemie und deren Folgen auf die PatientInnenversorgung – eine qualitative Studie T1 - GPs' experiences of the COVID-19 pandemic and its impact on patient care - a qualitative study N2 - HausärztInnen sind für die Primärversorgung von PatientInnen mit COVID-19 zuständig. Zum Zeitpunkt der Planung und Durchführung dieser Studie ließen sie kaum Untersuchungen zu den Erfahrungen von HausärztInnen während der ersten Pandemiewelle finden. Das Ziel der Arbeit war, durch eine qualitative Datenerhebung Einblicke zu gewinnen, wie HausärztInnen die ersten Monate der COVID-19-Pandemie erlebt haben. Die Untersuchung war Teil einer übergeordneten Querschnittsstudie, in der Erhebungen mit strukturierten Fragebögen und qualitativen Befragungen stattfanden. Für den qualitativen Abschnitt wurden semistrukturierte Interviews mit 22 HausärztInnen aus vier Bundesländern durchgeführt. Die Einladung zur Teilnahme erfolgte mit der Aussendung von Fragebögen im Rahmen der quantitativen Datenerhebung. Die Daten wurden anhand der inhaltlich strukturierenden qualitativen Inhaltsanalyse nach Kuckartz ausgewertet. In der Studie zeigte sich, dass HausärztInnen ihr Praxismanagement und ihre PatientInnenversorgung in der Pandemie rasch umstrukturieren mussten. Mangel an Schutzmaterialien, die Trennung infektiöser PatientInnen und schnell wechselnde Vorgaben wurden als große Herausforderungen identifiziert. In den Interviews wurden außerdem Bedenken über die Folgen der sozialen Distanzierung auf die therapeutische Beziehung geäußert. Teamarbeit in der Praxis und kollegialer Austausch in Gemeinschaftspraxen stellten besonders wichtige Faktoren dar, um die zahlreichen Herausforderungen zu überwinden. Die Teilnehmenden nahmen sich selbst als Vorbilder mit einer hohen Verantwortung für die Gesundheit ihrer PatientInnen wahr.. Sie betonten die Relevanz von klaren und konsistenten Regelungen durch den öffentlichen Gesundheitsdienst sowie von zuverlässigen Informationen. Um die hausärztliche Versorgung in zukünftigen Pandemien zu unterstützen, sollten bürokratische Hürden so weit wie möglich reduziert und verständliche Informationen bereitgestellt werden. Da HausärztInnen eine zentrale Rolle in der Beratung und Therapie von PatientInnen mit COVID-19 spielten, erscheint deren konsistente Einbeziehung in Entscheidungsprozesse durch Institutionen des öffentlichen Gesundheitsdienstes von besonderer Wichtigkeit. N2 - General practitioners (GPs) are responsible for providing primary care for patients with COVID-19. At the time of planning and conducting this study, little was known about the experiences of GPs during the first wave of the pandemic. In this qualitative study, the aim was to gain insight into GPs’ experiences of the first months of the COVID-19 pandemic. The investigation was part of a cross-sectional study, using questionnaires and qualitative interviews. In the qualitative study, semi-structured interviews were conducted with 22 GPs from four federal states. The participants were invited to participate by sending out the quantitative surveys. Data was analysed using Kuckartz’s qualitative structuring content analysis. The study showed that GPs had to quickly restructure their practice routines and patient care during the pandemic. Lack of personal protective equipment, separation of infectious patients and rapidly changing guidelines were identified as major barriers. In the interviews, GPs expressed concerns about how social distancing might affect the therapeutic relationship. Teamwork in the practice and collegial exchange were important factors in overcoming numerous challenges. The participants perceived themselves as role models with a high responsibility for the health of their patients. They stressed the relevance of clear and consistent guidance by health authorities and reliable information. To support primary care in future health crises, bureaucratic hurdles should be reduced as much as possible and clear information should be provided. As GPs played a key role in providing care for patients with COVID-19, their consistent involvement in decision-making processes from health authorities seems particularly important. KW - Hausarzt KW - COVID-19 KW - Qualitative Methode KW - Hausarzt/-ärztin KW - Qualitative Studie KW - COVID-19-Pandemie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371233 ER - TY - THES A1 - Dorband, Moritz T1 - Geometric Phases and Factorisation in Quantum Physics and Gravity T1 - Geometrische Phasen und Faktorisierung in Quantenphysik und Gravitation N2 - 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. N2 - In dieser Arbeit untersuche ich das Zusammenspiel von Geometrie und Quanteninformation mit Hilfe des holografischen Prinzips. Dabei konzentriere ich mich besonders auf geometrische Phasen in Quantensystemen wie zwei wechselwirkenden Qubits und darauf, wie sie mit Verschränkungsmaßen und Hilbert-Raum-Faktorisierung zusammenhängen. Ich führe geometrische Phasen als Indikator für die Faktorisierung des Hilbert-Raums ein, sowohl in einem abstrakten Sinne unter Verwendung von von Neumann-Operator-Algebren als auch angewandt auf das ewige Schwarze Loch im Rahmen der AdS/CFT-Korrespondenz. im zweiten Fall zeige ich, dass geometrische Phasen es erlauben, die Nicht-Faktorisierung von der Randperspektive aus zu diagnostizieren. Außerdem führe ich die geometrische Quantendiskordanz als zweites geometrisches Maß für die Nicht-Faktorisierung ein und zeige ihre möglichen Auswirkungen auf die Untersuchung von Mikrozuständen Schwarzer Löcher auf. KW - AdS-CFT-Korrespondenz KW - Schwarzes Loch KW - Quanteninformation KW - VonNeumann-Algebra KW - Berry-Phase KW - Hilbert space factorisation KW - Quantum information KW - AdS/CFT correspondence KW - Geometric phase KW - VonNeumann algebra Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370937 ER - TY - THES A1 - Kappenberger, Jeannette Sarah T1 - Biochemical characterization of the TFIIH translocase XPB from \(Chaetomium\) \(thermophilum\) T1 - Biochemische Charakterisierung der TFIIH Translokase XPB aus \(Chaetomium\) \(thermophilum\) N2 - 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. N2 - DNA Reparatur und Genexpression sind zwei fundamentale zelluläre Prozesse die unabdingbar für die Aufrechterhaltung des biologischen Lebens sind. Beide Prozesse benötigen die Enzymaktivität der Superfamilie 2 Helikase XPB, welche eine Untereinheit des Transkriptionsfaktors TFIIH darstellt. Während der Transkriptions-Initiation katalysiert XPB das initiale Aufschmelzen der Promoter-DNA und befähigt dadurch die RNA-Polymerase II dazu an den codierenden DNA Strang zu binden und die Genexpression zu starten. In der Nukleotid-Exzisions-Reparatur agiert XPB zusammen mit der zweiten TFIIH Helikase, XPD, und bewirkt die Öffnung des DNA Stranges an der Stelle des DNA-Schadens. Mutationen des XPB-Gens oder der Gene der anderen TFIIH Untereinheiten sind mit verschiedenen Krebsarten, sowie den autosomal rezessiv vererbten Krankheiten Xeroderma Pigmentosum und Trichothiodystrophie assoziiert. In seltenen Fällen kann eine kombinierte Form von Xeroderma Pigmentosum und Cockayne Syndrom auftreten. In den letzten Jahren wurde mittels der Cryo-EM die Strukturaufklärung von TFIIH und seinen Untereinheiten einschließlich XPB signifikant vorangebracht. Diese neuen strukturellen Einsichten haben unser Verständnis über den molekularen Aufbau des TFIIH Komplexes entscheidend verbessert. Jedoch sind die Regulationsmechanismen, die XPB auf funktionaler Ebene kontrollieren, noch größtenteils unbekannt. Um das funktionelle Netzwerk, das XPB innerhalb von TFIIH reguliert, zu erforschen, haben wir die biochemische Charakterisierung von XPB verfolgt. Aufgrund ihrer erhöhten Stabilität gegenüber den humanen Proteinen wurden für diese Analyse die Proteine des thermophilen Pilzes Chaetomium thermophilum als Modellorganismus für TFIIH verwendet. Die vorgelegte Arbeit liefert neue Erkenntnisse über die enzymatische Funktion und Regulation von XPB. Wir konnten zeigen, dass sowohl DNA, als auch die TFIIH Untereinheit p52 die ATPase Aktivität von XPB stimulieren und dass die p52-vermittelte Aktivierung durch p8, eine weitere Untereinheit von TFIIH, noch weiter verstärkt wird. In Gegenwart von DNA beobachtet man jedoch die höchste ATPase Aktivität. Wenn beide Aktivatoren, also p52/p8 und DNA, gleichzeitig anwesend waren, dominierte die niedrige p52-vermittelte Aktivierung gegenüber der DNA-vermittelten Aktivierung. Das p52-Protein agiert also als Aktivator und Deaktivator indem es die enzymatische Aktivität des XPB-Proteins gleichzeitig aktiviert und hemmt und kann damit folglich als Hauptregulator von XPB bezeichnet werden. Basierend auf einer korrelativen Mutagenese-Analyse der Interaktionsfläche zwischen p52 und XPB sowie auf den aktuellsten Strukturdaten, wurde ein Modell für die p52-vermittelte Aktivierung und Geschwindigkeitsregulierung von XPBs ATPase generiert. Des Weiteren wurde der Einfluss des Naturproduktes Triptolid auf die Hemmung der enzymatischen Aktivität des XPB Proteins untersucht. Darüber hinaus haben wir die doppelsträngige DNA-Translokase-Aktivität von XPB analysiert und konnten feststellen, dass die Translokation nur erfolgen kann, wenn XPB vollständig in den Kern-TFIIH-Komplex integriert ist. Der Nukleotid-Exzisions-Reparatur- Faktor XPA stimulierte diese Translokase-Aktivität zusätzlich. Fluoreszenz-Polarisations-Messungen mit Nukleotid-Analoga zeigten, dass XPB die höchste Affinität für DNA im ADP + Pi gebundenen Zustand aufweist und dass diese Bindung gelockert wird, wenn ADP gebunden oder das Nukleotid dissoziiert ist. Dies deutet auf einen Bewegungsmechanismus auf der DNA während der verschiedenen Stadien des ATPase-Zyklus hin. Abschließend konnten wir zeigen, dass das hochkonservierte RED-Motiv eine entscheidende Rolle für die Translokase Bewegung des XPB-Proteins einnimmt. Zusammenfassend präsentiert diese Arbeit neue Erkenntnisse, die unser Verständnis des Regulierungsnetzwerkes, das die enzymatische Aktivität von XPB innerhalb von TFIIH steuert, entscheidend vorangebracht haben. KW - DNS-Reparatur KW - Xeroderma pigmentosum KW - Helicasen KW - Transkriptionsfaktor KW - Nucleotide Excision Repair Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244096 ER - TY - JOUR T1 - Electron and photon energy calibration with the ATLAS detector using 2015-2016 LHC proton-proton collision data JF - Journal of Instrumentation N2 - 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. KW - Calorimeter methods KW - Partib distributions KW - Pattern recognition KW - cluster finding KW - calibration and fitting methods KW - Performance of High Energy Physics Detectors KW - Liquid AR KW - Calorimeter KW - KR Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-314093 VL - 14 ER - TY - JOUR A1 - Müntze, Jonas A1 - Gensler, Daniel A1 - Maniuc, Octavian A1 - Liu, Dan A1 - Cairns, Tereza A1 - Oder, Daniel A1 - Hu, Kai A1 - Lorenz, Kristina A1 - Frantz, Stefan A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year JF - Clinical Pharmacology & Therapeutics N2 - 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. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231626 VL - 105 ER - TY - JOUR A1 - Schubert, Frank K. A1 - Hagedorn, Nicolas A1 - Yoshii, Taishi A1 - Helfrich-Förster, Charlotte A1 - Rieger, Dirk T1 - Neuroanatomical details of the lateral neurons of Drosophila melanogaster support their functional role in the circadian system JF - Journal of Comparative Neurology N2 - 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. KW - circadian clock neurons KW - Drosophila melanogaster KW - flybow KW - morphology KW - RRID: AB_760350 KW - RRID: AB_2315460 KW - RRID: AB_2314242 KW - RRID: AB_2315311 KW - RRID: AB_2314041 KW - RRID: AB_300798 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234477 VL - 526 ER - TY - JOUR A1 - Schwarz, Christopher A1 - Scharf, Lennart T. A1 - Scherpf, Thorsten A1 - Weismann, Julia A1 - Gessner, Viktoria H. T1 - Isolation of the Metalated Ylides [Ph3P−C−CN]M (M=Li, Na, K): Influence of the Metal Ion on the Structure and Bonding Situation JF - Chemistry – A European Journal N2 - 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. KW - alkali metals KW - bond theory KW - lithium KW - structure elucidation KW - solid-state structures KW - ylides Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235445 VL - 25 ER - TY - JOUR A1 - Chen, Dan A1 - Gehringer, Matthias A1 - Lorenz, Sonja T1 - Developing Small-Molecule Inhibitors of HECT-Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities JF - ChemBioChem N2 - 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. KW - drug discovery KW - enzymes KW - inhibitors KW - reaction mechanisms KW - structure-activity relationships KW - ubiquitin Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222412 VL - 19 ER - TY - JOUR A1 - Wilson, Duncan A1 - Ambler, Gareth A1 - Lee, Keon-Joo A1 - Lim, Jae-Sung A1 - Shiozawa, Masayuki A1 - Koga, Masatoshi A1 - Li, Linxin A1 - Lovelock, Caroline A1 - Chabriat, Hugues A1 - Hennerici, Michael A1 - Wong, Yuen Kwun A1 - Mak, Henry Ka Fung A1 - Prats-Sánchez, Luis A1 - Martínez-Domeño, Alejandro A1 - Inamura, Shigeru A1 - Yoshifuji, Kazuhisa A1 - Arsava, Ethem Murat A1 - Horstmann, Solveig A1 - Purrucker, Jan A1 - Lam, Bonnie Yin Ka A1 - Wong, Adrian A1 - Kim, Young Dae A1 - Song, Tae-Jin A1 - Schrooten, Maarten A1 - Lemmens, Robin A1 - Eppinger, Sebastian A1 - Gattringer, Thomas A1 - Uysal, Ender A1 - Tanriverdi, Zeynep A1 - Bornstein, Natan M A1 - Ben Assayag, Einor A1 - Hallevi, Hen A1 - Tanaka, Jun A1 - Hara, Hideo A1 - Coutts, Shelagh B A1 - Hert, Lisa A1 - Polymeris, Alexandros A1 - Seiffge, David J A1 - Lyrer, Philippe A1 - Algra, Ale A1 - Kappelle, Jaap A1 - Salman, Rustam Al-Shahi A1 - Jäger, Hans R A1 - Lip, Gregory Y H A1 - Mattle, Heinrich P A1 - Panos, Leonidas D A1 - Mas, Jean-Louis A1 - Legrand, Laurence A1 - Karayiannis, Christopher A1 - Phan, Thanh A1 - Gunkel, Sarah A1 - Christ, Nicolas A1 - Abrigo, Jill A1 - Leung, Thomas A1 - Chu, Winnie A1 - Chappell, Francesca A1 - Makin, Stephen A1 - Hayden, Derek A1 - Williams, David J A1 - Kooi, M Eline A1 - van Dam-Nolen, Dianne H K A1 - Barbato, Carmen A1 - Browning, Simone A1 - Wiegertjes, Kim A1 - Tuladhar, Anil M A1 - Maaijwee, Noortje A1 - Guevarra, Christine A1 - Yatawara, Chathuri A1 - Mendyk, Anne-Marie A1 - Delmaire, Christine A1 - Köhler, Sebastian A1 - van Oostenbrugge, Robert A1 - Zhou, Ying A1 - Xu, Chao A1 - Hilal, Saima A1 - Gyanwali, Bibek A1 - Chen, Christopher A1 - Lou, Min A1 - Staals, Julie A1 - Bordet, Régis A1 - Kandiah, Nagaendran A1 - de Leeuw, Frank-Erik A1 - Simister, Robert A1 - van der Lugt, Aad A1 - Kelly, Peter J A1 - Wardlaw, Joanna M A1 - Soo, Yannie A1 - Fluri, Felix A1 - Srikanth, Velandai A1 - Calvet, David A1 - Jung, Simon A1 - Kwa, Vincent I H A1 - Engelter, Stefan T A1 - Peters, Nils A1 - Smith, Eric E A1 - Yakushiji, Yusuke A1 - Necioglu Orken, Dilek A1 - Fazekas, Franz A1 - Thijs, Vincent A1 - Heo, Ji Hoe A1 - Mok, Vincent A1 - Veltkamp, Roland A1 - Ay, Hakan A1 - Imaizumi, Toshio A1 - Gomez-Anson, Beatriz A1 - Lau, Kui Kai A1 - Jouvent, Eric A1 - Rothwell, Peter M A1 - Toyoda, Kazunori A1 - Bae, Hee-Yoon A1 - Marti-Fabregas, Joan A1 - Werring, David J T1 - Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies JF - The Lancet Neurology N2 - 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. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233710 VL - 18 ER - TY - JOUR A1 - Waszak, Sebastian M A1 - Northcott, Paul A A1 - Buchhalter, Ivo A1 - Robinson, Giles W A1 - Sutter, Christian A1 - Groebner, Susanne A1 - Grund, Kerstin B A1 - Brugières, Laurence A1 - Jones, David T W A1 - Pajtler, Kristian W A1 - Morrissy, A Sorana A1 - Kool, Marcel A1 - Sturm, Dominik A1 - Chavez, Lukas A1 - Ernst, Aurelie A1 - Brabetz, Sebastian A1 - Hain, Michael A1 - Zichner, Thomas A1 - Segura-Wang, Maia A1 - Weischenfeldt, Joachim A1 - Rausch, Tobias A1 - Mardin, Balca R A1 - Zhou, Xin A1 - Baciu, Cristina A1 - Lawerenz, Christian A1 - Chan, Jennifer A A1 - Varlet, Pascale A1 - Guerrini-Rousseau, Lea A1 - Fults, Daniel W A1 - Grajkowska, Wiesława A1 - Hauser, Peter A1 - Jabado, Nada A1 - Ra, Young-Shin A1 - Zitterbart, Karel A1 - Shringarpure, Suyash S A1 - De La Vega, Francisco M A1 - Bustamante, Carlos D A1 - Ng, Ho-Keung A1 - Perry, Arie A1 - MacDonald, Tobey J A1 - Driever, Pablo Hernáiz A1 - Bendel, Anne E A1 - Bowers, Daniel C A1 - McCowage, Geoffrey A1 - Chintagumpala, Murali M A1 - Cohn, Richard A1 - Hassall, Timothy A1 - Fleischhack, Gudrun A1 - Eggen, Tone A1 - Wesenberg, Finn A1 - Feychting, Maria A1 - Lannering, Birgitta A1 - Schüz, Joachim A1 - Johansen, Christoffer A1 - Andersen, Tina V A1 - Röösli, Martin A1 - Kuehni, Claudia E A1 - Grotzer, Michael A1 - Kjaerheim, Kristina A1 - Monoranu, Camelia M A1 - Archer, Tenley C A1 - Duke, Elizabeth A1 - Pomeroy, Scott L A1 - Shelagh, Redmond A1 - Frank, Stephan A1 - Sumerauer, David A1 - Scheurlen, Wolfram A1 - Ryzhova, Marina V A1 - Milde, Till A1 - Kratz, Christian P A1 - Samuel, David A1 - Zhang, Jinghui A1 - Solomon, David A A1 - Marra, Marco A1 - Eils, Roland A1 - Bartram, Claus R A1 - von Hoff, Katja A1 - Rutkowksi, Stefan A1 - Ramaswamy, Vijay A1 - Gilbertson, Richard J A1 - Korshunov, Andrey A1 - Taylor, Michael D A1 - Lichter, Peter A1 - Malkin, David A1 - Gajjar, Amar A1 - Korbel, Jan O A1 - Pfister, Stefan M T1 - Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort JF - The Lancet Oncology N2 - 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. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233425 VL - 19 ER - TY - JOUR A1 - Kampf, Thomas A1 - Reiter, Theresa A1 - Bauer, Wolfgang Rudolf T1 - 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 JF - Zeitschrift für Medizinische Physik N2 - 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. T2 - Ein analytisches Modell, das die apparente T1 Zeit für Modfied Look-Locker Inversion Recovery bestimmt-Analyse der longitudinalen Relaxation unter dem Einfluss diskontinuierlicher balanced (klassische MOLLI) und spoiled gradient echo readouts KW - longitudinal relaxation KW - T1 KW - T2 KW - Lock Locker KW - MOLLI KW - balanced steady state free precession KW - spoiled gradient echo Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325498 VL - 28 ER - TY - JOUR A1 - Kampf, Thomas A1 - Bauer, Wolfgang Rudolf A1 - Reiter, Theresa T1 - Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function JF - Zeitschrift für Medizinische Physik N2 - 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. KW - T1-mapping KW - ECV KW - MOLLI KW - post-processing Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325481 VL - 28 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Fomin, Victor V. A1 - Hilz, Max J. A1 - Jovanovic, Ana A1 - Kantola, Ilkka A1 - Linhart, Aleš A1 - Renzo, Mignani A1 - Namdar, Mehdi A1 - Nowak, Albina A1 - Oliveira, João-Paulo A1 - Pieroni, Maurizio A1 - Viana-Baptista, Miguel A1 - Wanner, Christoph A1 - Spada, Marco T1 - 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 JF - Molecular Genetics and Metabolism Reports N2 - 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. KW - Fabry disease KW - systematic literature review KW - agalsidase beta KW - agalsidase alfa KW - enzyme replacement therapy KW - adult male patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232987 VL - 19 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Urlaub, Daniela A1 - Mayer, Christine A1 - Uehlein, Sabrina A1 - Held, Melissa A1 - Sommer, Claudia T1 - Tumor necrosis factor-α links heat and inflammation with Fabry pain JF - Molecular Genetics and Metabolism N2 - 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. KW - Fabry disease KW - Fabry pain KW - tumor necrosis factor-α KW - peripheral blood mononuclear cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229190 VL - 127 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Arad, Michael A1 - Burlina, Alessandro A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Feldt-Rasmussen, Ulla A1 - Hilz, Max J. A1 - Hughes, Derralynn A. A1 - Ortiz, Alberto A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Spada, Marco T1 - 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 JF - Molecular Genetics and Metabolism N2 - 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. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - adult female patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232963 VL - 126 ER - TY - JOUR A1 - Spada, Marco A1 - Baron, Ralf A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Hilz, Max J. A1 - Monserrat, Lorenzo A1 - Tøndel, Camilla A1 - Tylki-Szymańska, Anna A1 - Wanner, Christoph A1 - Germain, Dominique P. T1 - 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 JF - Molecular Genetics and Metabolism N2 - 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. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - paediatric patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239287 VL - 126 ER - TY - JOUR A1 - Flunkert, Julia A1 - Maierhofer, Anna A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Horvath, Steve A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts JF - Experimental Cell Research N2 - 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. KW - copy number variation (CNV) KW - delayed radiation effects KW - DNA methylation (DNAm) age KW - global DNA methylation KW - loss of chromosome Y (LOY); KW - methylation array analysis KW - radiation-induced genome instability (RIGI) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228177 VL - 370 ER - TY - JOUR A1 - Omeñaca, Felix A1 - Vázquez, Liliana A1 - Garcia-Corbeira, Pilar A1 - Mesaros, Narcisa A1 - Hanssens, Linda A1 - Dolhain, Jan A1 - Puente Gómez, Ivonne A1 - Liese, Johannes A1 - Knuf, Markus T1 - 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 JF - Vaccine N2 - 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. KW - DTPa-HBV-IPV/Hib KW - hexavalent vaccine KW - primary vaccination KW - preterm KW - premature Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234450 VL - 36 ER - TY - JOUR A1 - Feistauer, Daniela A1 - Richter, Tobias T1 - Validity of students’ evaluations of teaching: Biasing effects of likability and prior subject interest JF - Studies in Educational Evaluation N2 - 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. KW - cross-classified multilevel analysis KW - likability KW - prior subject interest KW - student evaluations of teaching KW - variance components Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228005 VL - 59 ER - TY - JOUR A1 - Grayston, Rebecca A1 - Czanner, Gabriela A1 - Elhadd, Kareim A1 - Goebel, Andreas A1 - Frank, Bernhard A1 - Üçeyler, Nurcan A1 - Malik, Rayaz A A1 - Alam, Uazman T1 - A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis JF - Seminars in Arthritis and Rheumatism N2 - 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. KW - small nerve fibres KW - pain KW - fibromyalgia KW - skin biopsy KW - corneal confocal microscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227566 VL - 48 ER - TY - JOUR A1 - Taubenböck, H. A1 - Weigand, M. A1 - Esch, T. A1 - Staab, J. A1 - Wurm, M. A1 - Mast, J. A1 - Dech, S. T1 - A new ranking of the world's largest cities—Do administrative units obscure morphological realities? JF - Remote Sensing of Environment N2 - 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. KW - city size KW - urban agglomeration KW - rank-size distribution KW - remote sensing KW - global urban footprint KW - urban morphology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240634 VL - 232 ER - TY - JOUR A1 - Nanadikar, Maithily S. A1 - Vergel Leon, Ana M. A1 - Borowik, Sergej A1 - Hillemann, Annette A1 - Zieseniss, Anke A1 - Belousov, Vsevolod V. A1 - Bogeski, Ivan A1 - Rehling, Peter A1 - Dudek, Jan A1 - Katschinski, Dörthe M. T1 - O2 affects mitochondrial functionality ex vivo JF - Redox Biology N2 - 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. KW - glutathione redox potential KW - hypoxia KW - mitochondrial matrix KW - Grx1-roGFP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232217 VL - 22 ER - TY - JOUR A1 - Kiser, Dominik P. A1 - Popp, Sandy A1 - Schmitt-Böhrer, Angelika G. A1 - Strekalova, Tatyana A1 - van den Hove, Daniel L. A1 - Lesch, Klaus-Peter A1 - Rivero, Olga T1 - Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice JF - Progress in Neuropsychopharmacology & Biological Psychiatry N2 - 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 naïve 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. KW - Cadherin-13 (CDH13) KW - T-cadherin KW - neurodevelopment KW - autism KW - ADHD KW - depression KW - psychiatric disorders KW - early-life stress KW - mouse KW - RNA sequencing KW - endoplasmic reticulum stress KW - adhesion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325859 VL - 89 ER - TY - JOUR A1 - Faber, T. A1 - Hudec, M. A1 - Malinský, M. A1 - Meinzinger, P. A1 - Porod, W. A1 - Staub, F. T1 - A unified leptoquark model confronted with lepton non-universality in B-meson decays JF - Physics Letters B N2 - 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. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227419 VL - 787 ER - TY - RPRT A1 - Geßner, Daniel T1 - Rethinking renewable energy policies for hydrogen – How the intercept of electricity and hydrogen markets can be addressed N2 - 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. T3 - Würzburg Economic Papers (W. E. P.) - 111 KW - Wasserstoff KW - Öffentliche Förderung KW - Contract for Difference KW - Elektrizitätsmarkt KW - Erneuerbare Energien KW - Hydrogen Policy KW - Renewable Energy Policy KW - Electricity Markets KW - Support Mechanisms KW - Contracts for Difference Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370973 ER - TY - JOUR A1 - Hauke, Jan A1 - Horvath, Judit A1 - Groß, Eva A1 - Gehrig, Andrea A1 - Honisch, Ellen A1 - Hackmann, Karl A1 - Schmidt, Gunnar A1 - Arnold, Norbert A1 - Faust, Ulrike A1 - Sutter, Christian A1 - Hentschel, Julia A1 - Wang-Gohrke, Shan A1 - Smogavec, Mateja A1 - Weber, Bernhard H. F. A1 - Weber-Lassalle, Nana A1 - Weber-Lassalle, Konstantin A1 - Borde, Julika A1 - Ernst, Corinna A1 - Altmüller, Janine A1 - Volk, Alexander E. A1 - Thiele, Holger A1 - Hübbel, Verena A1 - Nürnberg, Peter A1 - Keupp, Katharina A1 - Versmold, Beatrix A1 - Pohl, Esther A1 - Kubisch, Christian A1 - Grill, Sabine A1 - Paul, Victoria A1 - Herold, Natalie A1 - Lichey, Nadine A1 - Rhiem, Kerstin A1 - Ditsch, Nina A1 - Ruckert, Christian A1 - Wappenschmidt, Barbara A1 - Auber, Bernd A1 - Rump, Andreas A1 - Niederacher, Dieter A1 - Haaf, Thomas A1 - Ramser, Juliane A1 - Dworniczak, Bernd A1 - Engel, Christoph A1 - Meindl, Alfons A1 - Schmutzler, Rita K. A1 - Hahnen, Eric T1 - 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 JF - Cancer Medicine N2 - 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. KW - breast cancer predisposition KW - hereditary breast cancer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227902 ER - TY - JOUR A1 - Lumma, Anna-Lena A1 - Valk, Sofie L. A1 - Böckler, Anne A1 - Vrtička, Pascal A1 - Singer, Tania T1 - Change in emotional self-concept following socio-cognitive training relates to structural plasticity of the prefrontal cortex JF - Brain and Behavior N2 - 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. KW - cortical thickness KW - emotional word use KW - meditation KW - mental training KW - neuroplasticity KW - self-concept content KW - self-descriptions Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237395 VL - 8 ER - TY - JOUR A1 - Bäumer, Nils A1 - Kartha, Kalathil K. A1 - Kumar Allampally, Naveen A1 - Yagai, Shiki A1 - Albuquerque, Rodrigo Q. A1 - Fernández, Gustavo T1 - Exploiting Coordination Isomerism for Controlled Self-Assembly JF - Angewandte Chemie International Edition N2 - 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. KW - coordination isomerism KW - photoresponsive behavior KW - self-assembly KW - supramolecular polymers KW - p-conjugated systems Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221362 VL - 58 ER - TY - JOUR A1 - Sol, Jeroen A. H. P. A1 - Dehm, Volker A1 - Hecht, Reinhard A1 - Würthner, Frank A1 - Schenning, Albertus P. H. J. A1 - Debije, Michael G. T1 - Temperature-Responsive Luminescent Solar Concentrators: Tuning Energy Transfer in a Liquid Crystalline Matrix JF - Angewandte Chemie International Edition N2 - Temperature-responsive luminescent solar concentrators (LSCs) have been fabricated in which the Förster 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. KW - energy transfer KW - fluorescence KW - liquid crystals KW - luminescent solar concentrators KW - perylene dyes Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238778 VL - 57 ER - TY - JOUR A1 - Gole, Bappaditya A1 - Stepanenko, Vladimir A1 - Rager, Sabrina A1 - Grüne, Matthias A1 - Medina, Dana D. A1 - Bein, Thomas A1 - Würthner, Frank A1 - Beuerle, Florian T1 - Microtubular Self-Assembly of Covalent Organic Frameworks JF - Angewandte Chemie International Edition N2 - 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. KW - covalent organic frameworks KW - diketopyrrolopyrroles KW - imines KW - microtubes KW - porphyrins Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227373 VL - 57 ER - TY - JOUR A1 - Griemert, Eva-Verena A1 - Schwarzmaier, Susanne M. A1 - Hummel, Regina A1 - Gölz, Christina A1 - Yang, Dong A1 - Neuhaus, Winfried A1 - Burek, Malgorzata A1 - Förster, Carola Y. A1 - Petkovic, Ivan A1 - Trabold, Raimund A1 - Plesnila, Nikolaus A1 - Engelhard, Kristin A1 - Schäfer, Michael K. A1 - Thal, Serge C. T1 - Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury JF - Annals of Neurology N2 - 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 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228682 VL - 85 ER - TY - JOUR A1 - Charbonnier, Baptiste A1 - Baradaran, Aslan A1 - Sato, Daisuke A1 - Alghamdi, Osama A1 - Zhang, Zishuai A1 - Zhang, Yu-Ling A1 - Gbureck, Uwe A1 - Gilardino, Mirko A1 - Harvey, Edward A1 - Makhoul, Nicholas A1 - Barralet, Jake T1 - Material-Induced Venosome-Supported Bone Tubes JF - Advanced Science N2 - 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. KW - angiogenesis KW - axial vascularization KW - bioceramic KW - bioinorganic KW - material-host interactions KW - osteogenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222318 VL - 6 ER - TY - JOUR A1 - Kirsch, Anna Dalal A1 - Hassin-Baer, Sharon A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Steigerwald, Frank T1 - Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects JF - Parkinsonism and Related Disorders N2 - 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. KW - deep brain stimulation KW - subthalamic nucleus KW - Parkinson's disease KW - anodic stimulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325820 VL - 55 ER - TY - JOUR A1 - Counsell, John R. A1 - Karda, Rajvinder A1 - Diaz, Juan Antiano A1 - Carey, Louise A1 - Wiktorowicz, Tatiana A1 - Buckley, Suzanne M. K. A1 - Ameri, Shima A1 - Ng, Joanne A1 - Baruteau, Julien A1 - Almeida, Filipa A1 - de Silva, Rohan A1 - Simone, Roberto A1 - Lugarà, Eleonora A1 - Lignani, Gabriele A1 - Lindemann, Dirk A1 - Rethwilm, Axel A1 - Rahim, Ahad A. A1 - Waddington, Simon N. A1 - Howe, Steven J. T1 - Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice JF - Molecular Therapy: Nucleic Acids N2 - 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. KW - foamy virus KW - spumavirus KW - viral vector KW - gene therapy KW - vector tropism KW - bioimaging KW - hippocampus Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223379 VL - 12 ER - TY - JOUR A1 - Argyrousi, Elentina K. A1 - de Nijs, Laurence A1 - Lagatta, Davi C. A1 - Schlütter, Anna A1 - Weidner, Magdalena T. A1 - Zöller, Johanna A1 - van Goethem, Nick P. A1 - Joca, Sâmia R. L. A1 - van den Hove, Daniel L. A. A1 - Prickaerts, Jos T1 - Effects of DNA methyltransferase inhibition on pattern separation performance in mice JF - Neurobiology of Learning and Memory N2 - 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. KW - object pattern separation KW - DNA methyltransferase inhibitors KW - BDNF KW - CpG islands KW - epigenetics KW - hippocampal plasticity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221226 VL - 159 ER - TY - JOUR A1 - Figel, Benedikt A1 - Brinkmann, Leonie A1 - Buff, Christine A1 - Heitmann, Carina Y. A1 - Hofmann, David A1 - Bruchmann, Maximilian A1 - Becker, Michael P. I. A1 - Herrmann, Martin J. A1 - Straube, Thomas T1 - Phasic amygdala and BNST activation during the anticipation of temporally unpredictable social observation in social anxiety disorder patients JF - NeuroImage: Clinical N2 - 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. KW - FMRI KW - threat anticipation KW - social anxiety disorder KW - bed nucleus of stria terminalis KW - amygdala Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228071 VL - 22 ER - TY - JOUR A1 - Godel, Tim A1 - Pham, Mirko A1 - Kele, Henrich A1 - Kronlage, Moritz A1 - Schwarz, Daniel A1 - Brunée, Merle A1 - Heiland, Sabine A1 - Bendszus, Martin A1 - Bäumer, Philipp T1 - Diffusion tensor imaging in anterior interosseous nerve syndrome – functional MR Neurography on a fascicular level JF - NeuroImage: Clinical N2 - 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. KW - anterior interosseous nerve syndrome KW - diffusion tensor imaging KW - functional MR Neurography Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233061 VL - 21 ER - TY - JOUR A1 - Gorlova, Anna A1 - Pavlov, Dmitrii A1 - Anthony, Daniel C. A1 - Ponomarev, Eugene D. A1 - Sambon, Margaux A1 - Proshin, Andrey A1 - Shafarevich, Igor A1 - Babaevskaya, Diana A1 - Lesch, Klaus-Peter A1 - Bettendorff, Lucien A1 - Strekalova, Tatyana T1 - Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice JF - Neuropharmacology N2 - 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’. KW - aggression KW - emotional stress KW - brain oxidative stress KW - plasticity KW - thiamine KW - mice Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227439 VL - 156 ER - TY - JOUR A1 - Verheijen, Bert M. A1 - Stevens, Jo A. A. A1 - Gentier, Romina J. G. A1 - van't Hekke, Christian D. A1 - van den Hove, Daniel L. A. A1 - Hermes, Denise J. H. P. A1 - Steinbusch, Harry W. M. A1 - Ruijter, Jan M. A1 - Grimm, Marcus O. W. A1 - Haupenthal, Viola J. A1 - Annaert, Wim A1 - Hartmann, Tobias A1 - van Leeuwen, Fred W. T1 - Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model JF - Neurobiology of Aging N2 - 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. KW - mutant ubiquitin KW - ubiquitin-proteasome system KW - γ-secretase KW - amyloid-β KW - behavior KW - Alzheimer's disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233185 VL - 72 ER - TY - JOUR A1 - Hedrich, Rainer A1 - Mueller, Thomas D. A1 - Becker, Dirk A1 - Marten, Irene T1 - Structure and Function of TPC1 Vacuole SV Channel Gains Shape JF - Molecular Plant N2 - 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. KW - Ca2+ sensors KW - TPC1/SV channel KW - vacuole membrane voltage KW - voltage sensor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228046 VL - 11 ER - TY - JOUR A1 - Mühlemann, Markus A1 - Zdzieblo, Daniela A1 - Friedrich, Alexandra A1 - Berger, Constantin A1 - Otto, Christoph A1 - Walles, Heike A1 - Koepsell, Hermann A1 - Metzger, Marco T1 - Altered pancreatic islet morphology and function in SGLT1 knockout mice on a glucose-deficient, fat-enriched diet JF - Molecular Metabolism N2 - 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. KW - glucose transporter SGLT1 KW - pancreatic islet cytomorphology KW - pancreatic islet function KW - β-cell KW - α-cell Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224230 VL - 13 ER - TY - JOUR A1 - Baluapuri, Apoorva A1 - Hofstetter, Julia A1 - Dudvarski Stankovic, Nevenka A1 - Endres, Theresa A1 - Bhandare, Pranjali A1 - Vos, Seychelle Monique A1 - Adhikari, Bikash A1 - Schwarz, Jessica Denise A1 - Narain, Ashwin A1 - Vogt, Markus A1 - Wang, Shuang-Yan A1 - Düster, Robert A1 - Jung, Lisa Anna A1 - Vanselow, Jens Thorsten A1 - Wiegering, Armin A1 - Geyer, Matthias A1 - Maric, Hans Michael A1 - Gallant, Peter A1 - Walz, Susanne A1 - Schlosser, Andreas A1 - Cramer, Patrick A1 - Eilers, Martin A1 - Wolf, Elmar T1 - MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation JF - Molecular Cell N2 - 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. KW - MYC KW - SPT5 KW - SUPT5H KW - SPT6 KW - RNA polymerase II KW - transcription KW - elongation rate KW - processivity KW - directionality KW - tumorigenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221438 VL - 74 ER - TY - JOUR A1 - Bugai, Andrii A1 - Quaresma, Alexandre J. C. A1 - Friedel, Caroline C. A1 - Lenasi, Tina A1 - Düster, Robert A1 - Sibley, Christopher R. A1 - Fujinaga, Koh A1 - Kukanja, Petra A1 - Hennig, Thomas A1 - Blasius, Melanie A1 - Geyer, Matthias A1 - Ule, Jernej A1 - Dölken, Lars A1 - Barborič, Matjaž T1 - P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress JF - Molecular Cell N2 - 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. KW - Pol II elongation KW - Pol II pause release KW - P-TEFb KW - CDK9 KW - 7SK snRNP KW - RBM7 KW - genotoxic stress KW - DNA damage response KW - p38 MAP kinase KW - apoptosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221726 VL - 74 ER - TY - JOUR A1 - Žutić, Igor A1 - Matos-Abiague, Alex A1 - Scharf, Benedikt A1 - Dery, Hanan A1 - Belashchenko, Kirill T1 - Proximitized materials JF - Materials Today N2 - 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. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233972 VL - 22 ER - TY - JOUR A1 - McColl, Erin A1 - Groll, Jürgen A1 - Jungst, Tomasz A1 - Dalton, Paul D. T1 - Design and fabrication of melt electrowritten tubes using intuitive software JF - Materials and Design N2 - 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. KW - additive manufacturing KW - 3D printing KW - electrohydrodynamic printing KW - biomaterials KW - polycaprolactone Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223891 VL - 155 ER - TY - JOUR A1 - Fazzini, Federica A1 - Lamina, Claudia A1 - Fendt, Liane A1 - Schultheiss, Ulla T. A1 - Kotsis, Fruzsina A1 - Hicks, Andrew A. A1 - Meiselbach, Heike A1 - Weissensteiner, Hansi A1 - Forer, Lukas A1 - Krane, Vera A1 - Eckardt, Kai-Uwe A1 - Köttgen, Anna A1 - Kronenberg, Florian T1 - Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease JF - Kidney International N2 - 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. KW - chronic kidney disease KW - infections KW - mitochondrial DNA copy number KW - mortality Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227662 VL - 96 ER - TY - THES A1 - Fuhl, Lucas T1 - Photolumineszenzmikroskopie und -spektroskopie endohedraler Farbstoffe in Bornitridnanoröhren T1 - Photoluminescence microscopy and spectroscopy of endohedral dyes in boron nitride nanotubes N2 - Im Rahmen der vorliegenden Dissertation wurde untersucht, wie die Einkapselung organischer Farbstoffmoleküle in Bornitridnanoröhren (BNNTs) die photophysikalischen Eigenschaften der Fluorophore beeinflusst. Als Farbstoffe wurden hierbei alpha-Quaterthiophen (4T), alpha-Sexithiophen (6T), alpha-Octithiophen (8T) sowie Nilrot (NR) ausgewählt. Die eingesetzten BNNTs besitzen einen nominellen Durchmesser von \(5 \pm 2\)nm. Für die Charakterisierung der reinen Farbstoffe und der hybriden Systeme aus Farbstoff und Nanoröhre kam ein Laboraufbau zum Einsatz, der neben Absorptions- und Photolumineszenz (PL)-Spektroskopie auch PL-Mikroskopie ermöglicht. Zusätzlich lässt sich damit auch eine zeitaufgelöste Untersuchung der PL (engl. time correlated single photon counting, TCSPC) im Ensemble und an einzelnen, separierten Nano-Objekten (mit Farbstoff gefüllte BNNTs) umsetzen. In Kapitel 5 wurden zunächst die freien Farbstoffe in Lösung charakterisiert. Es hat sich gezeigt, dass sowohl 4T als auch NR im verwendeten Lösemittel Dimethylformamid (DMF) löslich sind, wohingegen 6T und 8T hier eine geringere Löslichkeit zeigen. Die unterschiedlichen Verläufe der konzentrationsabhängigen PL-Spektren für 4T und 6T in DMF lassen sich vermutlich auf diesen Löslichkeitsunterschied zurückführen. Zudem wurden Extinktionskoeffizienten für 4T und NR mittels konzentrationsabhängiger Absorptionsspektren bestimmt und es zeigte sich eine gute Übereinstimmung mit der Literatur. Für 6T und 8T war eine Bestimmung aufgrund der geringen Löslichkeit nicht möglich, weshalb auf Literaturwerte zurückgegriffen wurde oder diese extrapoliert wurden (8T). In Kapitel 6 erfolgte die detaillierte Charakterisierung der mit Oligothiophenen gefüllten BNNTs. Die Befüllung wurde dabei im Wesentlichen nach einem von C. Allard publizierten Verfahren durchgeführt und auf die zusätzlichen Fluorophore 4T, 8T und NR übertragen. Für Messungen mittels UV-Vis-Spektroskopie in Lösung bzw. Dispersion hat sich beim Farbstoff 6T gezeigt, dass sich das Absorptionsmaximum von 407nm (freies 6T) hin zu 506nm (6T@BNNT) verschiebt. Ursache hierfür ist vermutlich die Bildung von J-Aggregaten im Inneren der Röhren. Die entsprechenden PL-Spektren von freiem 6T und dem Hybridsystem zeigen dabei keine signifikanten Unterschiede. Für konzentrationsabhängige PL-Spektren von 6T@BNNT ergibt sich (anders als bei freiem 6T in DMF) keine Änderung des Verlaufs der Kurven, was als ein Indiz für 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 Abhängigkeit des Außendurchmessers ließ sich jedoch keine klare Korrelation zwischen Struktur und Emissionscharakteristiken erkennen. Diese Beobachtung lässt sich vermutlich dadurch erklären, dass mit Hilfe der Rasterkraftmikroskopie lediglich der Außendurchmesser der (teils mehrwandigen) BNNTs bestimmt werden kann. Die entscheidende Größe an dieser Stelle ist allerdings der innere Durchmesser der BNNTs, welcher die Ausrichtung und damit auch die Polarisation der Farbstoffmoleküle beeinflusst. Ein Vergleich des mittleren maximalen Polarisationsgrades der jeweiligen Hybridsysteme hat gezeigt, dass 4T@BNNT den geringsten und 6T@BNNT mit den höchsten Wert aufweist. Dies bestätigt die Annahme, dass mit zunehmender Moleküllänge die Polarisation, aufgrund des höheren Templat-Effektes der Röhre, zunimmt. 8T@BNNT liegt zwischen den beiden anderen Werten, was dieser Annahme widerspricht. Der mittlere Verkippungswinkel der eingekapselten Farbstoffmoleküle gegenüber der Röhrenachse liegt für 4T@BNNT bei etwa 16° und ist damit etwas größer als derjenige von 6T@BNNT. Somit zeigt sich auch hier, dass kürzere Moleküle mehr sterische Freiheitsgerade im Innern der Röhren besitzen. Für 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 \(\tau\) für 4T und 6T (jeweils in DMF) infolge der Einkapselung deutlich zunimmt wenn die Hybridsysteme ebenfalls in DMF dispergiert sind. Die ermittelten Werte für \(\tau\) der separierten Nanoobjekte lagen für 4T@BNNT und 6T@BNNT unterhalb der entsprechenden in DMF. Für 8T bzw. 8T@BNNT ergab sich eine deutlich kürzerer Lebensdauer der separierten Nanoobjekte im Vergleich zum freien Farbstoff in kolloidaler Suspension. Ein erster Ansatz, um den zugrundeliegende Mechanismus aufzuklären, bestand darin, die TCSPC-Spektren (für 6T in DMF und 6T@BNNT in DMF) hinsichtlich der einzelnen Zerfallskanäle zu analysieren. Die erhaltenen Ergebnisse deuteten darauf hin, dass bei freiem 6T in DMF andere Zerfallskanäle dominieren als beim Hybridsystem 6T@BNNT (in DMF). Eine Korrelation der Fluorezenslebensdauer von 6T@BNNT vom äußeren Durchmesser der Nanoröhren 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 Permittivität des Lösemittels bzw. der Umgebung bekannt. Dies erlaubte eine Abschätzung der relativen Permittivät im Inneren der BNNTs. Der ermittelte Wert von ca. 4 für ein isoliertes NR@BNNT Objekt deutet auf eine relativ unpolare Umgebung im Röhreninneren hin. Zum Vergleich dazu, liegt der Wert von freiem NR in DMF bei 47, was die relativ hohe Polarität von DMF bestätigt. Der ermittelte Wert für die mittlere maximale Polarisation lag leicht über dem der hybriden Systeme aus Oligothiophenen und Nanoröhren. Für die Auslenkung der NR-Moleküle gegenüber der Röhrenachse ergab sich ein Winkel von etwa 16°, was im Bereich der Werte von 4T@BNNT und 6T@BNNT liegt. Die Messung der zeitaufgelösten Fluoreszenz von freiem und eingekapseltem Nilrot hat ergeben, dass auch in diesem Fall eine Verkürzung der Lebensdauer (von 4091 ps auf 812 ps) erfolgte. Eine solche Verkürzung der Lebensdauer von Chromophoren wird in der Literatur unter anderem mit der Bildung von J-Aggregaten in Zusammenhang gebracht. N2 - This dissertation investigated how the encapsulation of organic dye molecules in boron nitride nanotubes (BNNTs) influences the photophysical properties of the fluorophores. The dyes chosen were alpha-quaterthiophene (4T), alpha-sexithiophene (6T), alpha-octithiophene (8T) and Nile red (NR). The BNNTs used have a nominal diameter of \(5 \pm 2\)nm. To characterize the pure dyes and the hybrid systems consisting of dye and nanotube, a laboratory setup was used that enables PL microscopy in addition to absorption and photoluminescence (PL) spectroscopy. In addition, a time-resolved study of PL (time correlated single photon counting, TCSPC) can be implemented in the ensemble and on individual, separated nano-objects (BNNTs filled with dye). In Chapter 5, the free dyes in solution were first characterized. It has been shown that both 4T and NR are soluble in the solvent used, dimethylformamide (DMF), whereas 6T and 8T show lower solubility. The different profiles of the concentration-dependent PL spectra for 4T and 6T in DMF can probably be attributed to this difference in solubility. In addition, extinction coefficients for 4T and NR were determined using concentration-dependent absorption spectra and there was good agreement with the literature. For 6T and 8T, a determination was not possible due to the low solubility, which is why literature values ​​were used or extrapolated (8T). Chapter 6 detailed the characterization of the BNNTs filled with oligothiophenes. The filling was essentially carried out according to a method published by C. Allard and transferred to the additional fluorophores 4T, 8T and NR. For measurements using UV-Vis spectroscopy in solution or dispersion, it has been shown that the absorption maximum for the dye 6T shifts from 407nm (free 6T) to 506nm (6T@BNNT). The reason for this is probably the formation of J-aggregates inside the tubes. The corresponding PL spectra of free 6T and the hybrid system show no significant differences. For concentration-dependent PL spectra of 6T@BNNT (unlike free 6T in DMF), there is no change in the shape of the curves, which can be interpreted as an indication of successful encapsulation. By combining atomic force and PL microscopy, the outer diameters of individual 6T@BNNT objects could be determined and directly related to their photophysical properties. However, when analyzing the polarization of the emission light from 6T@BNNT depending on the outer diameter, no clear correlation between structure and emission characteristics could be seen. This observation can probably be explained by the fact that only the outer diameter of the (some multi-walled) BNNTs can be determined using atomic force microscopy. The crucial size at this point, however, is the inner diameter of the BNNTs, which influences the alignment and thus also the polarization of the dye molecules. A comparison of the average maximum degree of polarization of the respective hybrid systems showed that 4T@BNNT has the lowest value and 6T@BNNT has the highest value. This confirms the assumption that as the molecule length increases, the polarization increases due to the higher template effect of the tube. 8T@BNNT lies between the other two values, which contradicts this assumption. The average tilt angle of the encapsulated dye molecules relative to the tube axis is about 16° for 4T@BNNT and is therefore slightly larger than that of 6T@BNNT. This also shows that shorter molecules have more steric freedom inside the tubes. For 8T@BNNT the angle is approximately 28° and again contradicts the assumption. TCSPC measurements on free oligothiophene dyes and on the hybrid systems showed that the fluorescence lifetime \(\tau\) for 4T and 6T (each in DMF) increases significantly as a result of encapsulation when the hybrid systems are also dispersed in DMF. The determined values ​​for \(\tau\) of the separated nanoobjects for 4T@BNNT and 6T@BNNT were below the corresponding ones in DMF. For 8T or 8T@BNNT, the lifespan of the separated nanoobjects was significantly shorter compared to the free dye in colloidal suspension. A first approach to elucidate the underlying mechanism was to analyze the TCSPC spectra (for 6T in DMF and 6T@BNNT in DMF) with respect to the individual decay channels. The results obtained indicated that different decay channels dominate for free 6T in DMF than for the hybrid system 6T@BNNT (in DMF). Correlating the fluorescence lifetime of 6T@BNNT with the outer diameter of the nanotubes showed no clear relationship. The characterization of Nile red or NR@BNNT (analogous to the oligothiophenes) took place in Chapter 4. Here, too, there was a shift in the PL spectrum of the fluorophore due to the encapsulation in the BNNTs. However, the PL spectrum of the hybrid system (NR@BNNT) is hypsochromically shifted by about 20 nm. Nile red is also known in the literature as a nanoprobe for determining the permittivity of the solvent or the environment. This allowed an estimation of the relative permittivity inside the BNNTs. The determined value of approx. 4 for an isolated NR@BNNT object indicates a relatively non-polar environment inside the tube. For comparison, the value of free NR in DMF is 47, confirming the relatively high polarity of DMF. The value determined for the average maximum polarization was slightly higher than that of the hybrid systems made of oligothiophenes and nanotubes. The deflection of the NR molecules relative to the tube axis resulted in an angle of approximately 16°, which is in the range of the values ​​for 4T@BNNT and 6T@BNNT. The measurement of the time-resolved fluorescence of free and encapsulated Nile Red showed that in this case too there was a shortening of the lifespan (from 4091 ps to 812 ps). In the literature, such a shortening of the lifespan of chromophores is associated, among other things, with the formation of J-aggregates. KW - Fluoreszenzmikroskopie KW - Spektroskopie KW - Oligothiophene KW - Nanoröhre KW - Nanomaterialien KW - Endohedrale Farbstoffe KW - Nanomaterials KW - Endohedral dyes Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371150 ER - TY - THES A1 - Adolf, Jonas Michael T1 - Die Zusammenarbeit zwischen der stationären beziehungsweise teilstationären psychotherapeutischen Behandlung und niedergelassenen Psychotherapeut:innen T1 - The Collaboration between inpatient and semi-inpatient psychotherapeutic treatment and outpatient psychotherapists N2 - Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuität in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)stationären und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und – falls möglich – erste Möglichkeiten zur Verbesserung der derzeitigen Versorgungskontinuität aufzuzeigen. In Zusammenarbeit mit dem Arbeitsbereich für Medizinische Psychologie und Psychotherapie im Zentrum für psychische Gesundheit des Universitätsklinikums Würzburg wurde hierzu ein Fragebogen entwickelt und acht ausgewählten 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 poststationären 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 für Lösungen auf. Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es – zur Ermöglichung einer adäquaten kontinuierlichen psychotherapeutischen Versorgung – eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. Für ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)stationären Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten Möglichkeiten der vorliegenden Arbeit gilt es große repräsentative und nationale Studien anzustreben. Hierzu wäre die Etablierung zentral verwalteter Register zur Bündelung der bisherigen und zukünftigen Forschungsarbeiten im Bereich der Psychotherapie wünschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und könnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen. N2 - The aim of the study was to identify the current continuity of care regarding psychotherapeutic care and the collaboration of the (semi-)inpatient and outpatient field from point of view of the outpatient psychotherapists. Furthermore, the study wants to integrate the findings in the recent scientific context and wants to reveal improvements regarding the continuity of care in the field of psychotherapy. An explorative survey was created in collaboration with the working group of medical psychology and psychotherapy at the centre for mental health of the university hospital of Würzburg. Eight selected psychotherapeutic organisations (psychotherapy chambers and societies) were invited to conduct the survey to their members. Apart from a general assessment the study took a closer look at the framework conditions, the field of exchange and the care of outpatient psychotherapy to patients after (semi-)inpatient care. The study results describe the current situation of the psychotherapy care in Germany from the point of view of the outpatient psychotherapists and demonstrate on the one hand deficits regarding the analysed aspects and – as part of the side questions – on the other hand possible approaches for improvements. To facilitate a better continuity of psychotherapeutic care, it is important to take a closer look at the demonstrated deficits reported by the study. Moreover further studies are necessary treating the point of view of (semi-)inpatient psychotherapists as well as to conduct large national-wide representative studies, especially against the backdrop of the limited possibilities of the present study. For this purpose, it is helpful to establish a central-managed register to collect all studies in the field of psychotherapy. That could contribute to improve the current situation of research and care in the field of psychotherapy, in particular against the backdrop of the numerous pilot projects. KW - Psychotherapie KW - Medizinische Versorgung KW - Versorgungskontinuität KW - Sektoren KW - Versorgung KW - Psychiatrie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371098 ER - TY - THES A1 - Schuhmair, Leah Sophia T1 - Etablierung eines in-situ-Immunfluoreszenzfärbeverfahrens zur dreidimensionalen Darstellung und Quantifizierung der Immunzellinfiltration in experimentellen Tumoren T1 - Establishment of an in-situ immunofluorescence staining method for three-dimensional imaging and quantification of immune cell infiltration in experimental tumours N2 - Brustkrebs ist die häufigste diagnostizierte Krebserkrankung weltweit. Trotz der vielfältigen Behandlungsmöglichkeiten endet die Diagnose Brustkrebs in vielen Fällen noch immer tödlich. Aus diesem Grund ist die Entwicklung neuer Therapieansätze 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 hierfür ist die geringe Immunzellinfiltration in Brusttumoren. Um Brustkrebs für Immuntherapie empfänglicher zu machen, müssten Immuntherapeutika in Kombination mit Medikamenten angewendet werden, die die Immunzellinfiltration steigern. Um die Wirksamkeit solcher Medikamente in präklinischen Studien zu testen, braucht es eine Methode, mit der man die T-Zellverteilung innerhalb des Tumors darstellen kann. Für umfassendes Verständnis ist dreidimensionale Darstellung der Zellen im Tumor notwendig, da es einen großen Unterschied macht, ob sich die T-Zellen im Tumorstroma oder in unmittelbarer Nähe zu den Tumorzellen befinden. Die starke Fibrotisierung der Extrazellulären Matrix, die typisch für Brusttumoren ist, erschwert nicht nur die Immunzellinfiltration, sondern auch die Diffusion der fluoreszierenden Antikörper 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 Immunfluoreszenzfärbung und anschließender dreidimensionaler Aufnahme mithilfe optischer Sektionierung am Lichtblattmikroskop. Erreicht wurde dies durch deutliche Erhöhung der Inkubationszeiten, aggressive Permeabilisierung des Gewebes, Testen unterschiedlicher Antikörper bzw. Antikörperkombinationen und Entfärbung sowie Klärung des Tumorgewebes. Darüber hinaus konnten erste Schritte in der nachträglichen Bearbeitung der Aufnahmen inklusive Rekonstruktion der Zellen gemacht werden. Für die Anwendung des Verfahrens in Studien zur Medikamentenwirksamkeit ist noch weitere Optimierung notwendig. N2 - Breast cancer is the most frequently diagnosed cancer worldwide. Despite the wide range of treatment options available, the diagnosis of breast cancer is still fatal in many cases. For this reason, the development of new therapeutic approaches is important. One therapeutic approach that has become increasingly important in the last ten years is immunotherapy. However has not yet been very successful in breast cancer. The reason for this is the low level of immune cell infiltration in breast tumours. To make breast cancer more receptive to immunotherapy, immunotherapeutics could be used in combination with drugs that increase immune cell infiltration. In order to test the efficacy of such drugs in preclinical studies, a method is needed that can be used to visualise the T cell distribution within the tumour. For a comprehensive understanding, three-dimensional visualisation of the cells in the tumour is necessary, as it makes a big difference whether the T cells are located in the tumour stroma or in close proximity to the tumour cells. The strong fibrotisation of the extracellular matrix, which is typical of breast tumours, not only makes T cell infiltration, but also the diffusion of the fluorescent antibodies into the tissue difficult. In the course of this work, a method was developed to visualise CD4 and CD8-positive T cells in breast tumours in three dimensions. This was achieved by significantly increasing incubation times, aggressive permeabilisation of the tissue, testing different antibodies and antibody combinations and decolourisation as well as clarification of the tumour tissue. In addition, the first steps were taken in the subsequent processing of the images, including reconstruction of the cells. However further optimisation is still required before the method can be used in drug efficacy studies. KW - Immunfluoreszenz KW - Brustkrebs KW - Dreidimensionales Bild KW - T-Lymphozyt KW - Immuntherapie KW - 3D imaging KW - Tumormikroumgebung KW - immun escape mechanism Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370945 ER - TY - THES A1 - Wanner, Maren T1 - Längsschnittanalyse von Stimmparametern bei gesunden Säuglingen im zweiten Lebenshalbjahr T1 - Systematic longitudinal analysis: Development of melodic structure in the second half of the first year of life N2 - In der vorliegenden Arbeit wurde die Melodiestrukturentwicklung im zweiten Lebenshalbjahr, exemplarisch an zehn gesunden Säuglingen mit deutscher Umgebungssprache, untersucht. Zusammen mit den zuvor erhobenen und vorliegenden Ergebnissen der ersten sechs Lebensmonate (Kottmann, 2023) war erstmalig eine systematische Längsschnittanalyse über das gesamte erste Lebensjahr möglich. Mithilfe des Lautanalyseprogramms CDAP wurden für die vorliegende Arbeit 4686 frühkindliche Lautaufahmen bezüglich ihres Melodiekonturverlaufs sowie ihrer auditiv und visuell wahrnehmbaren Feinstrukturmerkmale detailliert analysiert und ausgewertet. Der Datensatz spiegelt repräsentativ das typische Lautrepertoire von Säuglingen im zweiten Lebenshalbjahr mit den hier untersuchten Komfort-Vokalisationstypen wider: Übergangslaute, marginale und kanonische Babbellaute. In Übereinstimmung mit dem von Wermke und Mende postulierten MD-Modell, das eine vokalisationstyp-übergreifende Komplexitätszunahme frühkindlicher Lautäußerungen beschreibt, konnten erstmals die regelhaften Entwicklungsverläufe im zweiten Lebenshalbjahr gezeigt und ausführlich benannt werden. Dabei scheint die Zunahme der Komplexität vor allem im Zusammenhang mit artikulatorischen Reifeprozessen zu stehen. In der Melodie selbst fiel diesbezüglich vor allem der Einbau von Segmentierungen auf. Diese innermelodischen Unterbrechungen können wiederum als Vorläufer linguistischer Strukturen, wie beispielsweise Silben, angesehen werden. Der Übergang von einfachen zu fortgeschritteneren Vokalisationen, bis hin zu den ersten Wörtern, ist fließend. Zukünftig wäre für weitere empirische Untersuchungen interessant, inwiefern sich der Grundfrequenzverlauf zunehmend zur suprasegmentalen Intonationskurve entwickelt, was sich bereits in den durchgeführten Analysen angedeutet hat. Die kontinuierlich wachsende Kontrolle des Säuglings über den Vokaltrakt mit zunehmend gezielter Reproduktion erlernter Lautstrukturen wird durch die Ergebnisse der vorliegenden Arbeit belegt. Sie liefert einen wichtigen Beitrag zum Verständnis der Sprachentwicklung von Säuglingen und ermöglicht durch die Erkenntnisse der physiologisch ablaufenden Prozesse eine vorsprachliche Diagnostik, eine frühzeitige Intervention und Förderung der Sprache. Vor allem der Beginn des Babbelns scheint hierbei eine wichtige Evaluationsgröße zu sein. N2 - The present study investigated the development of melodic structure in the second half of their first year of life in ten healthy native German infants. Together with previously collected and published results of the first six months of life (Kottmann, 2023), a systematic longitudinal analysis of the entire first year of life was possible for the first time. Using the sound analysis programme CDAP, 4686 sound recordings from early childhood were analyzed and evaluated in detail with regard to their melodic contours as well as their auditorily and visually perceived fine structure features. The data set is representative of the typical sound repertoire of infants in the second half of their first year of life with the types of comfort vocalizations studied here: transitional, marginal and canonical baby sounds. Consistent with the MD model postulated by Wermke and Mende, which describes an increase in complexity of early infant vocalizations across vocalization types, the regular developmental trajectories in the second half of their first year of life could be shown and named in detail for the first time. The increase in complexity seems to be mainly related to articulatory maturation processes. In the melody itself, the integration of segmentations was particularly noticeable. These intra-melodic breaks can be seen as precursors of linguistic structures such as syllables. The transition from simple to more advanced vocalizations up to the first words is a smooth one. It would be interesting for future empirical studies to determine the extent to which the baseline frequency curve increasingly develops into the suprasegmental intonation curve that has already been suggested in the analyses conducted. The continuously increasing control of the vocal tract by infants with an increasingly specific reproduction of learned phonetic structures is supported by the results of the present study. The study makes an important contribution to the understanding of infant language development and, by providing insights into the physiological processes involved, enables pre-linguistic diagnostics, early intervention and language promotion. In particular, the onset of babbling appears to be an important assessment variable in this context. KW - Sprachentwicklung KW - vorsprachliche Entwicklung KW - MD-Modell Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370962 ER - TY - THES A1 - Liu, Yang T1 - Predictions for Composite Higgs Models Using Gauge/Gravity Duality T1 - Vorhersagen für zusammengesetzte Higgs-Modelle unter Verwendung der Eich-/Gravitationsdualität N2 - 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]. N2 - Diese Arbeit konstruiert ein nicht-abelsches holographisches dynamisches minimales Composite-Higgs-Modell. Wir erstellen zunächst ein nicht-abelsches Bottom-up-AdS/YM-Modell, das das QCD-Mesonenspektrum gut erklären kann. Das Modell ist nicht-abelsch, da die nicht-abelsche DBI-Wirkung im Top-Down-Modell berücksichtigt wird. Anschließend ändern wir die duale Theorie von der QCD auf das minimale Composite-Higgs-Modell U (4)/Sp(4). Durch das Hinzufügen einer zweiten expliziten Brechung U (4) → Sp(4), das die NJL-Wechselwirkung an der Grenze durchbricht, konstruierten wir in diesem Modell eine Composite-Higgs-Phase und eine Technicolor-Phase. Auch der Übergang zwischen den beiden Phasen wird realisiert, welcher durch die NJL-Kopplung gesteuert wird. Diese Arbeit basiert auf den Arbeiten [1, 2]. KW - Composite Higgs KW - Gauge/gravity duality KW - holographic model KW - Higgs-Modell Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370833 ER - TY - THES A1 - Müller, Nicole T1 - Modellierung klonaler Evolution beim Multiplen Myelom T1 - Modeling Clonal Evolution in Multiple Myeloma N2 - In dieser Arbeit wurde ein modulares Zelllinienmodell zur Visualisierung klonaler Evolutionsmechanismen etabliert. Hierfür 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 primären Patientenproben gewonnenen Mutationen in IKZF1 (A152T, E170D, R439H) oder den IKZF1 WT. Die Anwendung von immunmodulatorischen Medikamenten (IMiDs) führt zu einer Ubiquitinierung des Transkriptionsfaktors IKZF1 durch die E3-Ubiquitin-Protein-Ligase (CRBN-CUL4). Durch Mutationen in IKZF1 kommt es zu Störungen in diesem Prozess und damit zu einer Überexpression von IKZF1. Dies wirkt sich wachstumsfördert 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 für die Myelomzellen darstellt. Bei den IKZF1 Mutationen E170D und R439H konnte kein Selektionsvorteil gegenüber dem IKZF1 WT beobachtet werden. N2 - In this work, a modular cell line model was established to visualize clonal evolutionary mechanisms. Different fluorescent proteins (LSSmKate2, EGFP, mTagBFP2) were introduced into various sublines of the myeloma cell line L363 using a Sleeping Beauty-based vector system. These four sublines each contain one of three mutations in IKZF1 (A152T, E170D, R439H) derived from primary patient samples or the IKZF1 wild type (WT). The application of immunomodulatory drugs (IMiDs) leads to the ubiquitination of the transcription factor IKZF1 by the E3 ubiquitin-protein ligase (CRBN-CUL4). Mutations in IKZF1 disrupt this process, resulting in the overexpression of IKZF1, which promotes the growth of myeloma cells. The effects of individual mutations in IKZF1 are therefore a clinically relevant research topic. In this study, two sublines each with IKZF1 WT cells and cells with an IKZF1 mutation were labeled with different fluorescent proteins. These were incubated together under treatment with various concentrations of lenalidomide. Thus, the selection behavior could be visualized using flow cytometry analyses. It was shown that the IKZF1 mutation A152T provides a clear selective advantage for the myeloma cells. No selective advantage was observed for the IKZF1 E170D and R439H mutations compared to IKZF1 WT. KW - Lenalidomid KW - Plasmozytom KW - IKZF1 KW - klonale Evolution KW - Vektormodell KW - Multiples Myelom Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370818 ER - TY - THES A1 - Rode, Stefan T1 - Automated resummation of electroweak Sudakov logarithms in diboson production T1 - Automatisierte Resummierung elektroschwacher Sudakov-Logarithmen in Vektorboson-Paarproduktion N2 - 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. N2 - Das Thema ist der vorliegenen Arbeit ist die automatisierte Berechnung differenzieller und integrierter Wirkungsquerschnitte der Paarerzeugung schwerer Eichbosonen bei sehr hohen Streuenergien mit Resummierung der auftretenden elektroschwachen Sudakov-Logarithmen zu allen Ordnungen in der Feinstrukturkonstanten mittels Soft-Collinear Effective Theory. Die Suche nach Physik jenseits des Standardmodells an zukunftigen Teilchenbeschleunigern wie dem FCC oder dem CLIC erfordert hochpräzise Voraussagen fur Streuquerschnitte seitens der theoretischen Physik. Es ist seit langem bekannt, dass elektroschwache Sudakov-Logarithmen, die bereits gegenwärtig die Genauigkeit der Voraussagen in den Hochenergieschwänzen von Verteilungen limitieren, die Konvergenz der konventionellen Störungsreihen vollkommen zunichte machen, wenn hinreichend hohe Energien erreicht werden. Mittels Soft-Collinear Effective Theory wurden diese Logarithmen bereits in der Vergangenheit in einfachen Prozessen, die eine analytische Behandlung erlauben, resummiert. Im Rahmen dieser Arbeit wurden diese Methoden in ein Monte-Carlo-Integrationsprogramm implementiert, um somit vollständig differenzielle Vorhersagen präsentieren zu können. Dies erfordert die Behandlung von Infrarotdivergenzen mit Hilfe des Catani-Seymour-Algorithmus. Mit diesen Werkzeugen wurden resummierte Streuquerschnitte fur verschiedene Vektorboson-Paarproduktionsprozesse berechnet, u.a. fur den Photon-Photon-induzierten Produktionskanal zur W-Boson-Paarproduktion. Auf dem Weg dorthin sind verschiedene vereinfachende Annahmen notwendig, deren Gultigkeit im Rahmen dieser Arbeit ebenfalls getestet wurde, so z.B. die Qualität der Doppelpolnäherung. Des weiteren wurden Größenordnungen vernachlässigter Effekte abgeschätzt. Dabei haben sich vor allem nicht doppelt resonante Beiträge in bestimmten Phasenraumregionen als beträchtlich herausgestellt. Der Resummationseffekt der fuhrend logarithmischen Korrekturen verschiebt die integrierten Paarproduktionsstreuquerschnitte um mehr als 20% bezogen auf den Bornstreuquerschnitt im Falle von Leptonkollisionen bei einer Schwerpunktsenergie von 3 TeV. Diese Effekte werden allerdings teilweise von nicht-führenden Beiträgen kompensiert. Fur Proton-Proton-Kollisionen bei √ s = 100 TeV finden wir deutliche Resummationseffekte in allen Hochenergieschwänzen, während die integrierten Wirkungsquerschnitte von Phasenraumregionen dominiert werden, in denen Soft-Collinear Effective Theory nicht anwendbar ist. KW - High-energy physics Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371060 ER - TY - THES A1 - Aljasem, Anwar T1 - Der Einfluss des Hepatocyte growth factors auf die PD-L1-Expression in Kopf-Hals-Karzinomen: Die Bedeutung des MAPK-, AKT- und STAT3-Signalwegs T1 - The impact of Hepatocyte growth factor (HGF) on PD-L1 expression in HNSCC: The meaning of MAPK, AKT, and STAT3 signaling pathways N2 - Die zielgerichtete Therapie und die Immuncheckpoint-Inhibitoren haben die Tumortherapie revolutioniert. Während erstere die Tumorzellen gezielt angreift, verhindern letztere die Hemmung des Immunsystems durch Immuncheckpoints, um eine robuste Immunantwort zu erreichen. Zusätzlich ist das Nebenwirkungsprofil bei direktem Vergleich mit der konventionellen Chemotherapie günstiger. Beim HNSCC werden beide Ansätze angewendet. Cetuximab ist ein monoklonaler Antikörper, der sich gegen EGFR, welcher bei HNSCC überexprimiert 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 größte zu überwindende Herausforderung. Aufbauend auf dem Ergebnis vorangegangener Arbeiten, die zeigen konnten, dass HGF über c-MET die Expression des Immuncheckpointliganden PD-L1 steigert, setzt sich diese Arbeit weiter mit den intrazellulären nachgeschalteten Signalwegen nach c-MET Aktivierung auseinander. Dies ist von besonderem Interesse, weil diese Signalwege ebenfalls für die Resistenzentwicklung verantwortlich sein können, zeitgleich können diese im Rahmen der zielgerichteten Therapie gezielt inhibiert werden. Um den HGF-Einfluss auf die intrazellulären Signalwege zu prüfen, 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 Phosphorylierungsänderung der Schlüsselproteine der einzelnen Signalwege nachgewiesen. Daraus ergab sich, dass HGF die MAPK- und PIK3/AKT-Signalwege aktiviert. Während eine kombinierte Blockade des MAPK-Signalwegs den PD-L1-Anstieg vollständig verhindern konnte, hemmte die PIK3/AKT-Blockade den PD-L1-Anstieg nur partiell. Im zweiten Teil wurde mit siRNA der hauptsächlich für den PD-L1-Anstieg zuständige 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 funktionsfähigem MAPK-Signalweg eingeschränkt war. Weiter wurde der Effekt mit dem Medikament Trametinib, das im Rahmen der zielgerichteten Therapie bei malignem Melanom und NSCLC für die MAPK-Signalweg-Hemmung zugelassen ist, evaluiert. Sowohl im Western Blot als auch in der Durchflusszytometrie konnte bestätigt werden, dass Trametinib den HGF-induzierten Anstieg von PD-L1 signifikant blockiert. Darüber 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 erhöhte PI3K/AKT-Aktivität, Detroit562 und SCC9 eine erhöhte MAPK-Aktivität. Die PD-L1- Expression war in der SCC9-Zelllinie am höchsten. 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-Antikörper (Cetuximab) kann eine kombinierte Hemmung entweder von c-MET oder von den nachgeschalteten Signalwegen MAPK und PI3K/AKT bei Resistenzen, Progression oder Unverträglichkeiten eine Möglichkeit für eine wirksamere Therapie von HNSCC darstellen. Ein Screening der Signalwege und deren Aktivierungsmechanismen könnte bei Resistenzen oder bei einem Rezidiv/Progress dazu beitragen, gezielt die alternative Aktivierung zu hemmen und möglicherweise die Wirksamkeit einer Immuncheckpointblockade zu verbessern. N2 - Targeted therapy and immune checkpoint inhibitors have revolutionized tumor therapy. While the former specifically targets tumor cells, the latter prevents inhibitory immune responses via immune checkpoints to achieve a robust immune response. Additionally, the side effect profile is more favorable when directly compared to conventional chemotherapy. Both approaches are approved for the treatment of Head and Neck Squamous Cell Carcinoma (HNSCC). Cetuximab is a monoclonal antibody that targets EGFR, which is overexpressed in HNSCC. Nivolumab and Pembrolizumab target the immune checkpoint protein PD-1. Resistances, both initial and acquired, however, remain significant challenges to overcome. Building on a previous report that HGF upregulates the immune checkpoint ligand PD-L1 expression via the c-MET pathway, this study investigates the intracellular downstream signaling pathways activated by HGF. This is of particular interest because these signaling pathways contribute to resistance development, while at the same time, they can be specifically inhibited in the context of targeted therapy. To examine the influence of HGF on intracellular signaling pathways, four established HNSCC cell lines were utilized. In the first part of the study, the four HNSCC-derived cell lines were stimulated with HGF, and the increase in PD-L1 expression and changes in phosphorylation levels of key proteins in the individual signaling pathways were analyzed using Western Blots. It was found that HGF activates the MAPK and PI3K/AKT pathways. While MAPK inhibition completely blocked the PD-L1 increase, PI3K/AKT inhibition only partially did so after HGF stimulation. In the second part, the MAPK pathway, mainly responsible for the increase in PD-L1, was inhibited using siRNA. Quantitative PCR validated corresponding mRNA levels. Western Blots further showed that the increase in PD-L1 was reduced despite HGF stimulation when the MAPK pathway was non-functional. In line with previous results, inhibiting MAPKs with the drug Trametinib, which is approved as a targeted therapy for malignant melanoma and NSCLC, significantly blocks HGF-induced PD-L1 expression based on Western Blot and flow cytometry analysis. Notably, the activity of the different signaling pathways and the expression levels of PD-L1 vary among the different cell lines, as Western Blot analyses reveal. For instance, while the FaDu cell line manifested high activity in the PI3K/AKT pathway, Detroit562 and SCC9 showed increased MAPK activity. Nonetheless, the SCC9 cell line showed the highest PD-L1 expression level. This study demonstrated that HNSCC cell lines similarly respond to the growth factor HGF, which is frequently present in high concentrations in the tumor microenvironment of HNSCC. Additionally, the inhibition of c-MET and its downstream MAPK or PI3K/AKT pathways in combination with EGFR blockade by Cetuximab may offer a more effective treatment strategy for HNSCC patients in cases of therapeutic resistance, disease progression, or drug intolerance. Screening of the signaling pathways and their activation mechanisms could, in cases of resistance, recurrence, or progression, contribute to the specific inhibition of alternative activation and potentially improve the efficacy of immune checkpoint blockade. KW - Hepatozyten-Wachstumsfaktor KW - MAP-Kinase KW - Plattenepithelcarcinom KW - PD-L1 Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370358 ER - TY - THES A1 - Lechermeier, Carina T1 - Neuroanatomical and functional evaluation of ADHD candidate genes in the model organism zebrafish (\(Danio\) \(rerio\)) T1 - Neuroanatomische und funktionelle Auswertung von ADHS Kandidatengenen im Modellorganismus Zebrafisch (\(Danio\) \(rerio\)) N2 - 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. N2 - Die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist eine der am weitesten verbreiteten Entwicklungsstörungen, davon sind 5,9% Kinder und Jugendliche und 2,5% Erwachsene weltweit betroffen. Die Kernsymptome sind altersunangemessene Hyperaktivität, Impulsivität und Unaufmerksamkeit, oft begleitet von Begleiterkrankungen wie emotionale Dysregulation oder Verhal- tensauffälligkeiten sowie Lerndefiziten. In den meisten Fällen wird ADHS durch ein Zusammenspiel von angehäuften genetischen und umweltbedingten Risikofaktoren verursacht. Durch Zwillingsstudien gelang man zu einer errechneten Erblichkeit von 70–80%, jedoch erklären häufig auftretende genetische Varianten in der Bevölkerung nur ein Drittel der Erblichkeit. Der Rest der genetischen Veranlagung setzt sich aus seltenen Kopienzahlvariationen (CNV) und Interaktionen von Gen x Umwelt, einschließlich epigenetischer Veränderungen, zusammen. Durch genomweite Assoziationsstudien (GWAS) und Kopplungsanalysen wurden eine Reihe von wahrscheinlichen Kandidatengenen identifiziert. Eine Handvoll von ihnen spielen eine Rolle in den Dopamin oder Noradrenalin Neurotransmittersystemen. Diese Systeme sind gleichzeitig die Hauptangriffspunkte der gängigsten Medikamente, die zur Behandlung von ADHS eingesetzt werden. Allerdings ist für die Mehrheit der Kandidatengene die biologische Funktion in Bezug auf ADHS unbekannt. Es ist essentiell diese Funktionen zu identifizieren um ein tieferes Verständnis der Ätiopathogenese und der genetische Netzwerke, die möglicherweise für die Störung verantwortlich sind, zu erlangen. Diese Arbeit konzentriert sich auf die drei Kandidatengene GFOD1, SLC2A3 und LBX1 und ihre Rolle im gesunden Organismus sowie während ADHS. Die Neuroanatomie wurde durch Expressionsanalyse betrachtet und verschiedene aktivitätsbasierte Verhaltensessays wurden durchgeführt, um Veränderungen auf Transkriptebene mit den zugehörigen Phänotypen der neurologischen Entwick- lungsstörung in Verbindung zu bringen. Zebrafischorthologe der menschlichen Kandidatengene wurden identifiziert und umfangreiche zeitliche und räumli- che Expressionsanalysen via RNA in situ Hybridisierung durchgeführt. Durch Morpholino-Knockdown und mRNA-Überexpressions Zebrafischmodelle mit anschließender Verhaltensanalyse wurden sowohl hyper- als auch hypoaktive Phänotypen entdeckt. Eine zusätzliche Expressionsanalyse durch doppelte in situ Hybridisierung ergab eine Kolokalisierung während der Zebrafischneuroentwicklung von jeweils gfod1 und slc2a3a zusammen mit gad1b, einem Marker für GABAerge Neuronen. Interessanterweise wurden beide Risikogene zuvor mit der Glukosehomöostase und dem Energiestoffwechsel in Verbindung gebracht, die, wenn sie gestört werden, zu Veränderungen der Signalübertragung und der Lebensdauer von Neuronen führen können. Desgleichen spielt Lbx1 eine entscheidende Rolle bei der Spezifikation von GABAergen versus glutamatergenen Neuronen während der Entwicklung des Rückenmarks in der Wirbelsäule und im Hinterhirn von Mäusen und Hühnern. Vorläufige Ergebnisse dieser Arbeit deuten auf eine ähnliche Rolle beim Zebrafisch hin. Zusammengenommen stellen diese Erkenntnisse einerseits eine solide Grundlage für weitere Untersuchungen zur Funktion der Gene dar, andererseits eröffnet sich daraus die Möglichkeit neue Aspekte der ADHS-Forschung zu untersuchen, bei denen der Fokus auf der Rolle des GABAergen Neurotransmittersystems oder der Beziehung zwischen Energiestoffwechsel und psychiatrischen Erkrankungen liegt. KW - Aufmerksamkeitsdefizit-Syndrom KW - Zebrabärbling KW - ADHD KW - zebrafish KW - genes KW - behaviour KW - ADHS Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371084 ER - TY - JOUR A1 - Zhang, Zishuai A1 - Ye, Siyu A1 - Gbureck, Uwe A1 - Barralet, Jake E. A1 - Merle, Géraldine T1 - Cavitation Mediated 3D Microstructured Architectures from Nanocarbon JF - Advanced Functional Materials N2 - 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. KW - carbon nanotube microspheres KW - cavitation KW - oxygen reduction reaction KW - platinum nanostructures Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233926 VL - 28 ER - TY - JOUR A1 - McMaster, Rebecca A1 - Hoefner, Christiane A1 - Hrynevich, Andrei A1 - Blum, Carina A1 - Wiesner, Miriam A1 - Wittmann, Katharina A1 - Dargaville, Tim R. A1 - Bauer-Kreisel, Petra A1 - Groll, Jürgen A1 - Dalton, Paul D. A1 - Blunk, Torsten T1 - Tailored Melt Electrowritten Scaffolds for the Generation of Sheet-Like Tissue Constructs from Multicellular Spheroids JF - Advanced Healthcare Materials N2 - 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. KW - 3D printing KW - additive manufacturing KW - adipose tissue engineering Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223921 VL - 8 ER - TY - JOUR A1 - Selcuk, Nalan Alan A1 - Toklu, Turkay A1 - Beykan, Seval A1 - Karaaslan, Serife Ipek T1 - Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer JF - Journal of Applied Clinical Medical Physics N2 - 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. KW - bone marrow dosimetry KW - remnant tissue dosimetry KW - thyroid ablation treatment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235882 VL - 19 ER - TY - JOUR A1 - Göttlich, Claudia A1 - Kunz, Meik A1 - Zapp, Cornelia A1 - Nietzer, Sarah L. A1 - Walles, Heike A1 - Dandekar, Thomas A1 - Dandekar, Gudrun T1 - A combined tissue-engineered/in silico signature tool patient stratification in lung cancer JF - Molecular Oncology N2 - 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. KW - 3D lung tumor model KW - Boolean signaling network KW - chemoresistance KW - HSP90 inhibitor KW - insilico drug screening too KW - KRAS mutation signature Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233137 VL - 12 ER - TY - JOUR A1 - Stromecki, Margaret A1 - Tatari, Nazanin A1 - Coudière Morrison, Ludivine A1 - Kaur, Ravinder A1 - Zagozewski, Jamie A1 - Palidwor, Gareth A1 - Ramaswamy, Vijay A1 - Skowron, Patryk A1 - Wölfl, Matthias A1 - Milde, Till A1 - Del Bigio, Marc R. A1 - Taylor, Michael D. A1 - Werbowetski-Ogilvie, Tamra E. T1 - Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma JF - Molecular Oncology N2 - 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. KW - axon guidance genes KW - medulloblastoma KW - orthodenticle homeobox 2 KW - RHO KW - semaphorin KW - stem cells Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240089 VL - 12 ER - TY - JOUR A1 - Storey, Benjamin C. A1 - Staplin, Natalie A1 - Haynes, Richard A1 - Reith, Christina A1 - Emberson, Jonathan A1 - Herrington, William G. A1 - Wheeler, David C. A1 - Walker, Robert A1 - Fellström, Bengt A1 - Wanner, Christoph A1 - Landray, Martin J. A1 - Baigent, Colin T1 - Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation JF - Kidney International N2 - 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. KW - C-reactive protein KW - inflammation KW - LDL cholesterol KW - randomized trials KW - vascular disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240067 VL - 93 ER -