@article{IslesIngasonLowtheretal.2016, author = {Isles, Anthony R. and Ingason, Andr{\´e}s and Lowther, Chelsea and Walters, James and Gawlick, Micha and St{\"o}ber, Gerald and Rees, Elliott and Martin, Joanna and Little, Rosie B. and Potter, Harry and Georgieva, Lyudmila and Pizzo, Lucilla and Ozaki, Norio and Aleksic, Branko and Kushima, Itaru and Ikeda, Masashi and Iwata, Nakao and Levinson, Douglas F. and Gejman, Pablo V. and Shi, Jianxin and Sanders, Alan R. and Duan, Jubao and Willis, Joseph and Sisodiya, Sanjay and Costain, Gregory and Werge, Thomas M. and Degenhardt, Franziska and Giegling, Ina and Rujescu, Dan and Hreidarsson, Stefan J. and Saemundsen, Evald and Ahn, Joo Wook and Ogilvie, Caroline and Girirajan, Santhosh D. and Stefansson, Hreinn and Stefansson, Kari and O'Donovan, Michael C. and Owen, Michael J. and Bassett, Anne and Kirov, George}, title = {Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders}, series = {PLoS Genetics}, volume = {12}, journal = {PLoS Genetics}, number = {5}, doi = {10.1371/journal.pgen.1005993}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166706}, pages = {e1005993}, year = {2016}, abstract = {Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76\% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033\% compared to 0.0069\% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50\% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.}, language = {en} } @article{VendelovadeLimaLorenzattoetal.2016, author = {Vendelova, Emilia and de Lima, Jeferson Camargo and Lorenzatto, Karina Rodrigues and Monteiro, Karina Mariante and Mueller, Thomas and Veepaschit, Jyotishman and Grimm, Clemens and Brehm, Klaus and Hrčkov{\´a}, Gabriela and Lutz, Manfred B. and Ferreira, Henrique B. and Nono, Justin Komguep}, title = {Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions}, series = {PLoS Neglected Tropical Diseases}, volume = {10}, journal = {PLoS Neglected Tropical Diseases}, number = {10}, doi = {10.1371/journal.pntd.0005061}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166742}, pages = {e0005061}, year = {2016}, abstract = {Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts.}, language = {en} } @article{ShiKuaiLeietal.2016, author = {Shi, Yaoyao and Kuai, Yue and Lei, Lizhen and Weng, Yuanyuan and Berberich-Siebelt, Friederike and Zhang, Xinxia and Wang, Jinjie and Zhou, Yuan and Jiang, Xin and Ren, Guoping and Pan, Hongyang and Mao, Zhengrong and Zhou, Ren}, title = {The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {47}, doi = {10.18632/oncotarget.12680}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166500}, pages = {77444-77456}, year = {2016}, abstract = {Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5\% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (-87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis.}, language = {en} } @article{VučićevićGehreDhamijaetal.2016, author = {Vučićević, Dubravka and Gehre, Maja and Dhamija, Sonam and Friis-Hansen, Lennart and Meierhofer, David and Sauer, Sascha and {\O}rom, Ulf Andersson}, title = {The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {23}, doi = {10.18632/oncotarget.8985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166519}, pages = {33934-33947}, year = {2016}, abstract = {Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells.}, language = {en} } @article{EisenhardtSprengerRoeringetal.2016, author = {Eisenhardt, Anja E. and Sprenger, Adrian and R{\"o}ring, Michael and Herr, Ricarda and Weinberg, Florian and K{\"o}hler, Martin and Braun, Sandra and Orth, Joachim and Diedrich, Britta and Lanner, Ulrike and Tscherwinski, Natalja and Schuster, Simon and Dumaz, Nicolas and Schmidt, Enrico and Baumeister, Ralf and Schlosser, Andreas and Dengjel, J{\"o}rn and Brummer, Tilman}, title = {Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {18}, doi = {10.18632/oncotarget.8427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166529}, pages = {26628-26652}, year = {2016}, abstract = {B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase.}, language = {en} } @article{ChenariSeibelHauschildetal.2016, author = {Chenari, Hossein Mahmoudi and Seibel, Christoph and Hauschild, Dirk and Reinert, Friedrich and Abdollahian, Hossein}, title = {Titanium Dioxide Nanoparticles: Synthesis, X-Ray Line Analysis and Chemical Composition Study}, series = {Materials Research}, volume = {19}, journal = {Materials Research}, number = {6}, doi = {10.1590/1980-5373-MR-2016-0288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165807}, pages = {1319-1323}, year = {2016}, abstract = {TiO2 nanoparticleshave been synthesized by the sol-gel method using titanium alkoxide and isopropanolas a precursor. The structural properties and chemical composition of the TiO2 nanoparticles were studied usingX-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy.The X-ray powder diffraction pattern confirms that the particles are mainly composed of the anatase phase with the preferential orientation along [101] direction. The physical parameters such as strain, stress and energy density were investigated from the Williamson- Hall (W-H) plot assuming a uniform deformation model (UDM), and uniform deformation energy density model (UDEDM). The W-H analysis shows an anisotropic nature of the strain in nanopowders. The scanning electron microscopy image shows clear TiO2 nanoparticles with particle sizes varying from 60 to 80nm. The results of mean particle size of TiO2 nanoparticles show an inter correlation with the W-H analysis and SEM results. Our X-ray photoelectron spectroscopy spectra show that nearly a complete amount of titanium has reacted to TiO2}, language = {en} } @article{DingemansMonsieursYuetal.2016, author = {Dingemans, Josef and Monsieurs, Pieter and Yu, Sung-Huan and Crabb{\´e}, Aur{\´e}lie and F{\"o}rstner, Konrad U. and Malfroot, Anne and Cornelis, Pierre and Van Houdt, Rob}, title = {Effect of Shear Stress on Pseudomonas aeruginosa Isolated from the Cystic Fibrosis Lung}, series = {mBio}, volume = {7}, journal = {mBio}, number = {4}, doi = {10.1128/mBio.00813-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165821}, pages = {e00813-16}, year = {2016}, abstract = {Chronic colonization of the lungs by Pseudomonas aeruginosa is one of the major causes of morbidity and mortality in cystic fibrosis (CF) patients. To gain insights into the characteristic biofilm phenotype of P. aeruginosa in the CF lungs, mimicking the CF lung environment is critical. We previously showed that growth of the non-CF-adapted P. aeruginosa PAO1 strain in a rotating wall vessel, a device that simulates the low fluid shear (LS) conditions present in the CF lung, leads to the formation of in-suspension, self-aggregating biofilms. In the present study, we determined the phenotypic and transcriptomic changes associated with the growth of a highly adapted, transmissible P. aeruginosa CF strain in artificial sputum medium under LS conditions. Robust self-aggregating biofilms were observed only under LS conditions. Growth under LS conditions resulted in the upregulation of genes involved in stress response, alginate biosynthesis, denitrification, glycine betaine biosynthesis, glycerol metabolism, and cell shape maintenance, while genes involved in phenazine biosynthesis, type VI secretion, and multidrug efflux were downregulated. In addition, a number of small RNAs appeared to be involved in the response to shear stress. Finally, quorum sensing was found to be slightly but significantly affected by shear stress, resulting in higher production of autoinducer molecules during growth under high fluid shear (HS) conditions. In summary, our study revealed a way to modulate the behavior of a highly adapted P. aeruginosa CF strain by means of introducing shear stress, driving it from a biofilm lifestyle to a more planktonic lifestyle.}, language = {en} } @article{DrgonovaWaltherHartsteinetal.2016, author = {Drgonova, Jana and Walther, Donna and Hartstein, G Luke and Bukhari, Mohammad O and Baumann, Michael H and Katz, Jonathan and Hall, F Scott and Arnold, Elizabeth R and Flax, Shaun and Riley, Anthony and Rivero, Olga and Lesch, Klaus-Peter and Troncoso, Juan and Ranscht, Barbara and Uhl, George R}, title = {Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice}, series = {Molecular Medicine}, volume = {22}, journal = {Molecular Medicine}, doi = {10.2119/molmed.2015.00170}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165842}, pages = {537-547}, year = {2016}, abstract = {The Cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80\% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.}, language = {en} } @article{vandeKerkhofFekkesvanderHeijdenetal.2016, author = {van de Kerkhof, Nora WA and Fekkes, Durk and van der Heijden, Frank MMA and Hoogendijk, Witte JG and St{\"o}ber, Gerald and Egger, Jos IM and Verhoeven, Willem MA}, title = {Cycloid psychoses in the psychosis spectrum: evidence for biochemical differences with schizophrenia}, series = {Neuropsychiatric Disease and Treatment}, volume = {12}, journal = {Neuropsychiatric Disease and Treatment}, doi = {10.2147/NDT.S101317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166255}, pages = {1927-1933}, year = {2016}, abstract = {Cycloid psychoses (CP) differ from schizophrenia regarding symptom profile, course, and prognosis and over many decades they were thought to be a separate entity within the psychosis spectrum. As to schizophrenia, research into the pathophysiology has focused on dopamine, brain-derived neurotrophic factor, and glutamate signaling in which, concerning the latter, the N-methyl-d-aspartate receptor plays a crucial role. The present study aims to determine whether CP can biochemically be delineated from schizophrenia. Eighty patients referred for psychotic disorders were assessed with the Comprehensive Assessment of Symptoms and History, and (both at inclusion and after 6 weeks of antipsychotic treatment) with the Positive and Negative Syndrome Scale and Clinical Global Impression. From 58 completers, 33 patients were diagnosed with schizophrenia and ten with CP according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Leonhard criteria, respectively. Fifteen patients were diagnosed with other disorders within the psychosis spectrum. At both time points, blood levels of the dopamine metabolite homovanillic acid, brain-derived neurotrophic factor, and amino acids related to glutamate neurotransmission were measured and compared with a matched control sample. Patients with CP showed a significantly better response to antipsychotic treatment as compared to patients with schizophrenia. In CP, glycine levels were elevated and tryptophan levels were lowered as compared to schizophrenia. Glutamate levels were increased in both patient groups as compared to controls. These results, showing marked differences in both treatment outcome and glutamate-related variable parameters, may point at better neuroplasticity in CP, necessitating demarcation of this subgroup within the psychosis spectrum.}, language = {en} } @article{HargartRoyChoudhuryJohnetal.2016, author = {Hargart, F and Roy-Choudhury, K and John, T and Portalupi, S L and Schneider, C and H{\"o}fling, S and Kamp, M and Hughes, S and Michler, P}, title = {Probing different regimes of strong field light-matter interaction with semiconductor quantum dots and few cavity photons}, series = {New Journal of Physics}, volume = {18}, journal = {New Journal of Physics}, doi = {10.1088/1367-2630/aa5198}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166278}, year = {2016}, abstract = {In this work we present an extensive experimental and theoretical investigation of different regimes of strong field light-matter interaction for cavity-driven quantum dot (QD) cavity systems. The electric field enhancement inside a high-Q micropillar cavity facilitates exceptionally strong interaction with few cavity photons, enabling the simultaneous investigation for a wide range of QD-laser detuning. In case of a resonant drive, the formation of dressed states and a Mollow triplet sideband splitting of up to 45 μeV is measured for amean cavity photon number \(\leq\) 1. In the asymptotic limit of the linear ACStark effect we systematically investigate the power and detuning dependence of more than 400 QDs. Some QD-cavity systems exhibit an unexpected anomalous Stark shift, which can be explained by an extended dressed 4-levelQDmodel.Weprovide a detailed analysis of the QD-cavity systems properties enabling this novel effect. The experimental results are successfully reproduced using a polaron master equation approach for the QD-cavity system, which includes the driving laser field, exciton-cavity and exciton-phonon interactions}, language = {en} } @article{RedlichLingnauHolzingeretal.2016, author = {Redlich, Christoph and Lingnau, Benjamin and Holzinger, Steffen and Schlottmann, Elisabeth and Kreinberg, S{\"o}ren and Schneider, Christian and Kamp, Martin and H{\"o}fling, Sven and Wolters, Janik and Reitzenstein, Stephan and L{\"u}dge, Kathy}, title = {Mode-switching induced super-thermal bunching in quantum-dot microlasers}, series = {New Journal of Physics}, volume = {18}, journal = {New Journal of Physics}, number = {063011}, doi = {10.1088/1367-2630/18/6/063011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166286}, year = {2016}, abstract = {The super-thermal photon bunching in quantum-dot (QD) micropillar lasers is investigated both experimentally and theoretically via simulations driven by dynamic considerations. Using stochastic multi-mode rate equations we obtain very good agreement between experiment and theory in terms of intensity profiles and intensity-correlation properties of the examined QD micro-laser's emission. Further investigations of the time-dependent emission show that super-thermal photon bunching occurs due to irregular mode-switching events in the bimodal lasers. Our bifurcation analysis reveals that these switchings find their origin in an underlying bistability, such that spontaneous emission noise is able to effectively perturb the two competing modes in a small parameter region. We thus ascribe the observed high photon correlation to dynamical multistabilities rather than quantum mechanical correlations.}, language = {en} } @article{LisinetskayaBraunProchetal.2016, author = {Lisinetskaya, Polina and Braun, Christian and Proch, Sebastian and Kim, Young Dok and Gantef{\"o}r, Gerd and Mitrić, Roland}, title = {Excited state nonadiabatic dynamics of bare and hydrated anionic gold clusters Au\(^-_3\)[H\(_2\)O]\(_n\) (n=0-2)}, series = {Physical Chemistry Chemical Physics}, volume = {18}, journal = {Physical Chemistry Chemical Physics}, number = {9}, issn = {1463-9076}, doi = {10.1039/c5cp04297f}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159176}, pages = {6411-6419}, year = {2016}, abstract = {We present a joint theoretical and experimental study of excited state dynamics in pure and hydrated anionic gold clusters Au\(^-_3\)[H\(_2\)O]\(_n\) (n = 0-2). We employ mixed quantum-classical dynamics combined with femtosecond time-resolved photoelectron spectroscopy in order to investigate the influence of hydration on excited state lifetimes and photo-dissociation dynamics. A gradual decrease of the excited state lifetime with the number of adsorbed water molecules as well as gold cluster fragmentation quenching by two or more water molecules are observed both in experiment and in simulations. Non-radiative relaxation and dissociation in excited states are found to be responsible for the excited state population depletion. Time constants of these two processes strongly depend on the number of water molecules leading to the possibility to modulate excited state dynamics and fragmentation of the anionic cluster by adsorption of water molecules.}, language = {en} } @article{LisinetskayaRoehrMitrić2016, author = {Lisinetskaya, Polina and R{\"o}hr, Merle I. S. and Mitrić, Roland}, title = {First-principles simulation of light propagation and exciton dynamics in metal cluster nanostructures}, series = {Applied Physics B}, volume = {122}, journal = {Applied Physics B}, number = {6}, issn = {0946-2171}, doi = {10.1007/s00340-016-6436-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159193}, pages = {175}, year = {2016}, abstract = {We present a theoretical approach for the simulation of the electric field and exciton propagation in ordered arrays constructed of molecular-sized noble metal clusters bound to organic polymer templates. In order to describe the electronic coupling between individual constituents of the nanostructure we use the ab initio parameterized transition charge method which is more accurate than the usual dipole-dipole coupling. The electronic population dynamics in the nanostructure under an external laser pulse excitation is simulated by numerical integration of the time-dependent Schrodinger equation employing the fully coupled Hamiltonian. The solution of the TDSE gives rise to time-dependent partial point charges for each subunit of the nanostructure, and the spatio-temporal electric field distribution is evaluated by means of classical electrodynamics methods. The time-dependent partial charges are determined based on the stationary partial and transition charges obtained in the framework of the TDDFT. In order to treat large plasmonic nanostructures constructed of many constituents, the approximate self-consistent iterative approach presented in (Lisinetskaya and Mitric in Phys Rev B 89:035433, 2014) is modified to include the transition-charge-based interaction. The developed methods are used to study the optical response and exciton dynamics of Ag-3(+) and porphyrin-Ag-4 dimers. Subsequently, the spatio-temporal electric field distribution in a ring constructed of ten porphyrin-Ag-4 subunits under the action of circularly polarized laser pulse is simulated. The presented methodology provides a theoretical basis for the investigation of coupled light-exciton propagation in nanoarchitectures built from molecular size metal nanoclusters in which quantum confinement effects are important.}, language = {en} } @article{WohlgemuthMitric2016, author = {Wohlgemuth, Matthias and Mitric, Roland}, title = {Photochemical Chiral Symmetry Breaking in Alanine}, series = {Journal of Physical Chemistry A}, volume = {45}, journal = {Journal of Physical Chemistry A}, number = {120}, doi = {10.1021/acs.jpca.6b07611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158557}, pages = {8976-8982}, year = {2016}, abstract = {We introduce a general theoretical approach for the simulation of photochemical dynamics under the influence of circularly polarized light to explore the possibility of generating enantiomeric enrichment through polarized-light-selective photochemistry. The method is applied to the simulation of the photolysis of alanine, a prototype chiral amino acid. We show that a systematic enantiomeric enrichment can be obtained depending on the helicity of the circularly polarized light that induces the excited-state photochemistry of alanine. By analyzing the patterns of the photoinduced fragmentation of alanine we find an inducible enantiomeric enrichment up to 1.7\%, which is also in good correspondence to the experimental findings. Our method is generally applicable to complex systems and might serve to systematically explore the photochemical origin of homochirality.}, language = {en} } @article{RoehrLisinetskayaMitric2016, author = {R{\"o}hr, Merle I. S. and Lisinetskaya, Polina G. and Mitric, Roland}, title = {Excitonic Properties of Ordered Metal Nanocluster Arrays: 2D Silver Clusters at Multiporphyrin Templates}, series = {Journal of Physical Chemistry A}, volume = {120}, journal = {Journal of Physical Chemistry A}, number = {26}, doi = {10.1021/acs.jpca.6b04243}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159464}, pages = {4465-4472}, year = {2016}, abstract = {The design of ordered arrays of metal nanoclusters such as for example 2D cluster organic frameworks might open a new route towards the development of materials with tailored optical properties. Such systems could serve as plasmonically enhanced light-harvesting materials, sensors or catalysts. We present here a theoretical approach for the simulation of the optical properties of ordered arrays of metal clusters that is based on the ab initio parametrized Frenkel exciton model. We demonstrate that small atomically precise silver clusters can be assembled in one- and two-dimensional arrays on suitably designed porphyrin templates exhibiting remarkable optical properties. By employing explicit TDDFT calculations on smaller homologs, we show that the intrinsic optical properties of metal clusters are largely preserved but undergo J- and H-type excitonic coupling that results in controllable splitting of their excited states. Furthermore, ab initio parameterized Frenkel exciton model calculations allow us to predict an energetic splitting of up to 0.77 eV in extended two-dimensional square arrays and 0.79 eV in tilted square aggregates containing up to 25 cluster-porphyrin subunits.}, language = {en} } @article{DomschkeZwanzgerRehbeinetal.2016, author = {Domschke, Katharina and Zwanzger, Peter and Rehbein, Maimu A. and Steinberg, Christian and Knoke, Kathrin and Dobel, Christian and Klinkenberg, Isabelle and Kugel, Harald and Kersting, Anette and Arolt, Volker and Pantev, Christo and Junghofer, Markus}, title = {Magnetoencephalographic Correlates of Emotional Processing in Major Depression Before and After Pharmacological Treatment}, series = {International Journal of Neuropsychopharmacology}, volume = {2016}, journal = {International Journal of Neuropsychopharmacology}, doi = {10.1093/ijnp/pyv093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165523}, pages = {1-9}, year = {2016}, abstract = {Background: In major depressive disorder (MDD), electrophysiological and imaging studies suggest reduced neural activity in the parietal and dorsolateral prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were analyzed for the first time in a pre-/post-treatment design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain activation. Methods: Twenty-five medication-free Caucasian in-patients with MDD and 25 matched controls underwent a baseline MEG session with passive viewing of pleasant, unpleasant, and neutral pictures. Fifteen patients were followed-up with a second MEG session after 4 weeks of antidepressant monopharmacotherapy with mirtazapine. The corresponding controls received no intervention between the measurements. The clinical course of depression was assessed using the Hamilton Depression scale. Results: Prior to treatment, an overall neocortical hypoactivation during emotional processing, particularly at the parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150ms, suggesting dysfunctional processing of emotional stimuli at a preconscious level. Successful antidepressant treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal regions. Accordingly, both dlPFC regions revealed an increase of activity after therapy. Conclusions: The present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto-parieto-temporal network, possibly contributing to the pathogenesis of MDD. These activation patterns might have the potential to serve as biomarkers of treatment success.}, language = {en} } @article{PacheZimmermannMikolajczaketal.2016, author = {Pache, Florence and Zimmermann, Hanna and Mikolajczak, Janine and Schumacher, Sophie and Lacheta, Anna and Oertel, Frederike C. and Bellmann-Strobl, Judith and Jarius, Sven and Wildemann, Brigitte and Reindl, Markus and Waldman, Amy and Soelberg, Kerstin and Asgari, Nasrin and Ringelstein, Marius and Aktas, Orhan and Gross, Nikolai and Buttmann, Mathias and Ach, Thomas and Ruprecht, Klemens and Paul, Friedemann and Brandt, Alexander U.}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {282}, doi = {10.1186/s12974-016-0720-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165551}, year = {2016}, abstract = {Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Ringelstein, Marius and Trebst, Corinna and Winkelmann, Alexander and Schwarz, Alexander and Buttmann, Mathias and Zimmermann, Hanna and Kuchling, Joseph and Franciotta, Diego and Capobianco, Marco and Siebert, Eberhard and Lukas, Carsten and Korporal-Kuhnke, Mirjam and Haas, J{\"u}rgen and Fechner, Kai and Brandt, Alexander U. and Schanda, Kathrin and Aktas, Orhan and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {280}, doi = {10.1186/s12974-016-0718-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165570}, year = {2016}, abstract = {Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80\% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40\% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36\%) and markedly impaired ambulation due to paresis or ataxia (25\%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70\%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70\%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44\%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50\%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70\%, oligoclonal bands in only 13\%, and blood-CSF-barrier dysfunction in 32\%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9\%). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28\%, 32\%, 15\%, 33\%, respectively; MS had been suspected in 36\%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Trebst, Corinna and Ringelstein, Marius and Aktas, Orhan and Winkelmann, Alexander and Buttmann, Mathias and Schwarz, Alexander and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Capobianco, Marco and Kuchling, Joseph and Haas, J{\"u}rgen and Korporal-Kuhnke, Mirjam and Lillevang, Soeren Thue and Fechner, Kai and Schanda, Kathrin and Paul, Friedemann and Wildemann, Brigitte and Reindl, Markus}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {279}, doi = {10.1186/s12974-016-0717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165659}, pages = {1-16}, year = {2016}, abstract = {Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7\%) patients with a history of both ON and myelitis, 22/103 (21.4\%) with a history of ON but no myelitis and 6/45 (13.3\%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67\%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89\%) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.}, language = {en} } @article{KilianWehmeierWahletal.2016, author = {Kilian, Yvonne and Wehmeier, Udo F. and Wahl, Patrick and Mester, Joachim and Hilberg, Thomas and Sperlich, Billy}, title = {Acute Response of Circulating Vascular Regulating MicroRNAs during and after High-Intensity and High-Volume Cycling in Children}, series = {Frontiers in Physiology}, volume = {7}, journal = {Frontiers in Physiology}, number = {92}, doi = {10.3389/fphys.2016.00092}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165261}, year = {2016}, abstract = {Aim: The aim of the present study was to analyze the response of vascular circulating microRNAs (miRNAs; miR-16, miR-21, miR-126) and the VEGF mRNA following an acute bout of HIIT and HVT in children. Methods: Twelve healthy competitive young male cyclists (14.4 ± 0.8 years; 57.9 ± 9.4 ml•min-1•kg-1 peak oxygen uptake) performed one session of high intensity 4 × 4 min intervals (HIIT) at 90-95\% peak power output (PPO), each interval separated by 3 min of active recovery, and one high volume session (HVT) consisting of a constant load exercise for 90 min at 60\% PPO. Capillary blood from the earlobe was collected under resting conditions, during exercise (d1 = 20 min, d2 = 30 min, d3 = 60 min), and 0, 30, 60, 180 min after the exercise to determine miR-16, -21, -126, and VEGF mRNA. Results: HVT significantly increased miR-16 and miR-126 during and after the exercise compared to pre-values, whereas HIIT showed no significant influence on the miRNAs compared to pre-values. VEGF mRNA significantly increased during and after HIIT (d1, 30′, 60′, 180′) and HVT (d3, 0′, 60′). Conclusion: Results of the present investigation suggest a volume dependent exercise regulation of vascular regulating miRNAs (miR-16, miR-21, miR-126) in children. In line with previous data, our data show that acute exercise can alter circulating miRNAs profiles that might be used as novel biomarkers to monitor acute and chronic changes due to exercise in various tissues.}, language = {en} } @article{KempertGoetzBlatteretal.2016, author = {Kempert, Sebastian and G{\"o}tz, Regina and Blatter, Kristine and Tibken, Catharina and Artelt, Cordula and Schneider, Wolfgang and Stanat, Petra}, title = {Training Early Literacy Related Skills: To Which Degree Does a Musical Training Contribute to Phonological Awareness Development?}, series = {Frontiers in Psychology}, volume = {7}, journal = {Frontiers in Psychology}, number = {1803}, doi = {10.3389/fpsyg.2016.01803}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165272}, year = {2016}, abstract = {Well-developed phonological awareness skills are a core prerequisite for early literacy development. Although effective phonological awareness training programs exist, children at risk often do not reach similar levels of phonological awareness after the intervention as children with normally developed skills. Based on theoretical considerations and first promising results the present study explores effects of an early musical training in combination with a conventional phonological training in children with weak phonological awareness skills. Using a quasi-experimental pretest-posttest control group design and measurements across a period of 2 years, we tested the effects of two interventions: a consecutive combination of a musical and a phonological training and a phonological training alone. The design made it possible to disentangle effects of the musical training alone as well the effects of its combination with the phonological training. The outcome measures of these groups were compared with the control group with multivariate analyses, controlling for a number of background variables. The sample included N = 424 German-speaking children aged 4-5 years at the beginning of the study. We found a positive relationship between musical abilities and phonological awareness. Yet, whereas the well-established phonological training produced the expected effects, adding a musical training did not contribute significantly to phonological awareness development. Training effects were partly dependent on the initial level of phonological awareness. Possible reasons for the lack of training effects in the musical part of the combination condition as well as practical implications for early literacy education are discussed.}, language = {en} } @article{WunschPfisterHenningetal.2016, author = {Wunsch, Kathrin and Pfister, Roland and Henning, Anne and Aschersleben, Gisa and Weigelt, Matthias}, title = {No Interrelation of Motor Planning and Executive Functions across Young Ages}, series = {Frontiers in Psychology}, volume = {7}, journal = {Frontiers in Psychology}, number = {1031}, doi = {10.3389/fpsyg.2016.01031}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165281}, year = {2016}, abstract = {The present study examined the developmental trajectories of motor planning and executive functioning in children. To this end, we tested 217 participants with three motor tasks, measuring anticipatory planning abilities (i.e., the bar-transport-task, the sword-rotation-task and the grasp-height-task), and three cognitive tasks, measuring executive functions (i.e., the Tower-of-Hanoi-task, the Mosaic-task, and the D2-attention-endurance-task). Children were aged between 3 and 10 years and were separated into age groups by 1-year bins, resulting in a total of eight groups of children and an additional group of adults. Results suggested (1) a positive developmental trajectory for each of the sub-tests, with better task performance as children get older; (2) that the performance in the separate tasks was not correlated across participants in the different age groups; and (3) that there was no relationship between performance in the motor tasks and in the cognitive tasks used in the present study when controlling for age. These results suggest that both, motor planning and executive functions are rather heterogeneous domains of cognitive functioning with fewer interdependencies than often suggested.}, language = {en} } @article{GressmannJanczyk2016, author = {Gressmann, Marcel and Janczyk, Markus}, title = {The (Un)Clear Effects of Invalid Retro-Cues}, series = {Frontiers in Psychology}, volume = {7}, journal = {Frontiers in Psychology}, number = {244}, doi = {10.3389/fpsyg.2016.00244}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165296}, year = {2016}, abstract = {Studies with the retro-cue paradigm have shown that validly cueing objects in visual working memory long after encoding can still benefit performance on subsequent change detection tasks. With regard to the effects of invalid cues, the literature is less clear. Some studies reported costs, others did not. We here revisit two recent studies that made interesting suggestions concerning invalid retro-cues: One study suggested that costs only occur for larger set sizes, and another study suggested that inclusion of invalid retro-cues diminishes the retro-cue benefit. New data from one experiment and a reanalysis of published data are provided to address these conclusions. The new data clearly show costs (and benefits) that were independent of set size, and the reanalysis suggests no influence of the inclusion of invalid retro-cues on the retro-cue benefit. Thus, previous interpretations may be taken with some caution at present.}, language = {en} } @article{PeperkornDiemerAlpersetal.2016, author = {Peperkorn, Henrik M. and Diemer, Julia E. and Alpers, Georg W. and M{\"u}hlberger, Andreas}, title = {Representation of Patients' Hand Modulates Fear Reactions of Patients with Spider Phobia in Virtual Reality}, series = {frontiers in Psychology}, volume = {7}, journal = {frontiers in Psychology}, number = {268}, doi = {10.3389/fpsyg.2016.00268}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165307}, year = {2016}, abstract = {Embodiment (i.e., the involvement of a bodily representation) is thought to be relevant in emotional experiences. Virtual reality (VR) is a capable means of activating phobic fear in patients. The representation of the patient's body (e.g., the right hand) in VR enhances immersion and increases presence, but its effect on phobic fear is still unknown. We analyzed the influence of the presentation of the participant's hand in VR on presence and fear responses in 32 women with spider phobia and 32 matched controls. Participants sat in front of a table with an acrylic glass container within reaching distance. During the experiment this setup was concealed by a head-mounted display (HMD). The VR scenario presented via HMD showed the same setup, i.e., a table with an acrylic glass container. Participants were randomly assigned to one of two experimental groups. In one group, fear responses were triggered by fear-relevant visual input in VR (virtual spider in the virtual acrylic glass container), while information about a real but unseen neutral control animal (living snake in the acrylic glass container) was given. The second group received fear-relevant information of the real but unseen situation (living spider in the acrylic glass container), but visual input was kept neutral VR (virtual snake in the virtual acrylic glass container). Participants were instructed to touch the acrylic glass container with their right hand in 20 consecutive trials. Visibility of the hand was varied randomly in a within-subjects design. We found for all participants that visibility of the participant's hand increased presence independently of the fear trigger. However, in patients, the influence of the virtual hand on fear depended on the fear trigger. When fear was triggered perceptually, i.e., by a virtual spider, the virtual hand increased fear. When fear was triggered by information about a real spider, the virtual hand had no effect on fear. Our results shed light on the significance of different fear triggers (visual, conceptual) in interaction with body representations.}, language = {en} } @article{CitronAbugaberHerbert2016, author = {Citron, Francesca M. M. and Abugaber, David and Herbert, Cornelia}, title = {Approach and Withdrawal Tendencies during Written Word Processing: Effects of Task, Emotional Valence, and Emotional Arousal}, series = {frontiers in Psychology}, volume = {6}, journal = {frontiers in Psychology}, number = {1935}, doi = {10.3389/fpsyg.2015.01935}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165318}, year = {2016}, abstract = {The affective dimensions of emotional valence and emotional arousal affect processing of verbal and pictorial stimuli. Traditional emotional theories assume a linear relationship between these dimensions, with valence determining the direction of a behavior (approach vs. withdrawal) and arousal its intensity or strength. In contrast, according to the valence-arousal conflict theory, both dimensions are interactively related: positive valence and low arousal (PL) are associated with an implicit tendency to approach a stimulus, whereas negative valence and high arousal (NH) are associated with withdrawal. Hence, positive, high-arousal (PH) and negative, low-arousal (NL) stimuli elicit conflicting action tendencies. By extending previous research that used several tasks and methods, the present study investigated whether and how emotional valence and arousal affect subjective approach vs. withdrawal tendencies toward emotional words during two novel tasks. In Study 1, participants had to decide whether they would approach or withdraw from concepts expressed by written words. In Studies 2 and 3 participants had to respond to each word by pressing one of two keys labeled with an arrow pointing upward or downward. Across experiments, positive and negative words, high or low in arousal, were presented. In Study 1 (explicit task), in line with the valence-arousal conflict theory, PH and NL words were responded to more slowly than PL and NH words. In addition, participants decided to approach positive words more often than negative words. In Studies 2 and 3, participants responded faster to positive than negative words, irrespective of their level of arousal. Furthermore, positive words were significantly more often associated with "up" responses than negative words, thus supporting the existence of implicit associations between stimulus valence and response coding (positive is up and negative is down). Hence, in contexts in which participants' spontaneous responses are based on implicit associations between stimulus valence and response, there is no influence of arousal. In line with the valence-arousal conflict theory, arousal seems to affect participants' approach-withdrawal tendencies only when such tendencies are made explicit by the task, and a minimal degree of processing depth is required.}, language = {en} } @article{WittmannSiebervonStengeletal.2016, author = {Wittmann, Katharina and Sieber, Cornel and von Stengel, Simon and Kohl, Matthias and Freiberger, Ellen and Jakob, Franz and Lell, Michael and Engelke, Klaus and Kemmler, Wolfgang}, title = {Impact of whole body electromyostimulation on cardiometabolic risk factors in older women with sarcopenic obesity: the randomized controlled FORMOsA-sarcopenic obesity study}, series = {Clinical Interventions in Aging}, volume = {11}, journal = {Clinical Interventions in Aging}, doi = {10.2147/CIA.S116430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164930}, pages = {1697—1706}, year = {2016}, abstract = {Background: Sarcopenic obesity (SO) is characterized by a combination of low muscle and high fat mass with an additive negative effect of both conditions on cardiometabolic risk. The aim of the study was to determine the effect of whole-body electromyostimulation (WB-EMS) on the metabolic syndrome (MetS) in community-dwelling women aged ≥70 years with SO. Methods: The study was conducted in an ambulatory university setting. Seventy-five community-dwelling women aged ≥70 years with SO living in Northern Bavaria, Germany, were randomly allocated to either 6 months of WB-EMS application with (WB-EMS\&P) or without (WB-EMS) dietary supplementation (150 kcal/day, 56\% protein) or a non-training control group (CG). WB-EMS included one session of 20 min (85 Hz, 350 µs, 4 s of strain-4 s of rest) per week with moderate-to-high intensity. The primary study endpoint was the MetS Z-score with the components waist circumference (WC), mean arterial pressure (MAP), triglycerides, fasting plasma glucose, and high-density lipoprotein cholesterol (HDL-C); secondary study endpoints were changes in these determining variables. Results: MetS Z-score decreased in both groups; however, changes compared with the CG were significant (P=0.001) in the WB-EMS\&P group only. On analyzing the components of the MetS, significant positive effects for both WB-EMS groups (P≤0.038) were identified for MAP, while the WB-EMS group significantly differed for WC (P=0.036), and the WB-EMS\&P group significantly differed for HDL-C (P=0.006) from the CG. No significant differences were observed between the WB-EMS groups. Conclusion: The study clearly confirms the favorable effect of WB-EMS application on the MetS in community-dwelling women aged ≥70 years with SO. However, protein-enriched supplements did not increase effects of WB-EMS alone. In summary, we considered this novel technology an effective and safe method to prevent cardiometabolic risk factors and diseases in older women unable or unwilling to exercise conventionally.}, language = {en} } @article{PalamidesJodeleitFoehlingeretal.2016, author = {Palamides, Pia and Jodeleit, Henrika and F{\"o}hlinger, Michael and Beigel, Florian and Herbach, Nadja and Mueller, Thomas and Wolf, Eckhard and Siebeck, Matthias and Gropp, Roswitha}, title = {A mouse model for ulcerative colitis based on NOD-scid IL2R gamma(null) mice reconstituted with peripheral blood mononuclear cells from affected individuals}, series = {Disease Models \& Mechanisms}, volume = {9}, journal = {Disease Models \& Mechanisms}, doi = {10.1242/dmm.025452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164946}, pages = {985-997}, year = {2016}, abstract = {Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.}, language = {en} } @article{JonesFrucianoKelleretal.2016, author = {Jones, Julia C. and Fruciano, Carmelo and Keller, Anja and Schartl, Manfred and Meyer, Axel}, title = {Evolution of the elaborate male intromittent organ of Xiphophorus fishes}, series = {Ecology and Evolution}, volume = {6}, journal = {Ecology and Evolution}, number = {20}, doi = {10.1002/ece3.2396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164956}, pages = {7207-7220}, year = {2016}, abstract = {Internally fertilizing animals show a remarkable diversity in male genital morphology that is associated with sexual selection, and these traits are thought to be evolving particularly rapidly. Male fish in some internally fertilizing species have "gonopodia," highly modified anal fins that are putatively important for sexual selection. However, our understanding of the evolution of genital diversity remains incomplete. Contrary to the prediction that male genital traits evolve more rapidly than other traits, here we show that gonopodial traits and other nongonopodial traits exhibit similar evolutionary rates of trait change and also follow similar evolutionary models in an iconic genus of poeciliid fish (Xiphophorus spp.). Furthermore, we find that both mating and nonmating natural selection mechanisms are unlikely to be driving the diverse Xiphophorus gonopodial morphology. Putative holdfast features of the male genital organ do not appear to be influenced by water flow, a candidate selective force in aquatic habitats. Additionally, interspecific divergence in gonopodial morphology is not significantly higher between sympatric species, than between allopatric species, suggesting that male genitals have not undergone reproductive character displacement. Slower rates of evolution in gonopodial traits compared with a subset of putatively sexually selected nongenital traits suggest that different selection mechanisms may be acting on the different trait types. Further investigations of this elaborate trait are imperative to determine whether it is ultimately an important driver of speciation.}, language = {en} } @article{DrakulićFeldhaarLisičićetal.2016, author = {Drakulić, Sanja and Feldhaar, Heike and Lisičić, Duje and Mioč, Mia and Cizelj, Ivan and Seiler, Michael and Spatz, Theresa and R{\"o}del, Mark-Oliver}, title = {Population-specific effects of developmental temperature on body condition and jumping performance of a widespread European frog}, series = {Ecology and Evolution}, volume = {6}, journal = {Ecology and Evolution}, number = {10}, doi = {10.1002/ece3.2113}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164960}, pages = {3115-3128}, year = {2016}, abstract = {All physiological processes of ectotherms depend on environmental temperature. Thus, adaptation of physiological mechanisms to the thermal environments is important for achieving optimal performance and fitness. The European Common Frog, Rana temporaria, is widely distributed across different thermal habitats. This makes it an exceptional model for studying the adaptations to different thermal conditions. We raised tadpoles from Germany and Croatia at two constant temperature treatments (15°C, 20°C), and under natural temperature fluctuations (in outdoor treatments), and tested how different developmental temperatures affected developmental traits, that is, length of larval development, morphometrics, and body condition, as well as jumping performance of metamorphs. Our results revealed population-specific differences in developmental time, body condition, and jumping performance. Croatian frogs developed faster in all treatments, were heavier, in better body condition, and had longer hind limbs and better jumping abilities than German metamorphs. The populations further differed in thermal sensitivity of jumping performance. While metamorphs from Croatia increased their jumping performance with higher temperatures, German metamorphs reached their performance maximum at lower temperatures. These population-specific differences in common environments indicate local genetic adaptation, with southern populations being better adapted to higher temperatures than those from north of the Alps.}, language = {en} } @article{vanToorNewmanTakekawaetal.2016, author = {van Toor, Mari{\"e}lle L. and Newman, Scott H. and Takekawa, John Y. and Wegmann, Martin and Safi, Kamran}, title = {Temporal segmentation of animal trajectories informed by habitat use}, series = {Ecosphere}, volume = {7}, journal = {Ecosphere}, number = {10}, doi = {10.1002/ecs2.1498}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164970}, pages = {e01498}, year = {2016}, abstract = {Most animals live in seasonal environments and experience very different conditions throughout the year. Behavioral strategies like migration, hibernation, and a life cycle adapted to the local seasonality help to cope with fluctuations in environmental conditions. Thus, how an individual utilizes the environment depends both on the current availability of habitat and the behavioral prerequisites of the individual at that time. While the increasing availability and richness of animal movement data has facilitated the development of algorithms that classify behavior by movement geometry, changes in the environmental correlates of animal movement have so far not been exploited for a behavioral annotation. Here, we suggest a method that uses these changes in individual-environment associations to divide animal location data into segments of higher ecological coherence, which we term niche segmentation. We use time series of random forest models to evaluate the transferability of habitat use over time to cluster observational data accordingly. We show that our method is able to identify relevant changes in habitat use corresponding to both changes in the availability of habitat and how it was used using simulated data, and apply our method to a tracking data set of common teal (Anas crecca). The niche segmentation proved to be robust, and segmented habitat suitability outperformed models neglecting the temporal dynamics of habitat use. Overall, we show that it is possible to classify animal trajectories based on changes of habitat use similar to geometric segmentation algorithms. We conclude that such an environmentally informed classification of animal trajectories can provide new insights into an individuals' behavior and enables us to make sensible predictions of how suitable areas might be connected by movement in space and time.}, language = {en} } @article{ChubanovFerioliWisnowskyetal.2016, author = {Chubanov, Vladimir and Ferioli, Silvia and Wisnowsky, Annika and Simmons, David G. and Leitzinger, Christin and Einer, Claudia and Jonas, Wenke and Shymkiv, Yuriy and Gudermann, Thomas and Bartsch, Harald and Braun, Attila and Akdogan, Banu and Mittermeier, Lorenz and Sytik, Ludmila and Torben, Friedrich and Jurinovic, Vindi and van der Vorst, Emiel P. C. and Weber, Christian and Yildirim, {\"O}nder A. and Sotlar, Karl and Sch{\"u}rmann, Annette and Zierler, Susanna and Zischka, Hans and Ryazanov, Alexey G.}, title = {Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival}, series = {eLife}, volume = {5}, journal = {eLife}, doi = {10.7554/eLife.20914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164987}, pages = {e19686}, year = {2016}, abstract = {Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.}, language = {en} } @article{MenaDiegelmannWegeneretal.2016, author = {Mena, Wilson and Diegelmann, S{\"o}ren and Wegener, Christian and Ewer, John}, title = {Stereotyped responses of Drosophila peptidergic neuronal ensemble depend on downstream neuromodulators}, series = {eLife}, volume = {5}, journal = {eLife}, doi = {10.7554/eLife.19686}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165003}, pages = {e19686}, year = {2016}, abstract = {Neuropeptides play a key role in the regulation of behaviors and physiological responses including alertness, social recognition, and hunger, yet, their mechanism of action is poorly understood. Here, we focus on the endocrine control ecdysis behavior, which is used by arthropods to shed their cuticle at the end of every molt. Ecdysis is triggered by ETH (Ecdysis triggering hormone), and we show that the response of peptidergic neurons that produce CCAP (crustacean cardioactive peptide), which are key targets of ETH and control the onset of ecdysis behavior, depends fundamentally on the actions of neuropeptides produced by other direct targets of ETH and released in a broad paracrine manner within the CNS; by autocrine influences from the CCAP neurons themselves; and by inhibitory actions mediated by GABA. Our findings provide insights into how this critical insect behavior is controlled and general principles for understanding how neuropeptides organize neuronal activity and behaviors.}, language = {en} } @article{BuschNadalSchmidetal.2016, author = {Busch, Martin and Nadal, Jennifer and Schmid, Matthias and Paul, Katharina and Titze, Stephanie and H{\"u}bner, Silvia and K{\"o}ttgen, Anna and Schultheiss, Ulla T. and Baid-Agrawal, Seema and Lorenzen, Johan and Schlieper, Georg and Sommerer, Claudia and Krane, Vera and Hilge, Robert and Kielstein, Jan T. and Kronenberg, Florian and Wanner, Christoph and Eckardt, Kai-Uwe and Wolf, Gunter}, title = {Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort}, series = {BMC Nephrology}, volume = {17}, journal = {BMC Nephrology}, number = {59}, doi = {10.1186/s12882-016-0273-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164687}, year = {2016}, abstract = {Background Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD. Methods The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) between 30-60 mL/min/1.73 m2 or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure. Results At baseline, DM was present in 1842 patients (35 \%) and the median HbA1C was 7.0 \% (25th-75th percentile: 6.8-7.9 \%), equalling 53 mmol/mol (51, 63); 24.2 \% of patients received dietary treatment only, 25.5 \% oral antidiabetic drugs but not insulin, 8.4 \% oral antidiabetic drugs with insulin, and 41.8 \% insulin alone. Metformin was used by 18.8 \%. Factors associated with an HbA1C level >7.0 \% (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m2, 95 \% CI 1.02-1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 \% CI 1.04-1.18), treatment with insulin alone (OR = 5.63, 95 \% CI 4.26-7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 \% CI 2.77-6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides. Conclusions Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 \% receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels.}, language = {en} } @article{AlnawaisehSchubertNelisetal.2016, author = {Alnawaiseh, Maged and Schubert, Friederike and Nelis, Pieter and Wirths, Gabriele and Rosentreter, Andr{\´e} and Eter, Nicole}, title = {Optical coherence tomography (OCT) angiography findings in retinal arterial macroaneurysms}, series = {BMC Ophthalmology}, volume = {16}, journal = {BMC Ophthalmology}, number = {120}, doi = {10.1186/s12886-016-0293-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164702}, year = {2016}, abstract = {Background Optical coherence tomography angiography is a novel imaging technique that allows dyeless in vivo visualization of the retinal and choroidal vasculature. The purpose of this study was to describe optical coherence tomography (OCT) angiography findings in patients with retinal arterial macroaneurysms (RAMs). Methods Three eyes of three patients with RAMs were retrospectively included. Fundus photography, OCT, fluorescein angiography (FA), and OCT angiography were performed. The entire imaging data was analyzed in detail. Results OCT angiography could detect the RAMs noninvasively without dye injection. By simultaneously observing the OCT scans, it was possible to determine the depth of the RAMs in the retina, to detect the exact localization in relation to the main vessel, and to determine the level of blood flow in the RAMs. Conclusions OCT angiography can clearly visualize RAMs without use of a dye. It also allows layer-specific observation of blood flow in each layer of the RAM. OCT angiography provides additional dynamic information on RAMs, which is not obtained with FA and facilitates a better understanding of its morphology and activity. This information in combination with ICG and fluorescein angiography can help to optimize direct laser treatment.}, language = {en} } @article{TsiligianniAlmaKocksetal.2016, author = {Tsiligianni, Ioanna G. and Alma, Harma J. and Kocks, Janwillem W. H. and de Jong, Corina and Jelusic, Danijel and Wittmann, Michael and Schuler, Michael and Schultz, Konrad and Kollen, Boudewijn J. and van der Molen, Thys}, title = {Investigating sensitivity, specificity, and area under the curve of the Clinical COPD Questionnaire, COPD Assessment Test, and Modified Medical Research Council scale according to GOLD using St George's Respiratory Questionnaire cutoff 25 (and 20) as reference}, series = {International Journal of COPD}, volume = {11}, journal = {International Journal of COPD}, doi = {10.2147/COPD.S99793}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165427}, pages = {1045-1052}, year = {2016}, abstract = {Background: In the GOLD (Global initiative for chronic Obstructive Lung Disease) strategy document, the Clinical COPD Questionnaire (CCQ), COPD Assessment Test (CAT), or modified Medical Research Council (mMRC) scale are recommended for the assessment of symptoms using the cutoff points of CCQ ≥1, CAT ≥10, and mMRC scale ≥2 to indicate symptomatic patients. The current study investigates the criterion validity of the CCQ, CAT and mMRC scale based on a reference cutoff point of St George's Respiratory Questionnaire (SGRQ) ≥25, as suggested by GOLD, following sensitivity and specificity analysis. In addition, areas under the curve (AUCs) of the CCQ, CAT, and mMRC scale were compared using two SGRQ cutoff points (≥25 and ≥20). Materials and methods: Two data sets were used: study A, 238 patients from a pulmonary rehabilitation program; and study B, 101 patients from primary care. Receiver-operating characteristic (ROC) curves were used to assess the correspondence between the recommended cutoff points of the questionnaires. Results: Sensitivity, specificity, and AUC scores for cutoff point SGRQ ≥25 were: study A, 0.99, 0.43, and 0.96 for CCQ ≥1, 0.92, 0.48, and 0.89 for CAT ≥10, and 0.68, 0.91, and 0.91 for mMRC ≥2; study B, 0.87, 0.77, and 0.9 for CCQ ≥1, 0.76, 0.73, and 0.82 for CAT ≥10, and 0.21, 1, and 0.81 for mMRC ≥2. Sensitivity, specificity, and AUC scores for cutoff point SGRQ ≥20 were: study A, 0.99, 0.73, and 0.99 for CCQ ≥1, 0.91, 0.73, and 0.94 for CAT ≥10, and 0.66, 0.95, and 0.94 for mMRC ≥2; study B, 0.8, 0.89, and 0.89 for CCQ ≥1, 0.69, 0.78, and 0.8 for CAT ≥10, and 0.18, 1, and 0.81 for mMRC ≥2. Conclusion: Based on data from these two different samples, this study showed that the suggested cutoff point for the SGRQ (≥25) did not seem to correspond well with the established cutoff points of the CCQ or CAT scales, resulting in low specificity levels. The correspondence with the mMRC scale seemed satisfactory, though not optimal. The SGRQ threshold of ≥20 corresponded slightly better than SGRQ ≥25, recently suggested by GOLD 2015, with the established cutoff points for the CCQ, CAT, and mMRC scale.}, language = {en} } @article{LudwigWernerBackesetal.2016, author = {Ludwig, Nicole and Werner, Tamara V. and Backes, Christina and Trampert, Patrick and Gessler, Manfred and Keller, Andreas and Lenhof, Hans-Peter and Graf, Norbert and Meese, Eckart}, title = {Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes}, series = {International Journal of Mokecular Sciences}, volume = {17}, journal = {International Journal of Mokecular Sciences}, number = {4}, doi = {10.3390/ijms17040475}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165430}, pages = {475}, year = {2016}, abstract = {Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT}, language = {en} } @article{LugoQuitadamoBianchietal.2016, author = {Lugo, Zulay R. and Quitadamo, Lucia R. and Bianchi, Luigi and Pellas, Fr{\´e}deric and Veser, Sandra and Lesenfants, Damien and Real, Ruben G. L. and Herbert, Cornelia and Guger, Christoph and Kotchoubey, Boris and Mattia, Donatella and K{\"u}bler, Andrea and Laureys, Steven and Noirhomme, Quentin}, title = {Cognitive Processing in Non-Communicative Patients: What Can Event-Related Potentials Tell Us?}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {569}, doi = {10.3389/fnhum.2016.00569}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165165}, year = {2016}, abstract = {Event-related potentials (ERP) have been proposed to improve the differential diagnosis of non-responsive patients. We investigated the potential of the P300 as a reliable marker of conscious processing in patients with locked-in syndrome (LIS). Eleven chronic LIS patients and 10 healthy subjects (HS) listened to a complex-tone auditory oddball paradigm, first in a passive condition (listen to the sounds) and then in an active condition (counting the deviant tones). Seven out of nine HS displayed a P300 waveform in the passive condition and all in the active condition. HS showed statistically significant changes in peak and area amplitude between conditions. Three out of seven LIS patients showed the P3 waveform in the passive condition and five of seven in the active condition. No changes in peak amplitude and only a significant difference at one electrode in area amplitude were observed in this group between conditions. We conclude that, in spite of keeping full consciousness and intact or nearly intact cortical functions, compared to HS, LIS patients present less reliable results when testing with ERP, specifically in the passive condition. We thus strongly recommend applying ERP paradigms in an active condition when evaluating consciousness in non-responsive patients.}, language = {en} } @article{EngeFleischhauerGaertneretal.2016, author = {Enge, S{\"o}ren and Fleischhauer, Monika and G{\"a}rtner, Anne and Reif, Andreas and Lesch, Klaus-Peter and Kliegel, Matthias and Strobel, Alexander}, title = {Brain-Derived Neurotrophic Factor (Val66Met) and Serotonin Transporter (5-HTTLPR) Polymorphisms Modulate Plasticity in Inhibitory Control Performance Over Time but Independent of Inhibitory Control Training}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {370}, doi = {10.3389/fnhum.2016.00370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165176}, year = {2016}, abstract = {Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements.}, language = {en} } @article{GroteKrysciakPetersenetal.2016, author = {Grote, Jessica and Krysciak, Dagmar and Petersen, Katrin and G{\"u}llert, Simon and Schmeisser, Christel and F{\"o}rstner, Konrad U. and Krishnan, Hari B. and Schwalbe, Harald and Kubatova, Nina and Streit, Wolfgang R.}, title = {The Absence of the N-acyl-homoserine-lactone Autoinducer Synthase Genes tral and ngrl Increases the Copy Number of the Symbiotic Plasmid in Sinorhizobium fredii NGR234}, series = {Frontiers in Microbiology}, volume = {7}, journal = {Frontiers in Microbiology}, number = {1858}, doi = {10.3389/fmicb.2016.01858}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165185}, year = {2016}, abstract = {Plant-released flavonoids induce the transcription of symbiotic genes in rhizobia and one of the first bacterial responses is the synthesis of so called Nod factors. They are responsible for the initial root hair curling during onset of root nodule development. This signal exchange is believed to be essential for initiating the plant symbiosis with rhizobia affiliated with the Alphaproteobacteria. Here, we provide evidence that in the broad host range strain Sinorhizobium fredii NGR234 the complete lack of quorum sensing molecules results in an elevated copy number of its symbiotic plasmid (pNGR234a). This in turn triggers the expression of symbiotic genes and the production of Nod factors in the absence of plant signals. Therefore, increasing the copy number of specific plasmids could be a widespread mechanism of specialized bacterial populations to bridge gaps in signaling cascades.}, language = {en} } @article{LupianezVillaescusaCarvalhoetal.2016, author = {Lupia{\~n}ez, Carmen B. and Villaescusa, Maria T. and Carvalho, Agostinho and Springer, Jan and Lackner, Michaela and S{\´a}nchez-Maldonado, Jos{\´e} M. and Canet, Luz M. and Cunha, Cristina and Segura-Catena, Joana and Alcazar-Fuoli, Laura and Solano, Carlos and Fianchi, Luana and Pagano, Livio and Potenza, Leonardo and Aguado, Jos{\´e} M. and Luppi, Mario and Cuenca-Estrella, Manuel and Lass-Fl{\"o}rl, Cornelia and Einsele, Hermann and V{\´a}zquez, Lourdes and R{\´i}os-Tamayo, Rafael and Loeffler, J{\"u}rgen and Jurado, Manuel and Sainz, Juan}, title = {Common Genetic Polymorphisms within NF kappa B-Related Genes and the Risk of Developing Invasive Aspergillosis}, series = {Frontiers in Microbiology}, volume = {7}, journal = {Frontiers in Microbiology}, number = {1243}, doi = {10.3389/fmicb.2016.01243}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165209}, year = {2016}, abstract = {Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95\%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.}, language = {en} } @article{KonteTerpitzPlemenitaš2016, author = {Konte, Tilen and Terpitz, Ulrich and Plemenitaš, Ana}, title = {Reconstruction of the High-Osmolarity Glycerol (HOG) Signaling Pathway from the Halophilic Fungus Wallemia ichthyophaga in Saccharomyces cerevisiae}, series = {Frontiers in Microbiology}, journal = {Frontiers in Microbiology}, doi = {10.3389/fmicb.2016.00901}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165214}, year = {2016}, abstract = {The basidiomycetous fungus Wallemia ichthyophaga grows between 1.7 and 5.1 M NaCl and is the most halophilic eukaryote described to date. Like other fungi, W. ichthyophaga detects changes in environmental salinity mainly by the evolutionarily conserved high-osmolarity glycerol (HOG) signaling pathway. In Saccharomyces cerevisiae, the HOG pathway has been extensively studied in connection to osmotic regulation, with a valuable knock-out strain collection established. In the present study, we reconstructed the architecture of the HOG pathway of W. ichthyophaga in suitable S. cerevisiae knock-out strains, through heterologous expression of the W. ichthyophaga HOG pathway proteins. Compared to S. cerevisiae, where the Pbs2 (ScPbs2) kinase of the HOG pathway is activated via the SHO1 and SLN1 branches, the interactions between the W. ichthyophaga Pbs2 (WiPbs2) kinase and the W. ichthyophaga SHO1 branch orthologs are not conserved: as well as evidence of poor interactions between the WiSho1 Src-homology 3 (SH3) domain and the WiPbs2 proline-rich motif, the absence of a considerable part of the osmosensing apparatus in the genome of W. ichthyophaga suggests that the SHO1 branch components are not involved in HOG signaling in this halophilic fungus. In contrast, the conserved activation of WiPbs2 by the S. cerevisiae ScSsk2/ScSsk22 kinase and the sensitivity of W. ichthyophaga cells to fludioxonil, emphasize the significance of two-component (SLN1-like) signaling via Group III histidine kinase. Combined with protein modeling data, our study reveals conserved and non-conserved protein interactions in the HOG signaling pathway of W. ichthyophaga and therefore significantly improves the knowledge of hyperosmotic signal processing in this halophilic fungus.}, language = {en} } @article{ContarinoSmitvandenDooletal.2016, author = {Contarino, Maria Fiorella and Smit, Marenka and van den Dool, Joost and Volkmann, Jens and Tijssen, Marina A. J.}, title = {Unmet Needs in the Management of Cervical Dystonia}, series = {Frontiers in Neurology}, volume = {7}, journal = {Frontiers in Neurology}, number = {165}, doi = {10.3389/fneur.2016.00165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165225}, year = {2016}, abstract = {Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.}, language = {en} } @article{ArimanyNardiMinuesaPastorAngladaetal.2016, author = {Arimany-Nardi, Cristina and Minuesa, Gerard and Pastor-Anglada, Mar{\c{c}}al and Keller, Thorsten and Erkizia, Itziar and Koepsell, Hermann and Martinez-Picado, Javier}, title = {Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions}, series = {Frontiers in Pharmacology}, volume = {7}, journal = {Frontiers in Pharmacology}, number = {175}, doi = {10.3389/fphar.2016.00175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165236}, year = {2016}, abstract = {Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.}, language = {en} } @article{ProppingLorenzMicheletal.2016, author = {Propping, Stefan and Lorenz, Kristina and Michel, Martin C. and Wirth, Manfred P. and Ravens, Ursula}, title = {beta-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in beta 2-Adrenoceptor Knockout Mice}, series = {Frontiers in Pharmacology}, volume = {7}, journal = {Frontiers in Pharmacology}, number = {118}, doi = {10.3389/fphar.2016.00118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165245}, year = {2016}, abstract = {Background and Objective: In order to characterize the β-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and β2-AR knockout (β2-AR KO) mice. Materials and Methods: Urinary bladders were isolated from male WT and β2-AR KO mice. β-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or β3-AR agonist CL 316,243 in the presence and absence of the subtype-selective β-AR blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Results: Quantitative real-time PCR confirmed lack of β2-AR expression in bladder tissue from β2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in β2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in β2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 μM). The -logEC50 values for (-)-isoprenaline in WT and β2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of β2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and β2-AR KO mice with a potency corresponding to the drug's affinity for β3-AR. L743,337 shifted the CRCs to the right. Conclusion: Our findings in β2-AR KO mice suggest that there is a large receptor reserve for β2-AR in WT mice so that this β-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, β3-AR can also mediate murine detrusor relaxation.}, language = {en} } @article{ZinnerMoralesAlamoOrtenbladetal.2016, author = {Zinner, Christoph and Morales-Alamo, David and {\O}rtenblad, Niels and Larsen, Filip J. and Schiffer, Tomas A. and Willis, Sarah J. and Gelabert-Rebato, Miriam and Perez-Valera, Mario and Boushel, Robert and Calbet, Jose A. L. and Holmberg, Hans-Christer}, title = {The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans}, series = {Frontiers in Physiology}, volume = {7}, journal = {Frontiers in Physiology}, number = {426}, doi = {10.3389/fphys.2016.00426}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165257}, year = {2016}, abstract = {To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3-11\% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8\%, P < 0.05), but not the legs (-0.6\%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6\% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44\%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70\% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.}, language = {en} } @article{NyssenVanNieulandVandenbergheetal.2016, author = {Nyssen, Jan and Van Nieuland, Jasper and Vandenberghe, Dimitri and Juilleret, J{\´e}r{\^o}me and Terhorst, Birgit}, title = {Gr{\`e}zes lit{\´e}es and their genesis: the site of Enscherange in the Rhenish-Ardennes Massif as a case study}, series = {Die Erde : Journal of the Geographical Society of Berlin}, volume = {147}, journal = {Die Erde : Journal of the Geographical Society of Berlin}, number = {1}, doi = {10.12854/erde-147-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165032}, year = {2016}, abstract = {The freeze-thaw cycles in periglacial areas during the Quaternary glacials increased frost weathering, leading to a disintegration of rock formations. Transported downslope, clasts allowed in some areas the formation of stratified slope deposits known as "gr{\`e}zes lit{\´e}es". This study reviews the existing theories and investigates the gr{\`e}zes lit{\´e}es deposits of Enscherange and Rodershausen in Luxembourg. This process was reinforced by the lithostructural control of the parent material expressed by the dip of schistosity (66°) and its orientation parallel to the main slopes in the area. This gave opportunities to activate the frost-weathering process on top of the ridge where the parent material outcropped. As the stratified slope deposits have a dip of 23° and as there is no significant lateral variation in rock fragment size, slope processes that involve only gravity are excluded and transportation in solifluction lobes with significant slopewash and sorting processes is hypothesized. The Enscherange formation, the biggest known outcrop of gr{\`e}zes lit{\´e}es in north-western Europe, shows evidence of clear layering over the whole profile depth. A palaeolandscape reconstruction shows that ridges must have been tens of metres higher than presently. The investigation of the matrix composition shows Laacher See tephra in the overlying periglacial cover bed with infiltrations of the minerals in the reworked upper layer of the gr{\`e}zes lit{\´e}es deposit. Chronostratigraphic approaches using the underlying cryoturbation zone and Laacher See heavy minerals in the overlying topsoil place the formation of gr{\`e}zes lit{\´e}es deposits in the Late Pleistocene.}, language = {en} } @article{BechtleCamargoMolinaDeschetal.2016, author = {Bechtle, Philip and Camargo-Molina, Jos{\´e} Eliel and Desch, Klaus and Dreiner, Herbert K. and Hamer, Matthias and Kr{\"a}mer, Michael and O'Leary, Ben and Porod, Werner and Sarrazin, Bj{\"o}rn and Stefaniak, Tim and Uhlenbrock, Mathias and Wienemann, Peter}, title = {Killing the cMSSM softly}, series = {The European Physical Journal C}, volume = {76}, journal = {The European Physical Journal C}, number = {96}, doi = {10.1140/epjc/s10052-015-3864-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165045}, year = {2016}, abstract = {We investigate the constrained Minimal Supersymmetric Standard Model (cMSSM) in the light of constraining experimental and observational data from precision measurements, astrophysics, direct supersymmetry searches at the LHC and measurements of the properties of the Higgs boson, by means of a global fit using the program Fittino. As in previous studies, we find rather poor agreement of the best fit point with the global data. We also investigate the stability of the electro-weak vacuum in the preferred region of parameter space around the best fit point. We find that the vacuum is metastable, with a lifetime significantly longer than the age of the Universe. For the first time in a global fit of supersymmetry, we employ a consistent methodology to evaluate the goodness-of-fit of the cMSSM in a frequentist approach by deriving p values from large sets of toy experiments. We analyse analytically and quantitatively the impact of the choice of the observable set on the p value, and in particular its dilution when confronting the model with a large number of barely constraining measurements. Finally, for the preferred sets of observables, we obtain p values for the cMSSM below 10 \%, i.e. we exclude the cMSSM as a model at the 90 \% confidence level.}, language = {en} } @article{BoettcherPrifertWeissbrichetal.2016, author = {B{\"o}ttcher, S. and Prifert, C. and Weißbrich, B. and Adams, O. and Aldabbagh, S. and Eis-H{\"u}binger, A. M. and Diedrich, S.}, title = {Detection of enterovirus D68 in patients hospitalised in three tertiary university hospitals in Germany, 2013 to 2014}, series = {Eurosurveillance}, volume = {21}, journal = {Eurosurveillance}, number = {19}, doi = {10.2807/1560-7917.ES.2016.21.19.30227}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165068}, pages = {pii=30227}, year = {2016}, abstract = {Enterovirus D68 (EV-D68) has been recognised as a worldwide emerging pathogen associated with severe respiratory symptoms since 2009. We here report EV-D68 detection in hospitalised patients with acute respiratory infection admitted to three tertiary hospitals in Germany between January 2013 and December 2014. From a total of 14,838 respiratory samples obtained during the study period, 246 (1.7\%) tested enterovirus-positive and, among these, 39 (15.9\%) were identified as EV-D68. Infection was observed in children and teenagers (0-19 years; n=31), the majority (n=22) being under five years-old, as well as in adults > 50 years of age (n=8). No significant difference in prevalence was observed between the 2013 and 2014 seasons. Phylogenetic analyses based on viral protein 1 (VP1) sequences showed co-circulation of different EV-D68 lineages in Germany. Sequence data encompassing the entire capsid region of the genome were analysed to gain information on amino acid changes possibly relevant for immunogenicity and revealed mutations in two recently described pleconaril binding sites.}, language = {en} } @article{HeldBerzHensgenetal.2016, author = {Held, Martina and Berz, Annuska and Hensgen, Ronja and Muenz, Thomas S. and Scholl, Christina and R{\"o}ssler, Wolfgang and Homberg, Uwe and Pfeiffer, Keram}, title = {Microglomerular Synaptic Complexes in the Sky-Compass Network of the Honeybee Connect Parallel Pathways from the Anterior Optic Tubercle to the Central Complex}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {186}, doi = {10.3389/fnbeh.2016.00186}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165080}, year = {2016}, abstract = {While the ability of honeybees to navigate relying on sky-compass information has been investigated in a large number of behavioral studies, the underlying neuronal system has so far received less attention. The sky-compass pathway has recently been described from its input region, the dorsal rim area (DRA) of the compound eye, to the anterior optic tubercle (AOTU). The aim of this study is to reveal the connection from the AOTU to the central complex (CX). For this purpose, we investigated the anatomy of large microglomerular synaptic complexes in the medial and lateral bulbs (MBUs/LBUs) of the lateral complex (LX). The synaptic complexes are formed by tubercle-lateral accessory lobe neuron 1 (TuLAL1) neurons of the AOTU and GABAergic tangential neurons of the central body's (CB) lower division (TL neurons). Both TuLAL1 and TL neurons strongly resemble neurons forming these complexes in other insect species. We further investigated the ultrastructure of these synaptic complexes using transmission electron microscopy. We found that single large presynaptic terminals of TuLAL1 neurons enclose many small profiles (SPs) of TL neurons. The synaptic connections between these neurons are established by two types of synapses: divergent dyads and divergent tetrads. Our data support the assumption that these complexes are a highly conserved feature in the insect brain and play an important role in reliable signal transmission within the sky-compass pathway.}, language = {en} } @article{MeyerRichterSchreiberetal.2016, author = {Meyer, Neele and Richter, S. Helene and Schreiber, Rebecca S. and Kloke, Vanessa and Kaiser, Sylvia and Lesch, Klaus-Peter and Sachser, Norbert}, title = {The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {97}, doi = {10.3389/fnbeh.2016.00097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165090}, year = {2016}, abstract = {Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior.}, language = {en} } @article{ZhouAllisonKuebleretal.2016, author = {Zhou, Sijie and Allison, Brendan Z. and K{\"u}bler, Andrea and Cichocki, Andrzej and Wang, Xingyu and Jin, Jing}, title = {Effects of Background Music on Objective and Subjective Performance Measures in an Auditory BCI}, series = {Frontiers in Computational Neuroscience}, volume = {10}, journal = {Frontiers in Computational Neuroscience}, number = {105}, doi = {10.3389/fncom.2016.00105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165101}, year = {2016}, abstract = {Several studies have explored brain computer interface (BCI) systems based on auditory stimuli, which could help patients with visual impairments. Usability and user satisfaction are important considerations in any BCI. Although background music can influence emotion and performance in other task environments, and many users may wish to listen to music while using a BCI, auditory, and other BCIs are typically studied without background music. Some work has explored the possibility of using polyphonic music in auditory BCI systems. However, this approach requires users with good musical skills, and has not been explored in online experiments. Our hypothesis was that an auditory BCI with background music would be preferred by subjects over a similar BCI without background music, without any difference in BCI performance. We introduce a simple paradigm (which does not require musical skill) using percussion instrument sound stimuli and background music, and evaluated it in both offline and online experiments. The result showed that subjects preferred the auditory BCI with background music. Different performance measures did not reveal any significant performance effect when comparing background music vs. no background. Since the addition of background music does not impair BCI performance but is preferred by users, auditory (and perhaps other) BCIs should consider including it. Our study also indicates that auditory BCIs can be effective even if the auditory channel is simultaneously otherwise engaged.}, language = {en} } @article{WiedenmannBocquillonDeaconetal.2016, author = {Wiedenmann, J. and Bocquillon, E. and Deacon, R.S. and Hartinger, S. and Herrmann, O. and Klapwijk, T.M. and Maier, L. and Ames, C. and Br{\"u}ne, C. and Gould, C. and Oiwa, A. and Ishibashi, K. and Tarucha, S. and Buhmann, H. and Molenkamp, L.W.}, title = {4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms10303}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175353}, year = {2016}, abstract = {The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.}, language = {en} } @article{FroehlichHanekePapenfortetal.2016, author = {Fr{\"o}hlich, Kathrin S. and Haneke, Katharina and Papenfort, Kai and Vogel, J{\"o}rg}, title = {The target spectrum of SdsR small RNA in Salmonella}, series = {Nucleic Acids Research}, volume = {44}, journal = {Nucleic Acids Research}, number = {21}, doi = {10.1093/nar/gkw632}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175365}, pages = {10406-10422}, year = {2016}, abstract = {Model enteric bacteria such as Escherichia coli and Salmonella enterica express hundreds of small non-coding RNAs (sRNAs), targets for most of which are yet unknown. Some sRNAs are remarkably well conserved, indicating that they serve cellular functions that go beyond the necessities of a single species. One of these 'core sRNAs' of largely unknown function is the abundant ∼100-nucleotide SdsR sRNA which is transcribed by the general stress σ-factor, σ\(^{S}\) and accumulates in stationary phase. In Salmonella, SdsR was known to inhibit the synthesis of the species-specific porin, OmpD. However, sdsR genes are present in almost all enterobacterial genomes, suggesting that additional, conserved targets of this sRNA must exist. Here, we have combined SdsR pulse-expression with whole genome transcriptomics to discover 20 previously unknown candidate targets of SdsR which include mRNAs coding for physiologically important regulators such as the carbon utilization regulator, CRP, the nucleoid-associated chaperone, StpA and the antibiotic resistance transporter, TolC. Processing of SdsR by RNase E results in two cellular SdsR variants with distinct target spectra. While the overall physiological role of this orphan core sRNA remains to be fully understood, the new SdsR targets present valuable leads to determine sRNA functions in resting bacteria.}, language = {en} } @phdthesis{Forster2016, author = {Forster, Johannes}, title = {Variational Approach to the Modeling and Analysis of Magnetoelastic Materials}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147226}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {This doctoral thesis is concerned with the mathematical modeling of magnetoelastic materials and the analysis of PDE systems describing these materials and obtained from a variational approach. The purpose is to capture the behavior of elastic particles that are not only magnetic but exhibit a magnetic domain structure which is well described by the micromagnetic energy and the Landau-Lifshitz-Gilbert equation of the magnetization. The equation of motion for the material's velocity is derived in a continuum mechanical setting from an energy ansatz. In the modeling process, the focus is on the interplay between Lagrangian and Eulerian coordinate systems to combine elasticity and magnetism in one model without the assumption of small deformations. The resulting general PDE system is simplified using special assumptions. Existence of weak solutions is proved for two variants of the PDE system, one including gradient flow dynamics on the magnetization, and the other featuring the Landau-Lifshitz-Gilbert equation. The proof is based on a Galerkin method and a fixed point argument. The analysis of the PDE system with the Landau-Lifshitz-Gilbert equation uses a more involved approach to obtain weak solutions based on G. Carbou and P. Fabrie 2001.}, subject = {Magnetoelastizit{\"a}t}, language = {en} } @article{KunzLiangNillaetal.2016, author = {Kunz, Meik and Liang, Chunguang and Nilla, Santosh and Cecil, Alexander and Dandekar, Thomas}, title = {The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development}, series = {Database}, volume = {2016}, journal = {Database}, doi = {10.1093/database/baw041}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147369}, pages = {baw041}, year = {2016}, abstract = {The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure-activity relationships.}, language = {en} } @article{StrekalovaMarkovaShevtsovaetal.2016, author = {Strekalova, Tatyana and Markova, Nataliia and Shevtsova, Elena and Zubareva, Olga and Bakhmet, Anastassia and Steinbusch, Harry M. and Bachurin, Sergey and Lesch, Klaus-Peter}, title = {Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test}, series = {Neural Plasticity}, volume = {2016}, journal = {Neural Plasticity}, doi = {10.1155/2016/5098591}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147379}, pages = {5098591}, year = {2016}, abstract = {While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.}, language = {en} } @article{RieplMusselOsinskyetal.2016, author = {Riepl, Korbinian and Mussel, Patrick and Osinsky, Roman and Hewig, Johannes}, title = {Influences of State and Trait Affect on Behavior, Feedback-Related Negativity, and P3b in the Ultimatum Game}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0146358}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147386}, pages = {e0146358}, year = {2016}, abstract = {The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants' behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and anxiety.}, language = {en} } @article{KoesslerHermannWeberetal.2016, author = {Koessler, Juergen and Hermann, Stephanie and Weber, Katja and Koessler, Angela and Kuhn, Sabine and Boeck, Markus and Kobsar, Anna}, title = {Role of Purinergic Receptor Expression and Function for Reduced Responsiveness to Adenosine Diphosphate in Washed Human Platelets}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0147370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146400}, pages = {e0147370}, year = {2016}, abstract = {Background Washing of platelets is an important procedure commonly used for experimental studies, e.g. in cardiovascular research. As a known phenomenon, responsiveness to adenosine diphosphate (ADP) is reduced in washed platelets, although underlying molecular mechanisms—potentially interfering with experimental results—have not been thoroughly studied. Objectives Since ADP mediates its effects via three purinergic receptors P2Y1, P2X1 and P2Y12, their surface expression and function were investigated in washed platelets and, for comparison, in platelet-rich-plasma (PRP) at different time points for up to 2 hours after preparation. Results In contrast to PRP, flow cytometric analysis of surface expression in washed platelets revealed an increase of all receptors during the first 60 minutes after preparation followed by a significant reduction, which points to an initial preactivation of platelets and consecutive degeneration. The activity of the P2X1 receptor (measured by selectively induced calcium flux) was substantially maintained in both PRP and washed platelets. P2Y12 function (determined by flow cytometry as platelet reactivity index) was partially reduced after platelet washing compared to PRP, but remained stable in course of ongoing storage. However, the function of the P2Y1 receptor (measured by selectively induced calcium flux) continuously declined after preparation of washed platelets. Conclusion In conclusion, decreasing ADP responsiveness in washed platelets is particularly caused by impaired activity of the P2Y1 receptor associated with disturbed calcium regulation, which has to be considered in the design of experimental studies addressing ADP mediated platelet function.}, language = {en} } @article{FehrholzGlaserSeidenspinneretal.2016, author = {Fehrholz, Markus and Glaser, Kirsten and Seidenspinner, Silvia and Ottensmeier, Barbara and Curstedt, Tore and Speer, Christian P. and Kunzmann, Steffen}, title = {Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4\(^+\) Lymphocytes}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0153578}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146419}, pages = {e0153578}, year = {2016}, abstract = {Background Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP-) B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown. Aim The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4\(^+\) lymphocytes. Methods Purified human CD4\(^+\) T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®). Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry. Results Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4\(^+\) lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were significantly increased in CHF5633 exposed CD4\(^+\) lymphocytes. Conclusion For the first time, the immunomodulatory capacity of CHF5633 on CD4\(^+\) lymphocytes was evaluated. CHF5633 did not show any cytotoxicity on CD4\(^+\) cells. Moreover, our in vitro data indicate that CHF5633 does not exert unintended pro-inflammatory effects on non-activated and activated CD4+ T cells. As far as anti-inflammatory cytokines are concerned, it might lack an overall reductive ability in comparison to animal-derived surfactants, potentially leaving pro- and anti-inflammatory cytokine response in balance.}, language = {en} } @article{BuschBuschScholzetal.2016, author = {Busch, Albert and Busch, Martin and Scholz, Claus-J{\"u}rgen and Kellersmann, Richard and Otto, Christoph and Chernogubova, Ekaterina and Maegdefessel, Lars and Zernecke, Alma and Lorenz, Udo}, title = {Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology}, series = {International Journal of Molecular Science}, volume = {17}, journal = {International Journal of Molecular Science}, number = {1}, issn = {International Journal of Molecular Science}, doi = {10.3390/ijms17010081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146422}, pages = {81}, year = {2016}, abstract = {Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.}, language = {en} } @article{SchmittLindner2016, author = {Schmitt, Joachim and Lindner, Nathalie}, title = {A 3-week multimodal intervention involving high-intensity interval training in female cancer survivors: a randomized controlled trial}, series = {Physiological Reports}, volume = {4}, journal = {Physiological Reports}, number = {3}, doi = {10.14814/phy2.12693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146455}, pages = {e12693}, year = {2016}, abstract = {To compare the effects of a 3-week multimodal rehabilitation involving supervised high-intensity interval training (HIIT) on female breast cancer survivors with respect to key variables of aerobic fitness, body composition, energy expenditure, cancer-related fatigue, and quality of life to those of a standard multimodal rehabilitation program. A randomized controlled trial design was administered. Twenty-eight women, who had been treated for cancer were randomly assigned to either a group performing exercise of low-to-moderate intensity (LMIE; n = 14) or a group performing high-intensity interval training (HIIT; n = 14) as part of a 3-week multimodal rehabilitation program. No adverse events related to the exercise were reported. Work economy improved following both HIIT and LMIE, with improved peak oxygen uptake following LMIE. HIIT reduced mean total body fat mass with no change in body mass, muscle or fat-free mass (best P < 0.06). LMIE increased muscle and total fat-free body mass. Total energy expenditure (P = 0.45) did not change between the groups, whereas both improved quality of life to a similar high extent and lessened cancer-related fatigue. This randomized controlled study demonstrates that HIIT can be performed by female cancer survivors without adverse health effects. Here, HIIT and LMIE both improved work economy, quality of life and cancer-related fatigue, body composition or energy expenditure. Since the outcomes were similar, but HIIT takes less time, this may be a time-efficient strategy for improving certain aspects of the health of female cancer survivors.}, language = {en} } @article{KasangKalluvyaMajingeetal.2016, author = {Kasang, Christa and Kalluvya, Samuel and Majinge, Charles and Kongola, Gilbert and Mlewa, Mathias and Massawe, Irene and Kabyemera, Rogatus and Magambo, Kinanga and Ulmer, Albrecht and Klinker, Hartwig and Gschmack, Eva and Horn, Anne and Koutsilieri, Eleni and Preiser, Wolfgang and Hofmann, Daniela and Hain, Johannes and M{\"u}ller, Andreas and D{\"o}lken, Lars and Weissbrich, Benedikt and Rethwilm, Axel and Stich, August and Scheller, Carsten}, title = {Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0146678}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146479}, pages = {e0146678}, year = {2016}, abstract = {Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-na{\"i}ve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.}, language = {en} } @article{HerrmannBeierSimonsetal.2016, author = {Herrmann, Martin J. and Beier, Jennifer S. and Simons, Bibiane and Polak, Thomas}, title = {Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {352}, doi = {10.3389/fnhum.2016.00352}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146486}, year = {2016}, abstract = {Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F(2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t(24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders.}, language = {en} } @article{ZlamyAlmanzarParsonetal.2016, author = {Zlamy, Manuela and Almanzar, Giovanni and Parson, Walther and Schmidt, Christian and Leierer, Johannes and Weinberger, Birgit and Jeller, Verena and Unsinn, Karin and Eyrich, Matthias and W{\"u}rzner, Reinhard and Prelog, Martina}, title = {Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy}, series = {Immunity \& Ageing}, volume = {13}, journal = {Immunity \& Ageing}, number = {3}, doi = {10.1186/s12979-016-0058-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146497}, year = {2016}, abstract = {Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. Conclusions After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.}, language = {en} } @article{BeckerKucharskiRoessleretal.2016, author = {Becker, Nils and Kucharski, Robert and R{\"o}ssler, Wolfgang and Maleszka, Ryszard}, title = {Age-dependent transcriptional and epigenomic responses to light exposure in the honey bee brain}, series = {FEBS Open Bio}, volume = {6}, journal = {FEBS Open Bio}, number = {7}, doi = {10.1002/2211-5463.12084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147080}, pages = {622-639}, year = {2016}, abstract = {Light is a powerful environmental stimulus of special importance in social honey bees that undergo a behavioral transition from in-hive to outdoor foraging duties. Our previous work has shown that light exposure induces structural neuronal plasticity in the mushroom bodies (MBs), a brain center implicated in processing inputs from sensory modalities. Here, we extended these analyses to the molecular level to unravel light-induced transcriptomic and epigenomic changes in the honey bee brain. We have compared gene expression in brain compartments of 1- and 7-day-old light-exposed honey bees with age-matched dark-kept individuals. We have found a number of differentially expressed genes (DEGs), both novel and conserved, including several genes with reported roles in neuronal plasticity. Most of the DEGs show age-related changes in the amplitude of light-induced expression and are likely to be both developmentally and environmentally regulated. Some of the DEGs are either known to be methylated or are implicated in epigenetic processes suggesting that responses to light exposure are at least partly regulated at the epigenome level. Consistent with this idea light alters the DNA methylation pattern of bgm, one of the DEGs affected by light exposure, and the expression of microRNA miR-932. This confirms the usefulness of our approach to identify candidate genes for neuronal plasticity and provides evidence for the role of epigenetic processes in driving the molecular responses to visual stimulation.}, language = {en} } @phdthesis{Koch2016, author = {Koch, Julia Diana}, title = {Value Ranges for Schlicht Functions}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144978}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {This thesis deals with value sets, i.e. the question of what the set of values that a set of functions can take in a prescribed point looks like. Interest in such problems has been around for a long time; a first answer was given by the Schwarz lemma in the 19th century, and soon various refinements were proven. Since the 1930s, a powerful method for solving such problems has been developed, namely Loewner theory. We make extensive use of this tool, as well as variation methods which go back to Schiffer to examine the following questions: We describe the set of values a schlicht normalised function on the unit disc with prescribed derivative at the origin can take by applying Pontryagin's maximum principle to the radial Loewner equation. We then determine the value ranges for the set of holomorphic, normalised, and bounded functions that have only real coefficients in their power series expansion around 0, and for the smaller set of functions which are additionally typically real. Furthermore, we describe the values a univalent self-mapping of the upper half-plane with hydrodynamical normalization which is symmetric with respect to the imaginary axis can take. Lastly, we give a necessary condition for a schlicht bounded function f on the unit disc to have extremal derivative in a point z where its value f(z) is fixed by using variation methods.}, subject = {Pontrjagin-Maximumprinzip}, language = {en} } @article{LukasczikWolfGerlichetal.2016, author = {Lukasczik, Matthias and Wolf, Hans-Dieter and Gerlich, Christian and K{\"u}ffner, Roland and Vogel, Heiner and Neuderth, Silke}, title = {Addressing Work-Related Issues in Medical Rehabilitation: Revision of an Online Information Tool for Healthcare Professionals}, series = {Rehabilitation Research and Practice}, volume = {2016}, journal = {Rehabilitation Research and Practice}, doi = {10.1155/2016/7621690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146911}, pages = {7621690}, year = {2016}, abstract = {Background. Medical rehabilitation increasingly considers occupational issues as determinants of health and work ability. Information on work-related rehabilitation concepts should therefore be made available to healthcare professionals. Objective. To revise a website providing healthcare professionals in medical rehabilitation facilities with information on work-related concepts in terms of updating existing information and including new topics, based on recommendations from implementation research. Method. The modification process included a questionnaire survey of medical rehabilitation centers (n=28); two workshops with experts from rehabilitation centers, health payers, and research institutions (n=14); the selection of new topics and revision of existing text modules based on expert consensus; and an update of good practice descriptions of work-related measures. Results. Health payers' requirements, workplace descriptions, and practical implementation aids were added as new topics. The database of good practice examples was extended to 63 descriptions. Information on introductory concepts was rewritten and supplemented by current data. Diagnostic tools were updated by including additional assessments. Conclusions. Recommendations from implementation research such as assessing user needs and including expert knowledge may serve as a useful starting point for the dissemination of information on work-related medical rehabilitation into practice. Web-based information tools such as the website presented here can be quickly adapted to current evidence and changes in medicolegal regulations.}, language = {en} } @article{WunschHohmannMillesetal.2016, author = {Wunsch, Marie and Hohmann, Christopher and Milles, Bianca and Rostermund, Christina and Lehmann, Paul V. and Schroeter, Michael and Bayas, Antonios and Ulzheimer, Jochen and M{\"a}urer, Mathias and Erg{\"u}n, S{\"u}leyman and Kuerten, Stefanie}, title = {The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis}, series = {Viruses}, volume = {8}, journal = {Viruses}, number = {4}, doi = {10.3390/v8040105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146946}, pages = {105}, year = {2016}, abstract = {There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.}, language = {en} } @article{MusselUlrichAllenetal.2016, author = {Mussel, Patrick and Ulrich, Nathalie and Allen, John J. B. and Osinsky, Roman and Hewig, Johannes}, title = {Patterns of theta oscillation reflect the neural basis of individual differences in epistemic motivation}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep29245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146957}, pages = {29245}, year = {2016}, abstract = {Theta oscillations in the EEG have been shown to reflect ongoing cognitive processes related to mental effort. Here, we show that the pattern of theta oscillation in response to varying cognitive demands reflects stable individual differences in the personality trait epistemic motivation: Individuals with high levels of epistemic motivation recruit relatively more cognitive resources in response to situations possessing high, compared to low, cognitive demand; individuals with low levels do not show such a specific response. Our results provide direct evidence for the theory of the construct need for cognition and add to our understanding of the neural processes underlying theta oscillations. More generally, we provide an explanation how individual differences in personality traits might be represented on a neural level.}, language = {en} } @article{DotterweichTowerBrandletal.2016, author = {Dotterweich, Julia and Tower, Robert J. and Brandl, Andreas and M{\"u}ller, Marc and Hofbauer, Lorenz C. and Beilhack, Andreas and Ebert, Regina and Gl{\"u}er, Claus C. and Tiwari, Sanjay and Sch{\"u}tze, Norbert and Jakob, Franz}, title = {The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0155087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146960}, pages = {e0155087}, year = {2016}, abstract = {Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.}, language = {en} } @article{BankogluTschoppSchmittetal.2016, author = {Bankoglu, Ezgi Eyluel and Tschopp, Oliver and Schmitt, Johannes and Burkard, Philipp and Jahn, Daniel and Geier, Andreas and Stopper, Helga}, title = {Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0166956}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146970}, pages = {e0166956}, year = {2016}, abstract = {Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.}, language = {en} } @article{BrunetVolffSchartl2016, author = {Brunet, Fr{\´e}d{\´e}ric G. and Volff, Jean-Nicolas and Schartl, Manfred}, title = {Whole Genome Duplications Shaped the Receptor Tyrosine Kinase Repertoire of Jawed Vertebrates}, series = {Genome Biology Evolution}, volume = {8}, journal = {Genome Biology Evolution}, number = {15}, doi = {10.1093/gbe/evw103}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146988}, pages = {1600-1613}, year = {2016}, abstract = {The receptor tyrosine kinase (RTK) gene family, involved primarily in cell growth and differentiation, comprises proteins with a common enzymatic tyrosine kinase intracellular domain adjacent to a transmembrane region. The amino-terminal portion of RTKs is extracellular and made of different domains, the combination of which characterizes each of the 20 RTK subfamilies among mammals. We analyzed a total of 7,376 RTK sequences among 143 vertebrate species to provide here the first comprehensive census of the jawed vertebrate repertoire. We ascertained the 58 genes previously described in the human and mouse genomes and established their phylogenetic relationships. We also identified five additional RTKs amounting to a total of 63 genes in jawed vertebrates. We found that the vertebrate RTK gene family has been shaped by the two successive rounds of whole genome duplications (WGD) called 1R and 2R (1R/2R) that occurred at the base of the vertebrates. In addition, the Vegfr and Ephrin receptor subfamilies were expanded by single gene duplications. In teleost fish, 23 additional RTK genes have been retained after another expansion through the fish-specific third round (3R) of WGD. Several lineage-specific gene losses were observed. For instance, birds have lost three RTKs, and different genes are missing in several fish sublineages. The RTK gene family presents an unusual high gene retention rate from the vertebrate WGDs (58.75\% after 1R/2R, 64.4\% after 3R), resulting in an expansion that might be correlated with the evolution of complexity of vertebrate cellular communication and intracellular signaling.}, language = {en} } @phdthesis{Jung2016, author = {Jung, Lisa Anna}, title = {Targeting MYC Function as a Strategy for Tumor Therapy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146993}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {A large fraction of human tumors exhibits aberrant expression of the oncoprotein MYC. As a transcription factor regulating various cellular processes, MYC is also crucially involved in normal development. Direct targeting of MYC has been a major challenge for molecular cancer drug discovery. The proof of principle that its inhibition is nevertheless feasible came from in vivo studies using a dominant-negative allele of MYC termed OmoMYC. Systemic expression of OmoMYC triggered long-term tumor regression with mild and fully reversible side effects on normal tissues. In this study, OmoMYC's mode of action was investigated combining methods of structural biology and functional genomics to elucidate how it is able to preferentially affect oncogenic functions of MYC. The crystal structure of the OmoMYC homodimer, both in the free and the E-box-bound state, was determined, which revealed that OmoMYC forms a stable homodimer, and as such, recognizes DNA via the same base-specific DNA contacts as the MYC/MAX heterodimer. OmoMYC binds DNA with an equally high affinity as MYC/MAX complexes. RNA-sequencing showed that OmoMYC blunts both MYC-dependent transcriptional activation and repression. Genome-wide DNA-binding studies using chromatin immunoprecipitation followed by high-throughput sequencing revealed that OmoMYC competes with MYC/MAX complexes on chromatin, thereby reducing their occupancy at consensus DNA binding sites. The most prominent decrease in MYC binding was seen at low-affinity promoters, which were invaded by MYC at oncogenic levels. Strikingly, gene set enrichment analyses using OmoMYC-regulated genes enabled the identification of tumor subgroups with high MYC levels in multiple tumor entities. Together with a targeted shRNA screen, this identified novel targets for the eradication of MYC-driven tumors, such as ATAD3A, BOP1, and ADRM1. In summary, the findings suggest that OmoMYC specifically inhibits tumor cell growth by attenuating the expression of rate-limiting proteins in cellular processes that respond to elevated levels of MYC protein using a DNA-competitive mechanism. This opens up novel strategies to target oncogenic MYC functions for tumor therapy.}, subject = {Myc}, language = {en} } @article{KamawalSteinertHolzapfeletal.2016, author = {Kamawal, Yama and Steinert, Andre F and Holzapfel, Boris M and Rudert, Maximilian and Barthel, Thomas}, title = {Case report - calcification of the medial collateral ligament of the knee with simultaneous calcifying tendinitis of the rotator cuff}, series = {BMC Muscoskeletal Disorders}, volume = {17}, journal = {BMC Muscoskeletal Disorders}, number = {283}, doi = {10.1186/s12891-016-1147-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147669}, year = {2016}, abstract = {Calcification of the medial collateral ligament (MCL) of the knee is a very rare disease. We report on a case of a patient with a calcifying lesion within the MCL and simultaneous calcifying tendinitis of the rotator cuff in both shoulders. Case presentation: Calcification of the MCL was diagnosed both via x-ray and magnetic resonance imaging (MRI) and was successfully treated surgically. Calcifying tendinitis of the rotator cuff was successfully treated applying conservative methods. Conclusion: This is the first case report of a patient suffering from both a calcifying lesion within the medial collateral ligament and calcifying tendinitis of the rotator cuff in both shoulders. Clinical symptoms, radio-morphological characteristics and macroscopic features were very similar and therefore it can be postulated that the underlying pathophysiology is the same in both diseases. Our experience suggests that magnetic resonance imaging and x-ray are invaluable tools for the diagnosis of this inflammatory calcifying disease of the ligament, and that surgical repair provides a good outcome if conservative treatment fails. It seems that calcification of the MCL is more likely to require surgery than calcifying tendinitis of the rotator cuff. However, the exact reason for this remains unclear to date.}, language = {en} } @article{RichterPolatLawrenzetal.2016, author = {Richter, Anne and Polat, B{\"u}lent and Lawrenz, Ingulf and Weick, Stefan and Sauer, Otto and Flentje, Michael and Mantel, Frederick}, title = {Initial results for patient setup verification using transperineal ultrasound and cone beam CT in external beam radiation therapy of prostate cancer}, series = {Radiation Oncology}, volume = {11}, journal = {Radiation Oncology}, number = {147}, doi = {10.1186/s13014-016-0722-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147677}, year = {2016}, abstract = {Evaluation of set up error detection by a transperineal ultrasound in comparison with a cone beam CT (CBCT) based system in external beam radiation therapy (EBRT) of prostate cancer. Methods: Setup verification was performed with transperineal ultrasound (TPUS) and CBCT for 10 patients treated with EBRT for prostate cancer. In total, 150 ultrasound and CBCT scans were acquired in rapid succession and analyzed for setup errors. The deviation between setup errors of the two modalities was evaluated separately for each dimension. Results: A moderate correlation in lateral, vertical and longitudinal direction was observed comparing the setup errors. Mean differences between TPUS and CBCT were (-2.7 ± 2.3) mm, (3.0 ± 2.4) mm and (3.2 ± 2.7) mm in lateral, vertical and longitudinal direction, respectively. The mean Euclidean difference between TPUS and CBCT was (6.0 ± 3.1) mm. Differences up to 19.2 mm were observed between the two imaging modalities. Discrepancies between TPUS and CBCT of at least 5 mm occurred in 58 \% of monitored treatment sessions. Conclusion: Setup differences between TPUS and CBCT are 6 mm on average. Although the correlation of the setup errors determined by the two different image modalities is rather week, the combination of setup verification by CBCT and intrafraction motion monitoring by TPUS imaging can use the benefits of both imaging modalities.}, language = {en} } @article{SiminSoltamovPoshakinskiyetal.2016, author = {Simin, D. and Soltamov, V. A. and Poshakinskiy, A. V. and Anisimov, A. N. and Babunts, R. A. and Tolmachev, D. O. and Mokhov, E. N. and Trupke, M. and Tarasenko, S. A. and Sperlich, A. and Baranov, P. G. and Dyakonov, V. and Astakhov, G. V.}, title = {All-Optical dc Nanotesla Magnetometry Using Silicon Vacancy Fine Structure in Isotopically Purified Silicon Carbide}, series = {Physical Review X}, volume = {6}, journal = {Physical Review X}, doi = {10.1103/PhysRevX.6.031014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147682}, pages = {031014}, year = {2016}, abstract = {We uncover the fine structure of a silicon vacancy in isotopically purified silicon carbide (4H-\(^{28}\)SiC) and reveal not yet considered terms in the spin Hamiltonian, originated from the trigonal pyramidal symmetry of this spin-3/2 color center. These terms give rise to additional spin transitions, which would be otherwise forbidden, and lead to a level anticrossing in an external magnetic field. We observe a sharp variation of the photoluminescence intensity in the vicinity of this level anticrossing, which can be used for a purely all-optical sensing of the magnetic field. We achieve dc magnetic field sensitivity better than 100  nT/√Hz within a volume of 3×10\(^{-7}\)mm\(^3\) at room temperature and demonstrate that this contactless method is robust at high temperatures up to at least 500 K. As our approach does not require application of radio-frequency fields, it is scalable to much larger volumes. For an optimized light-trapping waveguide of 3  mm\(^3\), the projection noise limit is below 100  fT/√Hz.}, language = {en} } @article{RovitusoSchefflerWunschetal.2016, author = {Rovituso, Damiano M. and Scheffler, Laura and Wunsch, Marie and Kleinschnitz, Christoph and D{\"o}rck, Sebastian and Ulzheimer, Jochen and Bayas, Antonios and Steinman, Lawrence and Erg{\"u}n, S{\"u}leyman and Kuerten, Stefanie}, title = {CEACAM1 mediates B cell aggregation in central nervous system autoimmunity}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep29847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147690}, pages = {29847}, year = {2016}, abstract = {B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1\(^+\) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain -3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.}, language = {en} } @article{FalibeneRocesRoessleretal.2016, author = {Falibene, Augustine and Roces, Flavio and R{\"o}ssler, Wolfgang and Groh, Claudia}, title = {Daily Thermal Fluctuations Experienced by Pupae via Rhythmic Nursing Behavior Increase Numbers of Mushroom Body Microglomeruli in the Adult Ant Brain}, series = {Frontiers in Behavioral Neuroscience}, volume = {10}, journal = {Frontiers in Behavioral Neuroscience}, number = {73}, doi = {10.3389/fnbeh.2016.00073}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146711}, year = {2016}, abstract = {Social insects control brood development by using different thermoregulatory strategies. Camponotus mus ants expose their brood to daily temperature fluctuations by translocating them inside the nest following a circadian rhythm of thermal preferences. At the middle of the photophase brood is moved to locations at 30.8°C; 8 h later, during the night, the brood is transferred back to locations at 27.5°C. We investigated whether daily thermal fluctuations experienced by developing pupae affect the neuroarchitecture in the adult brain, in particular in sensory input regions of the mushroom bodies (MB calyces). The complexity of synaptic microcircuits was estimated by quantifying MB-calyx volumes together with densities of presynaptic boutons of microglomeruli (MG) in the olfactory lip and visual collar regions. We compared young adult workers that were reared either under controlled daily thermal fluctuations of different amplitudes, or at different constant temperatures. Thermal regimes significantly affected the large (non-dense) olfactory lip region of the adult MB calyx, while changes in the dense lip and the visual collar were less evident. Thermal fluctuations mimicking the amplitudes of natural temperature fluctuations via circadian rhythmic translocation of pupae by nurses (amplitude 3.3°C) lead to higher numbers of MG in the MB calyces compared to those in pupae reared at smaller or larger thermal amplitudes (0.0, 1.5, 9.6°C), or at constant temperatures (25.4, 35.0°C). We conclude that rhythmic control of brood temperature by nursing ants optimizes brain development by increasing MG densities and numbers in specific brain areas. Resulting differences in synaptic microcircuits are expected to affect sensory processing and learning abilities in adult ants, and may also promote interindividual behavioral variability within colonies.}, language = {en} } @phdthesis{Ziegler2016, author = {Ziegler, Christiane}, title = {Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146815}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10\%. Panic disorder (PD) has a life time prevalence of 2-5\% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue. In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called "hidden heritability", which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders. In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD. The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as - applying a psychotherapy-epigenetic approach - its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD. Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively.}, subject = {Angst}, language = {en} } @article{WalperWeisteMuelleretal.2016, author = {Walper, Elisabeth and Weiste, Christoph and Mueller, Martin J. and Hamberg, Mats and Dr{\"o}ge-Laser, Wolfgang}, title = {Screen Identifying Arabidopsis Transcription Factors Involved in the Response to 9-Lipoxygenase-Derived Oxylipins}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0153216}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146857}, pages = {e0153216}, year = {2016}, abstract = {13-Lipoxygenase-derived oxylipins, such as jasmonates act as potent signaling molecules in plants. Although experimental evidence supports the impact of oxylipins generated by the 9-Lipoxygenase (9-LOX) pathway in root development and pathogen defense, their signaling function in plants remains largely elusive. Based on the root growth inhibiting properties of the 9-LOX-oxylipin 9-HOT (9-hydroxy-10,12,15-octadecatrienoic acid), we established a screening approach aiming at identifying transcription factors (TFs) involved in signaling and/or metabolism of this oxylipin. Making use of the AtTORF-Ex (Arabidopsis thaliana Transcription Factor Open Reading Frame Expression) collection of plant lines overexpressing TF genes, we screened for those TFs which restore root growth on 9-HOT. Out of 6,000 lines, eight TFs were recovered at least three times and were therefore selected for detailed analysis. Overexpression of the basic leucine Zipper (bZIP) TF TGA5 and its target, the monoxygenase CYP81D11 reduced the effect of added 9-HOT, presumably due to activation of a detoxification pathway. The highly related ETHYLENE RESPONSE FACTORs ERF106 and ERF107 induce a broad detoxification response towards 9-LOX-oxylipins and xenobiotic compounds. From a set of 18 related group S-bZIP factors isolated in the screen, bZIP11 is known to participate in auxin-mediated root growth and may connect oxylipins to root meristem function. The TF candidates isolated in this screen provide starting points for further attempts to dissect putative signaling pathways involving 9-LOX-derived oxylipins.}, language = {en} } @article{BornZinnerDuekingetal.2016, author = {Born, Dennis-Peter and Zinner, Christoph and D{\"u}king, Peter and Sperlich, Billy}, title = {Multi-Directional Sprint Training Improves Change-Of-Direction Speed and Reactive Agility in Young Highly Trained Soccer Players}, series = {Journal of Sports Science and Medicine}, volume = {15}, journal = {Journal of Sports Science and Medicine}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146866}, pages = {314-319}, year = {2016}, abstract = {The aim of this study was to evaluate the effect of a repeated sprint training with multi-directional change-of-direction (COD) movements (RSmulti) compared to repeated shuttle sprints (RSS) on variables related to COD speed and reactive agility. Nineteen highly-trained male U15 soccer players were assigned into two groups performing either RSmulti or RSS. For both groups, each training session involved 20 repeated 15 s sprints interspersed with 30 s recovery. With RSmulti the COD movements were randomized and performed in response to a visual stimulus, while the RSS involved predefined 180° COD movements. Before and following the six training sessions, performance in the Illinois agility test (IAT), COD speed in response to a visual stimulus, 20 m linear sprint time and vertical jumping height were assessed. Both groups improved their performance in the IAT (p < 0.01, ES = 1.13; p = 0.01, ES = 0.55). The COD speed in response to a visual stimulus improved with the RSmulti (p < 0.01, ES = 1.03), but not the RSS (p = 0.46, ES = 0.28). No differences were found for 20 m sprint time (P=0.73, ES = 0.07; p = 0.14, ES = 0.28) or vertical jumping height (p = 0.46, ES = 0.11; p = 0.29, ES = 0.12) for the RSmulti and RSS, respectively. In conclusion, performance in the IAT improved with the RSmulti as well as RSS. With the RSmulti however, the COD movements are performed in response to a visual stimulus, which may result in specific adaptations that improve COD speed and reactive agility in young highly trained soccer players.}, language = {en} } @article{FuchsHartmannErnestusetal.2016, author = {Fuchs, Andreas and Hartmann, Stefan and Ernestus, Karen and Mutzbauer, Grit and Linz, Christian and Brands, Roman C. and K{\"u}bler, Alexander C. and M{\"u}ller-Richter, Urs D. A.}, title = {Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report}, series = {Journal of Medical Case Reports}, volume = {16}, journal = {Journal of Medical Case Reports}, number = {268}, doi = {10.1186/s13256-016-1052-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146873}, year = {2016}, abstract = {Background Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases. Case presentation The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved. Conclusions Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.}, language = {en} } @article{BeykanDamEberleinetal.2016, author = {Beykan, Seval and Dam, Jan S. and Eberlein, Uta and Kaufmann, Jens and Kj{\ae}rgaard, Benedict and J{\o}dal, Lars and Bouterfa, Hakim and Bejot, Romain and Lassmann, Michael and Jensen, Svend Borup}, title = {\(^{177}\)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model}, series = {EJNMMI Research}, volume = {6}, journal = {EJNMMI Research}, number = {50}, doi = {10.1186/s13550-016-0204-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146888}, year = {2016}, abstract = {Background \(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results \(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 \% in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 \% of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.}, language = {en} } @article{KaltdorfSrivastavaGuptaetal.2016, author = {Kaltdorf, Martin and Srivastava, Mugdha and Gupta, Shishir K. and Liang, Chunguang and Binder, Jasmin and Dietl, Anna-Maria and Meir, Zohar and Haas, Hubertus and Osherov, Nir and Krappmann, Sven and Dandekar, Thomas}, title = {Systematic Identification of Anti-Fungal Drug Targets by a Metabolic Network Approach}, series = {Frontiers in Molecular Bioscience}, volume = {3}, journal = {Frontiers in Molecular Bioscience}, doi = {10.3389/fmolb.2016.00022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147396}, pages = {22}, year = {2016}, abstract = {New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness ("hubs"), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.}, language = {en} } @article{WernerLueckerathSchmidetal.2016, author = {Werner, R. A. and L{\"u}ckerath, K. and Schmid, J. S. and Higuchi, T. and Kreissl, M. C. and Grelle, I. and Reiners, C. and Buck, A. K. and Lapa, C.}, title = {Thyroglobulin fluctuations in patients with iodine-refractory differentiated thyroid carcinoma on lenvatinib treatment - initial experience}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, doi = {10.1038/srep28081}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147407}, pages = {28081}, year = {2016}, abstract = {Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2-3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2\%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.}, language = {en} } @article{KrausHeiberVaethetal.2016, author = {Kraus, Hannes and Heiber, Michael C. and V{\"a}th, Stefan and Kern, Julia and Deibel, Carsten and Sperlich, Andreas and Dyakonov, Vladimir}, title = {Analysis of Triplet Exciton Loss Pathways in PTB7:PC\(_{71}\)BM Bulk Heterojunction Solar Cells}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {29158}, doi = {10.1038/srep29158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147413}, year = {2016}, abstract = {A strategy for increasing the conversion efficiency of organic photovoltaics has been to increase the VOC by tuning the energy levels of donor and acceptor components. However, this opens up a new loss pathway from an interfacial charge transfer state to a triplet exciton (TE) state called electron back transfer (EBT), which is detrimental to device performance. To test this hypothesis, we study triplet formation in the high performing PTB7:PC\(_{71}\)BM blend system and determine the impact of the morphology-optimizing additive 1,8-diiodoctane (DIO). Using photoluminescence and spin-sensitive optically detected magnetic resonance (ODMR) measurements at low temperature, we find that TEs form on PC\(_{71}\)BM via intersystem crossing from singlet excitons and on PTB7 via EBT mechanism. For DIO blends with smaller fullerene domains, an increased density of PTB7 TEs is observed. The EBT process is found to be significant only at very low temperature. At 300 K, no triplets are detected via ODMR, and electrically detected magnetic resonance on optimized solar cells indicates that TEs are only present on the fullerenes. We conclude that in PTB7:PC\(_{71}\)BM devices, TE formation via EBT is impacted by fullerene domain size at low temperature, but at room temperature, EBT does not represent a dominant loss pathway.}, language = {en} } @article{BiehlMerzDresleretal.2016, author = {Biehl, Stefanie C. and Merz, Christian J. and Dresler, Thomas and Heupel, Julia and Reichert, Susanne and Jacob, Christian P. and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?}, series = {International Journal of Neuropsychopharmacology}, volume = {19}, journal = {International Journal of Neuropsychopharmacology}, number = {10}, doi = {10.1093/ijnp/pyw049}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147551}, pages = {pyw049}, year = {2016}, abstract = {Background: Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Methods: Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. Results: There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Conclusions: Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.}, language = {en} } @article{UeceylerBikoHoseetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Biko, Lydia and Hose, Dorothea and Hoffmann, Lukas and Sommer, Claudia}, title = {Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development}, series = {Molecular Pain}, volume = {12}, journal = {Molecular Pain}, number = {1744806916646370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147562}, year = {2016}, abstract = {Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease. Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.}, language = {en} } @phdthesis{Ruf2016, author = {Ruf, Franziska}, title = {The circadian regulation of eclosion in \(Drosophila\) \(melanogaster\)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146265}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Eclosion is the emergence of an adult insect from the pupal case at the end of development. In the fruit fly Drosophila melanogaster, eclosion is a circadian clock-gated event and is regulated by various peptides. When studied on the population level, eclosion reveals a clear rhythmicity with a peak at the beginning of the light-phase that persists also under constant conditions. It is a long standing hypothesis that eclosion gating to the morning hours with more humid conditions is an adaption to reduce water loss and increase the survival. Eclosion behavior, including the motor pattern required for the fly to hatch out of the puparium, is orchestrated by a well-characterized cascade of peptides. The main components are ecdysis-triggering hormone (ETH), eclosion hormone (EH) and crustacean cardioactive peptide (CCAP). The molt is initiated by a peak level and pupal ecdysis by a subsequent decline of the ecdysteroid ecdysone. Ecdysteroids are produced by the prothoracic gland (PG), an endocrine tissue that contains a peripheral clock and degenerates shortly after eclosion. Production and release of ecdysteroids are regulated by the prothoracicotropic hormone (PTTH). Although many aspects of the circadian clock and the peptidergic control of the eclosion behavior are known, it still remains unclear how both systems are interconnected. The aim of this dissertation research was to dissect this connection and evaluate the importance of different Zeitgebers on eclosion rhythmicity under natural conditions. Potential interactions between the central clock and the peptides regulating ecdysis motor behavior were evaluated by analyzing the influence of CCAP on eclosion rhythmicity. Ablation and silencing of CCAP neurons, as well as CCAP null-mutation did not affect eclosion rhythmicity under either light or temperature entrainment nor under natural conditions. To dissect the connection between the central and the peripheral clock, PTTH neurons were ablated. Monitoring eclosion under light and temperature entrainment revealed that eclosion became arrhythmic under constant conditions. However, qPCR expression analysis revealed no evidence for cycling of Ptth mRNA in pharate flies. To test for a connection with pigment-dispersing factor (PDF)-expressing neurons, the PDF receptor (PDFR) and short neuropeptide F receptor (sNPFR) were knocked down in the PTTH neurons. Knockdown of sNPFR, but not PDFR, resulted in arrhythmic eclosion under constant darkness conditions. PCR analysis of the PTTH receptor, Torso, revealed its expression in the PG and the gonads, but not in the brain or eyes, of pharate flies. Knockdown of torso in the PG lead to arrhythmicity under constant conditions, which provides strong evidence for the specific effect of PTTH on the PG. These results suggest connections from the PDF positive lateral neurons to the PTTH neurons via sNPF signaling, and to the PG via PTTH and Torso. This interaction presumably couples the period of the peripheral clock in the PG to that of the central clock in the brain. To identify a starting signal for eclosion and possible further candidates in the regulation of eclosion behavior, chemically defined peptidergic and aminergic neurons were optogenetically activated in pharate pupae via ChR2-XXL. This screen approach revealed two candidates for the regulation of eclosion behavior: Dromyosuppressin (DMS) and myo-inhibitory peptides (MIP). However, ablation of DMS neurons did not affect eclosion rhythmicity or success and the exact function of MIP must be evaluated in future studies. To assess the importance of the clock and of possible Zeitgebers in nature, eclosion of the wildtype Canton S and the clock mutant per01 and the PDF signaling mutants pdf01 and han5304 was monitored under natural conditions. For this purpose, the W{\"u}rzburg eclosion monitor (WEclMon) was developed, which is a new open monitoring system that allows direct exposure of pupae to the environment. A general decline of rhythmicity under natural conditions compared to laboratory conditions was observed in all tested strains. While the wildtype and the pdf01 and han5304 mutants stayed weakly rhythmic, the per01 mutant flies eclosed mostly arrhythmic. PDF and its receptor (PDFR encoded by han) are required for the synchronization of the clock network and functional loss can obviously be compensated by a persisting synchronization to external Zeitgebers. The loss of the central clock protein PER, however, lead to a non-functional clock and revealed the absolute importance of the clock for eclosion rhythmicity. To quantitatively analyze the effect of the clock and abiotic factors on eclosion rhythmicity, a statistical model was developed in cooperation with Oliver Mitesser and Thomas Hovestadt. The modelling results confirmed the clock as the most important factor for eclosion rhythmicity. Moreover, temperature was found to have the strongest effect on the actual shape of the daily emergence pattern, while light has only minor effects. Relative humidity could be excluded as Zeitgeber for eclosion and therefore was not further analyzed. Taken together, the present dissertation identified the so far unknown connection between the central and peripheral clock regulating eclosion. Furthermore, a new method for the analysis of eclosion rhythms under natural conditions was established and the necessity of a functional clock for rhythmic eclosion even in the presence of multiple Zeitgebers was shown.}, subject = {Taufliege}, language = {en} } @article{DejungSubotaBuceriusetal.2016, author = {Dejung, Mario and Subota, Ines and Bucerius, Ferdinand and Dindar, G{\"u}lcin and Freiwald, Anja and Engstler, Markus and Boshart, Michael and Butter, Falk and Janzen, Chistian J.}, title = {Quantitative proteomics uncovers novel factors involved in developmental differentiation of Trypanosoma brucei}, series = {PLoS Pathogens}, volume = {12}, journal = {PLoS Pathogens}, number = {2}, doi = {10.1371/journal.ppat.1005439}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146362}, pages = {e1005439}, year = {2016}, abstract = {Developmental differentiation is a universal biological process that allows cells to adapt to different environments to perform specific functions. African trypanosomes progress through a tightly regulated life cycle in order to survive in different host environments when they shuttle between an insect vector and a vertebrate host. Transcriptomics has been useful to gain insight into RNA changes during stage transitions; however, RNA levels are only a moderate proxy for protein abundance in trypanosomes. We quantified 4270 protein groups during stage differentiation from the mammalian-infective to the insect form and provide classification for their expression profiles during development. Our label-free quantitative proteomics study revealed previously unknown components of the differentiation machinery that are involved in essential biological processes such as signaling, posttranslational protein modifications, trafficking and nuclear transport. Furthermore, guided by our proteomic survey, we identified the cause of the previously observed differentiation impairment in the histone methyltransferase DOT1B knock-out strain as it is required for accurate karyokinesis in the first cell division during differentiation. This epigenetic regulator is likely involved in essential chromatin restructuring during developmental differentiation, which might also be important for differentiation in higher eukaryotic cells. Our proteome dataset will serve as a resource for detailed investigations of cell differentiation to shed more light on the molecular mechanisms of this process in trypanosomes and other eukaryotes.}, language = {en} } @article{LiuHuNordbecketal.2016, author = {Liu, Dan and Hu, Kai and Nordbeck, Peter and Ertl, Georg and St{\"o}rk, Stefan and Weidemann, Frank}, title = {Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy}, series = {European Journal of Medical Research}, volume = {21}, journal = {European Journal of Medical Research}, number = {21}, doi = {10.1186/s40001-016-0216-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146373}, year = {2016}, abstract = {Despite substantial advances in the imaging techniques and pathophysiological understanding over the last decades, identification of the underlying causes of left ventricular hypertrophy by means of echocardiographic examination remains a challenge in current clinical practice. The longitudinal strain bull's eye plot derived from 2D speckle tracking imaging offers an intuitive visual overview of the global and regional left ventricular myocardial function in a single diagram. The bull's eye mapping is clinically feasible and the plot patterns could provide clues to the etiology of cardiomyopathies. The present review summarizes the longitudinal strain, bull's eye plot features in patients with various cardiomyopathies and concentric left ventricular hypertrophy and the bull's eye plot features might serve as one of the cardiac workup steps on evaluating patients with left ventricular hypertrophy.}, language = {en} } @article{WestermaierLinsenmannHomolaetal.2016, author = {Westermaier, Thomas and Linsenmann, Thomas and Homola, Gy{\"o}rgy A. and Loehr, Mario and Stetter, Christian and Willner, Nadine and Ernestus, Ralf-Ingo and Soymosi, Laszlo and Vince, Giles H.}, title = {3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms - assessment of feasibility and image quality}, series = {BMC Medical Imaging}, volume = {16}, journal = {BMC Medical Imaging}, number = {30}, doi = {10.1186/s12880-016-0133-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146381}, year = {2016}, abstract = {Background Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms. Materials and methods Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency. Results Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants. Conclusion This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.}, language = {en} } @article{WolfBraunHainingetal.2016, author = {Wolf, Karen and Braun, Attila and Haining, Elizabeth J. and Tseng, Yu-Lun and Kraft, Peter and Schuhmann, Michael K. and Gotru, Sanjeev K. and Chen, Wenchun and Hermanns, Heike M. and Stoll, Guido and Lesch, Klaus-Peter and Nieswandt, Bernhard}, title = {Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0147664}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146399}, pages = {e0147664}, year = {2016}, abstract = {Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.}, language = {en} } @phdthesis{Schmitz2016, author = {Schmitz, Tobias}, title = {Functional coatings by physical vapor deposition (PVD) for biomedical applications}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144825}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Metals are the most used materials for implant devices, especially in orthopedics, but despite their long history of application issues such as material failure through wear and corrosion remain unsolved leading to a certain number of revision surgeries. Apart from the problems associated with insufficient material properties, another serious issue is an implant associated infection due to the formation of a biofilm on the surface of the material after implantation. Thus, improvements in implant technology are demanded, especially since there is a projected rise of implants needed in the future. Surface modification methods such as physical vapour deposition (PVD), oxygen diffusion hardening and electrochemical anodization have shown to be efficient methods to improve the surfaces of metallic bulk materials regarding biomedical issues. This thesis was focused on the development of functional PVD coatings that are suitable for further treatment with surface modification techniques originally developed for bulk metals. The aim was to precisely adjust the surface properties of the implant according to the targeted application to prevent possible failure mechanisms such as coating delamination, wear or the occurrence of post-operative infections. Initially,  tantalum layers with approx 5 µm thickness were deposited at elevated substrate temperatures on cp Ti by RF magnetron sputtering. Due to the high affinity of tantalum to oxygen, these coatings are known to provide a self healing capacity since the rapid oxide formation is known to close surface cracks. Here, the work aimed to reduce the abrupt change of mechanical properties between the hard and brittle coating and the ductile substrate by creating an oxygen diffusion zone. It was found that the hardness and adhesion could be significantly increased when the coatings were treated afterwards by oxygen diffusion hardening in a two step process. Firstly, the surface was oxidized at a pressure of 6.7•10-3 mbar at 350 450 °C, followed by 1-2 h annealing in oxygen-free atmosphere at the same temperature leading to a diffusion of oxygen atoms into deeper parts of the substrate as proved by X-ray diffraction (XRD) analysis. The hereby caused mechanical stress in the crystal lattice led to an increase in Vickers hardness of the Ta layers from 570 HV to over 900 HV. Investigations into the adhesion of oxygen diffusion treated samples by Rockwell measurements demonstrated an increase of critical force for coating delamination from 12 N for untreated samples up to 25 N for diffusion treated samples. In a second approach, the development of modular targets aimed to produce functional coatings by metallic doping of titanium with biologically active agents. This was demonstrated by the fabrication of antimicrobial Ti(Ag) coatings using a single magnetron sputtering source equipped with a titanium target containing implemented silver modules under variation of bias voltage and substrate temperature. The deposition of both Ti and Ag was confirmed by X-ray diffraction and a clear correlation between the applied sputtering parameters and the silver content of the coatings was demonstrated by ICP-MS and EDX. Surface-sensitive XPS measurements revealed that higher substrate temperatures led to an accumulation of Ag in the near-surface region, while the application of a bias voltage had the opposite effect. SEM and AFM microscopy revealed that substrate heating during film deposition supported the formation of even and dense surface layers with small roughness values, which could even be enforced by applying a substrate bias voltage. Additional elution measurements using ICP-MS showed that the release kinetics depended on the amount of silver located at the film surface and hence could be tailored by variation of the sputter parameters. In a final step, the applied Ti and Ti(Ag) coatings deposited on cp Ti, stainless steel (316L) and glass substrates were subsequently nanostructured using a self-ordering process induced by electrochemical anodization in aqueous fluoride containing electrolytes. SEM analysis showed that nanotube arrays could be grown from the Ti and Ti(Ag) coatings deposited at elevated temperatures on any substrate, whereby no influence of the substrate on nanotube morphology could be observed. EDX measurements indicated that the anodization process led to the selective etching of Ti from Ti(Ag) coating. Further experiments on coatings deposited on glass surfaces revealed that moderate substrate temperatures during deposition resulting in smooth Ti layers as determined by AFM measurements, are favorable for the generation of highly ordered nanotube arrays. Such arrays exhibited superhydrophilic behavior as proved by contact angle measurements. XRD analysis revealed that the nanostructured coatings were amorphous after anodization but could be crystallized to anatase structure by thermal treatment at temperatures of 450°C.}, subject = {PVD-Verfahren}, language = {en} } @phdthesis{Cicova2016, author = {Cicova, Zdenka}, title = {Characterization of a novel putative factor involved in host adaptation in Trypanosoma brucei}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142462}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Trypanosomes are masters of adaptation to different host environments during their complex life cycle. Large-scale proteomic approaches provide information on changes at the cellular level in a systematic way. However, a detailed work on single components is necessary to understand the adaptation mechanisms on a molecular level. Here we have performed a detailed characterization of a bloodstream form (BSF) stage-specific putative flagellar host adaptation factor (Tb927.11.2400) identified previously in a SILAC-based comparative proteome study. Tb927.11.2400 shares 38\% amino acid identity with TbFlabarin (Tb927.11.2410), a procyclic form (PCF) stage specific flagellar BAR domain protein. We named Tb927.11.2400 TbFlabarin like (TbFlabarinL) and demonstrate that it is a result of a gene duplication event, which occurred in African trypanosomes. TbFlabarinL is not essential for growth of the parasites under cell culture conditions and it is dispensable for developmental differentiation from BSF to the PCF in vitro. We generated a TbFlabarinL-specific antibody and showed that it localizes in the flagellum. The co-immunoprecipitation experiment together with a biochemical cell fractionation indicated a dual association of TbFlabarinL with the flagellar membrane and the components of the paraflagellar rod.}, subject = {Trypanosoma brucei}, language = {en} } @unpublished{ArrowsmithBoehnkeBraunschweigetal.2016, author = {Arrowsmith, Merle and B{\"o}hnke, Julian and Braunschweig, Holger and Celik, Mehmet and Claes, Christina and Ewing, William and Krummenacher, Ivo and Lubitz, Katharina and Schneider, Christoph}, title = {Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition}, doi = {10.1002/anie.201602384}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142500}, pages = {4}, year = {2016}, abstract = {Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaro- matic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient con- ditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6p-aromatic dibora- benzene compound, a 2 p-aromatic triplet biradical 1,3-dibor- ete, and a phosphine-stabilized 2 p-homoaromatic 1,3-dihydro- 1,3-diborete. DFT calculations suggest that all three com- pounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6H6 and C4H42+, and homoaromatic C4H5+.}, subject = {Diborane}, language = {en} } @phdthesis{Kupper2016, author = {Kupper, Maria}, title = {The immune transcriptome and proteome of the ant Camponotus floridanus and vertical transmission of its bacterial endosymbiont Blochmannia floridanus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142534}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {The evolutionary success of insects is believed to be at least partially facilitated by symbioses between insects and prokaryotes. Bacterial endosymbionts confer various fitness advantages to their hosts, for example by providing nutrients lacking from the insects' diet thereby enabling the inhabitation of new ecological niches. The Florida carpenter ant Camponotus floridanus harbours endosymbiotic bacteria of the genus Blochmannia. These primary endosymbionts mainly reside in the cytoplasm of bacteriocytes, specialised cells interspersed into the midgut tissue, but they were also found in oocytes which allows their vertical transmission. The social lifestyle of C. floridanus may facilitate the rapid spread of infections amongst genetically closely related animals living in huge colonies. Therefore, the ants require an immune system to efficiently combat infections while maintaining a "chronic" infection with their endosymbionts. In order to investigate the immune repertoire of the ants, the Illumina sequencing method was used. The previously published genome sequence of C. floridanus was functionally re-annotated and 0.53\% of C. floridanus proteins were assigned to the gene ontology (GO) term subcategory "immune system process". Based on homology analyses, genes encoding 510 proteins with possible immune function were identified. These genes are involved in microbial recognition and immune signalling pathways but also in cellular defence mechanisms, such as phagocytosis and melanisation. The components of the major signalling pathways appear to be highly conserved and the analysis revealed an overall broad immune repertoire of the ants though the number of identified genes encoding pattern recognition receptors (PRRs) and antimicrobial peptides (AMPs) is comparatively low. Besides three genes coding for homologs of thioester-containing proteins (TEPs), which have been shown to act as opsonins promoting phagocytosis in other insects, six genes encoding the AMPs defesin-1 and defensin-2, hymenoptaecin, two tachystatin-like peptides and one crustin-like peptide are present in the ant genome. Although the low number of known AMPs in comparison to 13 AMPs in the honey bee Apis mellifera and 46 AMPs in the wasp Nasonia vitripennis may indicate a less potent immune system, measures summarised as external or social immunity may enhance the immune repertoire of C. floridanus, as it was discussed for other social insects. Also, the hymenoptaecin multipeptide precursor protein may be processed to yield seven possibly bioactive peptides. In this work, two hymenoptaecin derived peptides were heterologously expressed and purified. The preliminary antimicrobial activity assays indicate varying bacteriostatic effects of different hymenoptaecin derived peptides against Escherichia coli D31 and Staphylococcus aureus which suggests a functional amplification of the immune response further increasing the antimicrobial potency of the ants. Furthermore, 257 genes were differentially expressed upon immune challenge of C. floridanus and most of the immune genes showing differential expression are involved in recognition of microbes or encode immune effectors rather than signalling components. Additionally, genes coding for proteins involved in storage and metabolism were downregulated upon immune challenge suggesting a trade-off between two energy-intensive processes in order to enhance effectiveness of the immune response. The analysis of gene expression via qRT-PCR was used for validation of the transcriptome data and revealed stage-specific immune gene regulation. Though the same tendencies of regulation were observed in larvae and adults, expression of several immune-related genes was generally more strongly induced in larvae. Immune gene expression levels depending on the developmental stage of C. floridanus are in agreement with observations in other insects and might suggest that animals from different stages revert to individual combinations of external and internal immunity upon infection. The haemolymph proteome of immune-challenged ants further established the immune-relevance of several proteins involved in classical immune signalling pathways, e.g. PRRs, extracellularly active proteases of the Toll signalling pathway and effector molecules such as AMPs, lysozymes and TEPs. Additionally, non-canonical proteins with putative immune function were enriched in immune-challenged haemolymph, e.g. Vitellogenins, NPC2-like proteins and Hemocytin. As known from previous studies, septic wounding also leads to the upregulation of genes involved in stress responses. In the haemolymph, proteins implicated in protein stabilisation and in the protection against oxidative stress and insecticides were enriched upon immune challenge. In order to identify additional putative immune effectors, haemolymph peptide samples from immune-challenged larvae and adults were analysed. The analysis in this work focussed on the identification of putative peptides produced via the secretory pathway as previously described for neuropeptides of C. floridanus. 567 regulated peptides derived from 39 proteins were identified in the larval haemolymph, whereas 342 regulated peptides derived from 13 proteins were found in the adult haemolymph. Most of the peptides are derived from hymenoptaecin or from putative uncharacterised proteins. One haemolymph peptide of immune-challenged larvae comprises the complete amino acid sequence of a predicted peptide derived from a Vitellogenin. Though the identified peptide lacks similarities to any known immune-related peptide, it is a suitable candidate for further functional analysis. To establish a stable infection with the endosymbionts, the bacteria have to be transmitted to the next generation of the ants. The vertical transmission of B. floridanus is guaranteed by bacterial infestation of oocytes. This work presents the first comprehensive and detailed description of the localisation of the bacterial endosymbionts in C. floridanus ovaries during oogenesis. Whereas the most apical part of the germarium, which contains the germ-line stem cells, is not infected by the bacteria, small somatic cells in the outer layers of each ovariole were found to be infected in the lower germarium. Only with the beginning of cystocyte differentiation, endosymbionts are exclusively transported from follicle cells into the growing oocytes, while nurse cells were never infected with B. floridanus. This infestation of the oocytes by bacteria very likely involves exocytosis-endocytosis processes between follicle cells and the oocytes. A previous study suggested a down-modulation of the immune response in the midgut tissue which may promote endosymbiont tolerance. Therefore, the expression of several potentially relevant immune genes was analysed in the ovarial tissue by qRT-PCR. The relatively low expression of genes involved in Toll and IMD signalling, and the high expression of genes encoding negative immune regulators, such as PGRP-LB, PGRP-SC2, and tollip, strongly suggest that a down-modulation of the immune response may also facilitate endosymbiont tolerance in the ovaries and thereby contribute to their vertical transmission. Overall, the present thesis improves the knowledge about the immune repertoire of C. floridanus and provides new candidates for further functional analyses. Moreover, the involvement of the host immune system in maintaining a "chronic" infection with symbiotic bacteria was confirmed and extended to the ovaries.}, subject = {Camponotus floridanus}, language = {en} } @phdthesis{Wanzek2016, author = {Wanzek, Katharina}, title = {The investigation of the function of repair proteins at G-quadruplex structures in \(Saccharomyces\) \(cerevisiae\) revealed that Mms1 promotes genome stability}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142547}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {G-quadruplex structures are highly stable alternative DNA structures that can, when not properly regulated, impede replication fork progression and cause genome instability (Castillo Bosch et al, 2014; Crabbe et al, 2004; Koole et al, 2014; Kruisselbrink et al, 2008; London et al, 2008; Lopes et al, 2011; Paeschke et al, 2013; Paeschke et al, 2011; Piazza et al, 2015; Piazza et al, 2010; Piazza et al, 2012; Ribeyre et al, 2009; Sabouri et al, 2014; Sarkies et al, 2012; Sarkies et al, 2010; Schiavone et al, 2014; Wu \& Spies, 2016; Zimmer et al, 2016). The aim of this thesis was to identify novel G-quadruplex interacting proteins in Saccharomyces cerevisiae and to unravel their regulatory function at these structures to maintain genome integrity. Mms1 and Rtt101 were identified as G-quadruplex binding proteins in vitro via a pull-down experiment with subsequent mass spectrometry analysis. Rtt101, Mms1 and Mms22, which are all components of an ubiquitin ligase (Rtt101Mms1/Mms22), are important for the progression of the replication fork following fork stalling (Luke et al, 2006; Vaisica et al, 2011; Zaidi et al, 2008). The in vivo binding of endogenously tagged Mms1 to its target regions was analyzed genome-wide using chromatin-immunoprecipitation followed by deep-sequencing. Interestingly, Mms1 bound independently of Mms22 and Rtt101 to G-rich regions that have the potential to form G-quadruplex structures. In vitro, formation of G-quadruplex structures could be shown for the G-rich regions Mms1 bound to. This binding was observed throughout the cell cycle. Furthermore, the deletion of MMS1 caused replication fork stalling as evidenced by increased association of DNA Polymerase 2 at Mms1 dependent sites. A gross chromosomal rearrangement assay revealed that deletion of MMS1 results in a significantly increased genome instability at G-quadruplex motifs compared to G-rich or non-G-rich regions. Additionally, binding of the helicase Pif1, which unwinds G4 structures in vitro (Paeschke et al, 2013; Ribeyre et al, 2009; Sanders, 2010; Wallgren et al, 2016), to Mms1 binding sites was reduced in mms1 cells. The data presented in this thesis, together with published data, suggests a novel mechanistic model in which Mms1 binds to G-quadruplex structures and enables Pif1 association. This allows for replication fork progression and genome integrity.}, subject = {Quadruplex-DNS}, language = {en} } @phdthesis{Maurus2016, author = {Maurus, Katja}, title = {Melanoma Maintenance by the AP1 Transcription Factor FOSL1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142995}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Identifying novel driver genes in cancer remains a crucial step towards development of new therapeutic approaches and the basic understanding of the disease. This work describes the impact of the AP1 transcription activator component FOSL1 on melanoma maintenance. FOSL1 is strongly upregulated during the progression of melanoma and the protein abundance is highest in metastases. I found that the regulation of FOSL1 is strongly dependent on ERK1/2- and PI3K- signaling, two pathways frequently activated in melanoma. Moreover, the involvement of p53 in FOSL1 regulation in melanoma was investigated. Elevated levels of the tumor suppressor led to decreased FOSL1 protein levels in a miR34a/miR34c- dependent manner. The benefit of elevated FOSL1 amounts in human melanoma cell lines was analyzed by overexpression of FOSL1 in cell lines with low endogenous FOSL1 levels. Enhanced levels of FOSL1 had several pro-tumorigenic effects in human melanoma cell lines. Besides increased proliferation and migration rates, FOSL1 overexpression induced the colony forming ability of the cells. Additionally, FOSL1 was necessary for anchorage independent growth in 3D cell cultures. Microarray analyses revealed novel downstream effectors of FOSL1. On the one hand, FOSL1 was able to induce the transcription of different neuron-related genes, such as NEFL, NRP1 and TUBB3. On the other hand, FOSL1 influenced the transcription of DCT, a melanocyte specific gene, in dependence of the differentiation of the melanoma cell line, indicating dedifferentiation. Furthermore, FOSL1 induced the transcription of HMGA1, a chromatin remodeling protein with reprogramming ability, which is characteristic for stem cells. Consequently, the influence of HMGA1 on melanoma maintenance was investigated. In addition to decreased proliferation and reduced anoikis resistance, HMGA1 knockdown reduced melanoma cell survival. Interestingly, the FOSL1 induced pro-tumorigenic effects were demonstrated to be dependent on the HMGA1 level. HMGA1 manipulation reversed FOSL1 induced proliferation and colony forming ability, as well as the anchorage independent growth effect. In conclusion, I could show that additional FOSL1 confers a clear growth benefit to melanoma cells. This benefit is attributed to the induction of stem cell determinants, but can be blocked by the inhibition of the ERK1/2 or PI3K signaling pathways.}, subject = {Melanom}, language = {en} } @phdthesis{Erle2016, author = {Erle, Thorsten Michael}, title = {A Grounded Approach to Psychological Perspective-Taking}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143247}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {„Perspektiven{\"u}bernahme" bezeichnet die F{\"a}higkeit des Menschen, sich in die Lage eines anderen hineinzuversetzen. In der psychologischen Forschung unterscheidet man drei Arten der Perspektiven{\"u}bernahme, n{\"a}mlich perzeptuelle (visuo-spatiale), affektive (Empathie) und kognitive (Theory of Mind). Die letztgenannten Arten der Perspektiven{\"u}bernahme werden oft als „psychologische Perspektiven{\"u}bernahme" zusammengefasst. Diese Dissertation befasst sich mit der Frage, ob diese verschiedenen Arten der Perspektiven{\"u}bernahme als theoretisch unterscheidbare Konstrukte oder lediglich als Facetten ein und desselben Konstrukts angesehen werden sollten. Die Befundlage in der psychologischen Fachliteratur ist diesbez{\"u}glich nicht eindeutig. W{\"a}hrend einige Autoren Korrelationen zwischen verschiedenen Arten der Perspektiven{\"u}bernahme f{\"u}r zu gering erachten, um ein einheitliches Konstrukt zu konstatieren, bewerten andere Autoren Korrelationen derselben Gr{\"o}ße als Evidenz hierf{\"u}r. Ein weniger arbitr{\"a}res Vorgehen w{\"a}re es, experimentalpsychologisch zugrunde liegende Mechanismen zu identifizieren, die allen Arten der Perspektiven{\"u}bernahme gemein sind, und zu untersuchen, ob eine Manipulation dieser Mechanismen abh{\"a}ngige Maße affektiver, kognitiver und perzeptueller Perspektiven{\"u}bernahme gleichermaßen beeinflusst. Diesem Ansatz folgend macht die vorliegende Arbeit die Annahme, dass die mentale Selbstrotation des K{\"o}rperschemas in die Position einer anderen Person, der zentrale Mechanismus visuo-spatialer Perspektiven{\"u}bernahme, ein gemeinsamer Mechanismus aller Arten der Perspektiven{\"u}bernahme ist. Entgegen fr{\"u}herer Ans{\"a}tze wird diese Einheit somit nicht nur {\"u}ber die zentrale gemeinsame Funktionalit{\"a}t aller Arten von Perspektiven{\"u}bernahme, also dem Verlassen des egozentrischen Referenzrahmens zugunsten einer (visuellen, affektiven oder kognitiven) Fremdperspektive, gerechtfertigt, sondern mit der Annahme eines gemeinsamen zugrundeliegenden Mechanismus. Daraus wird die einfache Hypothese abgeleitet, dass visuo-spatiale Perspektiven{\"u}bernahme zu psychologischen Konsequenzen f{\"u}hren kann. Dies wurde in 6 Experimenten getestet. In diesen Experimenten mussten die Probanden zun{\"a}chst immer die visuelle Perspektive einer anderen Person einnehmen. Hierzu sahen die Probanden eine Person, die mit zwei Objekten an einem Tisch sitzt. In jedem Durchgang mussten die Probanden sich entscheiden, mit welcher Hand diese Person eines der beiden Objekte greifen w{\"u}rde. Dabei wurde die Position der Zielperson so manipuliert, dass sie in der H{\"a}lfte der F{\"a}lle im selben visuo-spatialen Referenzrahmen wie der Proband saß, was Perspektiven{\"u}bernahme zur L{\"o}sung der Aufgabe obsolet machte, w{\"a}hrend sie sich in den verbleibenden Durchg{\"a}ngen in einem anderen visuo-spatialen Referenzrahmen befand, so dass die Probanden die visuelle Perspektive der Zielperson {\"u}bernehmen mussten um die Aufgabe korrekt zu l{\"o}sen. Nach jedem Durchgang wurde dem Ziel dieser visuo-spatialen Aufgabe eine psychologische Eigenschaft zugeschrieben. Dies geschah im Rahmen eines abgewandelten Paradigmas zur Untersuchung der Ankerheuristik. Hierzu wurde den Probanden nach jedem Durchgang der visuo-spatialen Aufgabe eine Sch{\"a}tzfrage gestellt. Zeitgleich wurde die Antwort des Ziels bekannt gegeben. Entsprechend der Haupthypothese, dass visuo-spatiale Perspektiven{\"u}bernahme psychologische Konsequenzen erzeugen kann, konnte gezeigt werden, dass die Probanden nach visuo-spatialer Perspektiven{\"u}bernahme in h{\"o}herem Maße die Gedanken der Zielperson {\"u}bernahmen. Dies konnte sowohl anhand der absoluten Gr{\"o}ße des Ankereffekts, als auch anhand der Differenz zwischen den Urteilen der Probanden und der Zielperson, gezeigt werden. Weitere Experimente schlossen Stichprobeneigenschaften, die verwendeten Stimuli oder die Aufgabenschwierigkeit als Alternativerkl{\"a}rungen f{\"u}r diese Effekte aus. Die beiden letzten Experimente zeigten zudem, dass dieser Effekt spezifisch f{\"u}r alle Konstellationen ist, in denen eine mentale Selbstrotation in die Zielperspektive notwendig war und dass die {\"U}bernahme fremder Gedanken mit einem Gef{\"u}hl von {\"A}hnlichkeit assoziiert war. Zusammengenommen unterst{\"u}tzen die Ergebnisse dieser Arbeit die theoretisch abgeleitete Sicht eines einheitlichen Perspektiven{\"u}bernahme-Konstrukts und grenzen dieses zus{\"a}tzlich von verwandten Konstrukten ab. In der abschließenden Diskussion werden die Bedeutung dieser Befunde f{\"u}r die Forschung in den Bereichen Empathie, Theory of Mind, und Perspektiven{\"u}bernahme und ebenfalls praktische Implikationen der Ergebnisse aufgezeigt.}, subject = {Perspektiven{\"u}bernahme}, language = {en} }