TY - JOUR A1 - Zwink, Nadine A1 - Jenetzky, Ekkehart A1 - Schmiedeke, Eberhard A1 - Schmidt, Dominik A1 - Märzheuser, Schmidt A1 - Grasshoff-Derr, Sabine A1 - Holland-Cunz, Stefan A1 - Weih, Sandra A1 - Hosie, Stuart A1 - Reifferscheid, Peter A1 - Ameis, Helen A1 - Kujath, Christina A1 - Rissmann, Anke A1 - Obermayr, Florian A1 - Schwarzer, Nicole A1 - Bartels, Enrika A1 - Reutter, Heiko A1 - Brenner, Hermann T1 - Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study JF - Orphanet Journal of Rare Diseases N2 - Background: The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results: In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10%) and 129,982 controls (1%) were born after IVF or ICSI, which translates to an odds ratio (95% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births. Conclusions: There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births. KW - metaanalysis KW - in-vitro fertilization KW - reproductive medicine KW - anal atresia KW - imperforate anus KW - anorectal malformation KW - birth defects KW - prevalence KW - assisted reproductive techniques KW - congenital malformations KW - descriptive epidemiology KW - infants born KW - children born KW - IVF-methods KW - technology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134036 VL - 7 IS - 65 ER - TY - JOUR A1 - Zoephel, Judith A1 - Reiher, Wencke A1 - Rexer, Karl-Heinz A1 - Kahnt, Jörg A1 - Wegener, Christian T1 - Peptidomics of the Agriculturally Damaging Larval Stage of the Cabbage Root Fly Delia radicum (Diptera: Anthomyiidae) JF - PLoS One N2 - The larvae of the cabbage root fly induce serious damage to cultivated crops of the family Brassicaceae. We here report the biochemical characterisation of neuropeptides from the central nervous system and neurohemal organs, as well as regulatory peptides from enteroendocrine midgut cells of the cabbage maggot. By LC-MALDI-TOF/TOF and chemical labelling with 4-sulfophenyl isothiocyanate, 38 peptides could be identified, representing major insect peptide families: allatostatin A, allatostatin C, FMRFamide-like peptides, kinin, CAPA peptides, pyrokinins, sNPF, myosuppressin, corazonin, SIFamide, sulfakinins, tachykinins, NPLP1-peptides, adipokinetic hormone and CCHamide 1. We also report a new peptide (Yamide) which appears to be homolog to an amidated eclosion hormone-associated peptide in several Drosophila species. Immunocytochemical characterisation of the distribution of several classes of peptide-immunoreactive neurons and enteroendocrine cells shows a very similar but not identical peptide distribution to Drosophila. Since peptides regulate many vital physiological and behavioural processes such as moulting or feeding, our data may initiate the pharmacological testing and development of new specific peptide-based protection methods against the cabbage root fly and its larva. KW - adult drosophila KW - central-nervous-system KW - blowfly calliphora-vomitoria KW - drosophila melanogaster KW - mass spectometry KW - feeding behavior KW - fruit fly KW - functional characterization KW - immunoreactive neurons KW - neobellieria bullata Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131727 VL - 7 IS - 7 ER - TY - JOUR A1 - Zirkel, J. A1 - Cecil, A. A1 - Schäfer, F. A1 - Rahlfs, S. A1 - Ouedraogo, A. A1 - Xiao, K. A1 - Sawadogo, S. A1 - Coulibaly, B. A1 - Becker, K. A1 - Dandekar, T. T1 - Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling JF - Bioinformatics and Biology Insights N2 - BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data. RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs. CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas. KW - methylene blue KW - malaria KW - elementary mode analysis KW - drug KW - resistance KW - combination therapy KW - pathway KW - metabolic flux Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123751 N1 - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. VL - 6 ER - TY - JOUR A1 - Zhang, Shaowu A1 - Si, Aung A1 - Pahl, Mario T1 - Visually guided decision making in foraging honeybees JF - Frontiers in Neuroscience N2 - Honeybees can easily be trained to perform different types of discrimination tasks under controlled laboratory conditions. This review describes a range of experiments carried out with free-flying forager honeybees under such conditions. The research done over the past 30 or so years suggests that cognitive abilities (learning and perception) in insects are more intricate and flexible than was originally imagined. It has become apparent that honeybees are capable of a variety of visually guided tasks, involving decision making under challenging situations: this includes simultaneously making use of different sensory modalities, such as vision and olfaction, and learning to use abstract concepts such as “sameness” and “difference.” Many studies have shown that decision making in foraging honeybees is highly flexible. The trained animals learn how to solve a task, and do so with a high accuracy, but when they are presented with a new variation of the task, they apply the learnt rules from the earlier setup to the new situation, and solve the new task as well. Honeybees therefore not only feature a rich behavioral repertoire to choose from, but also make decisions most apt to the current situation. The experiments in this review give an insight into the environmental cues and cognitive resources that are probably highly significant for a forager bee that must continually make decisions regarding patches of resources to be exploited. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124228 VL - 6 IS - 88 ER - TY - JOUR A1 - Zeller, Daniel A1 - Dang, Su-Yin A1 - Weise, David A1 - Rieckmann, Peter A1 - Toyka, Klaus V. A1 - Classen, Joseph T1 - Excitability decreasing central motor plasticity is retained in multiple sclerosis patients N2 - Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS. KW - Medizin KW - Multiple sclerosis KW - LTD KW - Motor plasticity KW - TMS KW - Motor cortex Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76333 ER - TY - JOUR A1 - Yamakawa, Hisanori A1 - Fukushima, Yoshimasa A1 - Itoh, Shigeru A1 - Heber, Ulrich T1 - Three different mechanisms of energy dissipation of a desiccation-tolerant moss serve one common purpose: to protect reaction centres against photo-oxidation JF - Journal of Experimental Botany N2 - Three different types of non-photochemical de-excitation of absorbed light energy protect photosystem II of the sun- and desiccation-tolerant moss Rhytidium rugosum against photo-oxidation. The first mechanism, which is light-induced in hydrated thalli, is sensitive to inhibition by dithiothreitol. It is controlled by the protonation of a thylakoid protein. Other mechanisms are activated by desiccation. One of them permits exciton migration towards a far-red band in the antenna pigments where fast thermal deactivation takes place. This mechanism appears to be similar to a mechanism detected before in desiccated lichens. A third mechanism is based on the reversible photo-accumulation of a radical that acts as a quencher of excitation energy in reaction centres of photosystem II. On the basis of absorption changes around 800 nm, the quencher is suggested to be an oxidized chlorophyll. The data show that desiccated moss is better protected against photo-oxidative damage than hydrated moss. Slow drying of moss thalli in the light increases photo-protection more than slow drying in darkness. KW - reaction centre KW - photoprotection KW - energy dissipation KW - energy conservation KW - chlorophyll fluorescence KW - photosystem II Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126897 VL - 63 IS - 10 ER - TY - JOUR A1 - Wu, Lingdan A1 - Pu, Jie A1 - Allen, John J. B. A1 - Pauli, Paul T1 - Recognition of facial expressions in individuals with elevated levels of depressive symptoms: an eye-movement study JF - Depression Research and Treatment N2 - Previous studies consistently reported abnormal recognition of facial expressions in depression. However, it is still not clear whether this abnormality is due to an enhanced or impaired ability to recognize facial expressions, and what underlying cognitive systems are involved. The present study aimed to examine how individuals with elevated levels of depressive symptoms differ from controls on facial expression recognition and to assess attention and information processing using eye tracking. Forty participants (18 with elevated depressive symptoms) were instructed to label facial expressions depicting one of seven emotions. Results showed that the high-depression group, in comparison with the low-depression group, recognized facial expressions faster and with comparable accuracy. Furthermore, the high-depression group demonstrated greater leftwards attention bias which has been argued to be an indicator of hyperactivation of right hemisphere during facial expression recognition. KW - Depression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123153 VL - 2012 IS - 249030 ER - TY - JOUR A1 - Wolter, Steffen A1 - Aizezers, Janis A1 - Fennel, Franziska A1 - Seidel, Marcus A1 - Würthner, Frank A1 - Kühn, Oliver A1 - Lochbrunner, Stefan T1 - Size-dependent exciton dynamics in one-dimensional perylene bisimide aggregates JF - New Journal of Physics N2 - The size-dependent exciton dynamics of one-dimensional aggregates of substituted perylene bisimides are studied by ultrafast transient absorption spectroscopy and kinetic Monte-Carlo simulations as a function of the excitation density and the temperature in the range of 25-90 degrees C. For low temperatures, the aggregates can be treated as infinite chains and the dynamics is dominated by diffusion-driven exciton-exciton annihilation. With increasing temperature the aggregates dissociate into small fragments consisting of very few monomers. This scenario is also supported by the time-dependent anisotropy deduced from polarization-dependent experiments. KW - rotational diffusion KW - spectroscopy KW - dyes KW - annihilation KW - migration KW - films Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135190 VL - 14 IS - 105027 ER - TY - JOUR A1 - Wolff, Alexander A1 - Rutter, Iganz T1 - Augmenting the Connectivity of Planar and Geometric Graphs JF - Journal of Graph Algorithms and Applications N2 - In this paper we study connectivity augmentation problems. Given a connected graph G with some desirable property, we want to make G 2-vertex connected (or 2-edge connected) by adding edges such that the resulting graph keeps the property. The aim is to add as few edges as possible. The property that we consider is planarity, both in an abstract graph-theoretic and in a geometric setting, where vertices correspond to points in the plane and edges to straight-line segments. We show that it is NP-hard to � nd a minimum-cardinality augmentation that makes a planar graph 2-edge connected. For making a planar graph 2-vertex connected this was known. We further show that both problems are hard in the geometric setting, even when restricted to trees. The problems remain hard for higher degrees of connectivity. On the other hand we give polynomial-time algorithms for the special case of convex geometric graphs. We also study the following related problem. Given a planar (plane geometric) graph G, two vertices s and t of G, and an integer c, how many edges have to be added to G such that G is still planar (plane geometric) and contains c edge- (or vertex-) disjoint s{t paths? For the planar case we give a linear-time algorithm for c = 2. For the plane geometric case we give optimal worst-case bounds for c = 2; for c = 3 we characterize the cases that have a solution. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97587 ER - TY - JOUR A1 - Winter, Walter T1 - Neutrinos from Cosmic Accelerators Including Magnetic Field and Flavor Effects N2 - We review the particle physics ingredients affecting the normalization, shape, and flavor composition of astrophysical neutrinos fluxes, such as different production modes, magnetic field effects on the secondaries muons, pions, and kaons, and flavor mixing, where we focus on p? interactions. We also discuss the interplay with neutrino propagation and detection, including the possibility to detect flavor and its application in particle physics, and the use of the Glashow resonance to discriminate p? from pp interactions in the source. We illustrate the implications on fluxes and flavor composition with two different models: 1 the target photon spectrum is dominated by synchrotron emission of coaccelerated electrons and 2 the target photon spectrum follows the observed photon spectrum of gamma-ray bursts. In the latter case, the multimessenger extrapolation from the gamma-ray fluence to the expected neutrino flux is highlighted. KW - Magnetfeld Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75290 ER - TY - JOUR A1 - Wilms, Ina A1 - Overlöper, Aaron A1 - Nowrousian, Minou A1 - Sharma, Cynthia M. A1 - Narberhaus, Franz T1 - Deep sequencing uncovers numerous small RNAs on all four replicons of the plant pathogen Agrobacterium tumefaciens JF - RNA Biology N2 - Agrobacterium species are capable of interkingdom gene transfer between bacteria and plants. The genome of Agrobacterium tumefaciens consists of a circular and a linear chromosome, the At-plasmid and the Ti-plasmid, which harbors bacterial virulence genes required for tumor formation in plants. Little is known about promoter sequences and the small RNA (sRNA) repertoire of this and other α-proteobacteria. We used a differential RNA sequencing (dRNA-seq) approach to map transcriptional start sites of 388 annotated genes and operons. In addition, a total number of 228 sRNAs was revealed from all four Agrobacterium replicons. Twenty-two of these were confirmed by independent RNA gel blot analysis and several sRNAs were differentially expressed in response to growth media, growth phase, temperature or pH. One sRNA from the Ti-plasmid was massively induced under virulence conditions. The presence of 76 cis-antisense sRNAs, two of them on the reverse strand of virulence genes, suggests considerable antisense transcription in Agrobacterium. The information gained from this study provides a valuable reservoir for an in-depth understanding of sRNA-mediated regulation of the complex physiology and infection process of Agrobacterium. KW - regulatory RNA KW - plant-microbe interaction KW - deep sequencing KW - RNA-seq KW - small RNA Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127101 VL - 9 IS - 446-457 ER - TY - JOUR A1 - Willems, Coen H. M. P. A1 - Urlichs, Florian A1 - Seidenspinner, Silvia A1 - Kunzmann, Steffen A1 - Speer, Christian P. A1 - Kramer, Boris W. T1 - Poractant alfa (Curosurf (R)) increases phagocytosis of apoptotic neutrophils by alveolar macrophages in vivo JF - Respiratory Research N2 - Background: Clearance of apoptotic neutrophils in the lung is an essential process to limit inflammation, since they could become a pro-inflammatory stimulus themselves. The clearance is partially mediated by alveolar macrophages, which phagocytose these apoptotic cells. The phagocytosis of apoptotic immune cells by monocytes in vitro has been shown to be augmented by several constituents of pulmonary surfactant, e. g. phospholipids and hydrophobic surfactant proteins. In this study, we assessed the influence of exogenous poractant alfa (Curosurf (R)) instillation on the in vivo phagocytosis of apoptotic neutrophils by alveolar macrophages. Methods: Poractant alfa (200 mg/kg) was instilled intratracheally in the lungs of three months old adult male C57/Black 6 mice, followed by apoptotic neutrophil instillation. Bronchoalveloar lavage was performed and alveolar macrophages and neutrophils were counted. Phagocytosis of apoptotic neutrophils was quantified by determining the number of apoptotic neutrophils per alveolar macrophages. Results: Exogenous surfactant increased the number of alveolar macrophages engulfing apoptotic neutrophils 2.6 fold. The phagocytosis of apoptotic neutrophils was increased in the presence of exogenous surfactant by a 4.7 fold increase in phagocytosed apoptotic neutrophils per alveolar macrophage. Conclusions: We conclude that the anti-inflammatory properties of surfactant therapy may be mediated in part by increased numbers of alveolar macrophages and increased phagocytosis of apoptotic neutrophils by alveolar macrophages. KW - preterm KW - surfactant protein-A KW - respiratory-distress-syndrome KW - synthetic surfactant KW - human monocytes KW - SIRP-alpha KW - lung KW - cells KW - inflammation KW - resolution KW - anti inflammation KW - drug therapy KW - surfactant Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130721 VL - 13 IS - 17 ER - TY - JOUR A1 - Wild, J. M. A1 - Marshall, H. A1 - Bock, M. A1 - Schad, L. R. A1 - Jakob, P. M. A1 - Puderbach, M. A1 - Molinari, F. A1 - Van Beek, E. J. R. A1 - Biederer, J. T1 - MRI of the lung (1/3): methods JF - Insights into Imaging N2 - Proton magnetic resonance imaging (MRI) has recently emerged as a clinical tool to image the lungs. This paper outlines the current technical aspects of MRI pulse sequences, radiofrequency (RF) coils and MRI system requirements needed for imaging the pulmonary parenchyma and vasculature. Lung MRI techniques are presented as a “technical toolkit”, from which MR protocols will be composed in the subsequent papers for comprehensive imaging of lung disease and function (parts 2 and 3). This paper is pitched at MR scientists, technicians and radiologists who are interested in understanding and establishing lung MRI methods. Images from a 1.5 T scanner are used for illustration of the sequences and methods that are highlighted. Main Messages • Outline of the hardware and pulse sequence requirements for proton lung MRI • Overview of pulse sequences for lung parenchyma, vascular and functional imaging with protons • Demonstration of the pulse-sequence building blocks for clinical lung MRI protocols KW - MRI KW - lung KW - proton Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124238 VL - 3 IS - 4 ER - TY - JOUR A1 - Wiessner, M. A1 - Rodriguez Lastra, N. S. A1 - Ziroff, J. A1 - Forster, F. A1 - Puschnig, P. A1 - Dössel, L. A1 - Müllen, K. A1 - Schöll, A. A1 - Reinert, F. T1 - Different views on the electronic structure of nanoscale graphene: aromatic molecule versus quantum dot JF - New Journal of Physics N2 - Graphene's peculiar electronic band structure makes it of interest for new electronic and spintronic approaches. However, potential applications suffer from quantization effects when the spatial extension reaches the nanoscale. We show by photoelectron spectroscopy on nanoscaled model systems (disc-shaped, planar polyacenes) that the two-dimensional band structure is transformed into discrete states which follow the momentum dependence of the graphene Bloch states. Based on a simple model of quantum wells, we show how the band structure of graphene emerges from localized states, and we compare this result with ab initio calculations which describe the orbital structure. KW - well KW - confinement KW - states KW - Ag(111) KW - photoemission KW - vicinal surfaces KW - coronene KW - energy KW - films KW - nanographenes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130184 VL - 14 IS - 113008 ER - TY - JOUR A1 - Wieching, Anna A1 - Benser, Jasmin A1 - Kohlhauser-Vollmuth, Christina A1 - Weisbrich, Bendikt A1 - Streng, Andrea A1 - Liese, Johannes G. T1 - Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza a (H1N1) in Northern Bavaria, Germany N2 - Background: The 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18 years of age. All hospitalized cases of children <18 years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications. Results: Between July 2009 and March 2010, 94 PIAH (62% males) occurred in children <18 years of age, with a median age of 7 years (IQR: 3–12 years). Underlying diseases and predisposing factors were documented in 40 (43%) children; obesity (n = 12, 30%), asthma (n = 10, 25%) and neurologic disorders (n = 8, 20%) were most frequently reported. Sixteen (17%) children received oxygen supplementation; three (3%) children required mechanical ventilation. Six (6%) children were admitted to an intensive care unit, four of them with underlying chronic diseases. Conclusions: Most PIAH demonstrated a benign course of disease. However, six children (6%) needed treatment at an intensive care unit for severe complications. KW - Medizin KW - Influenza KW - Pediatric KW - Infectious disease KW - Hospitalization Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75657 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Raslan, Furat A1 - Vinc, Giles Hamilton A1 - Ernestus, Ralf-Ingo T1 - Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats N2 - Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH. KW - Medizin KW - Subarachnoid hemorrhage KW - Cerebral blood flow KW - Brain ischemia KW - Brain edema KW - Animal models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75765 ER - TY - JOUR A1 - Weiße, Sebastian A1 - Heddergott, Niko A1 - Heydt, Matthias A1 - Pflästerer, Daniel A1 - Maier, Timo A1 - Haraszti, Tamas A1 - Grunze, Michael A1 - Engstler, Markus A1 - Rosenhahn, Axel T1 - A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy JF - PLoS One N2 - We present a quantitative 3D analysis of the motility of the blood parasite Trypanosoma brucei. Digital in-line holographic microscopy has been used to track single cells with high temporal and spatial accuracy to obtain quantitative data on their behavior. Comparing bloodstream form and insect form trypanosomes as well as mutant and wildtype cells under varying external conditions we were able to derive a general two-state-run-and-tumble-model for trypanosome motility. Differences in the motility of distinct strains indicate that adaption of the trypanosomes to their natural environments involves a change in their mode of swimming. KW - african trypanosomes KW - actin cortex KW - flagellum KW - tracking KW - surface KW - models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130666 VL - 7 IS - 5 ER - TY - JOUR A1 - Weisschuh, Nicole A1 - Wissinger, Bernd A1 - Gramer, Eugen T1 - A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia JF - Molecular Vision N2 - Purpose: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. Methods: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. Results: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a ‘run on’ translation past the normal translational stop codon. Conclusions: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124379 VL - 18 ER - TY - JOUR A1 - Weise, Gesa A1 - Stoll, Guido T1 - Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant? JF - Frontiers in Neurology N2 - Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate. We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients. KW - contrast-enhanced MRI KW - neuroinflammation KW - gadolinium-DTPA KW - gadofluorine KW - iron oxide nanoparticles KW - blood brain barrier Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123359 VL - 3 IS - 178 ER - TY - JOUR A1 - Weber, Heike A1 - Scholz, Claus Jürgen A1 - Domschke, Katharina A1 - Baumann, Christian A1 - Klauke, Benedikt A1 - Jacob, Christian P. A1 - Maier, Wolfgang A1 - Fritze, Jürgen A1 - Bandelow, Borwin A1 - Zwanzger, Peter Michael A1 - Lang, Thomas A1 - Fehm, Lydia A1 - Ströhle, Andreas A1 - Hamm, Alfons A1 - Gerlach, Alexander L. A1 - Alpers, Georg W. A1 - Kircher, Tilo A1 - Wittchen, Hans-Ulrich A1 - Arolt, Volker A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Reif, Andreas T1 - Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder N2 - Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75830 ER - TY - JOUR A1 - Warnock, David G. A1 - Ortiz, Alberto A1 - Mauer, Michael A1 - Linthorst, Gabor E. A1 - Oliveira, João P. A1 - Serra, Andreas L. A1 - Maródi, László A1 - Mignani, Renzo A1 - Vujkovac, Bojan A1 - Beitner-Johnson, Dana A1 - Lemay, Roberta A1 - Cole, J. Alexander A1 - Svarstad, Einar A1 - Waldek, Stephen A1 - Germain, Dominique P. A1 - Wanner, Christoph T1 - Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation JF - Nephrology Dialysis Transplantation N2 - Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes. KW - proteinuria KW - enzyme replacement therapy KW - alpha galactosidase KW - Fabry disease KW - genetic renal disease Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124697 VL - 27 IS - 3 ER - TY - JOUR A1 - Wang, Huiqiang A1 - Chen, Nanhai G. A1 - Minev, Boris R. A1 - Szalay, Aladar A. T1 - Oncolytic vaccinia virus GLV-1h68 strain shows enhanced replication in human breast cancer stem-like cells in comparison to breast cancer cells JF - Journal of Translational Medicine N2 - Background: Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy. Methods: Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44\(^+\)CD24\(^+\)ESA\(^+\) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models. Results: We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44\(^+\)CD24\(^+\)ESA\(^+\) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44\(^+\)CD24\(^-\)ESA\(^+\) cells. Conclusions: Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors. KW - tumors KW - therapy KW - metastasis KW - identification KW - lines KW - gene expression KW - in-vitro propagation KW - acute myeloid leukemia KW - epithelial-mesenchymal transition KW - subpopulation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130019 VL - 10 IS - 167 ER - TY - JOUR A1 - Walsh, J. Bernard A1 - Lems, Willem F. A1 - Karras, Dimitrios A1 - Langdahl, Bente L. A1 - Ljunggren, Osten A1 - Fahrleitner-Pammer, Astrid A1 - Barrett, Annabel A1 - Rajzbaum, Gerald A1 - Jakob, Franz A1 - Marin, Fernando T1 - Effectiveness of Teriparatide in Women Over 75 Years of Age with Severe Osteoporosis: 36-Month Results from the European Forsteo Observational Study (EFOS) JF - Calcified Tissue International N2 - This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged ≥75 years. Data on clinical fractures, back pain (visual analogue scale, VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 %) women aged ≥75 years sustained a total of 111 new fractures: 37 (33.3 %) vertebral fractures and 74 (66.7 %) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 % in the 30 to <36–month interval compared with the first 6-month interval (P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged ≥75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study. KW - teriparatide KW - osteoporosis KW - health-related quality of life KW - fracture KW - back pain KW - age Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124746 VL - 90 IS - 5 ER - TY - JOUR A1 - Votteler, Miriam A1 - Carvajal Berrio, Daniel A. A1 - Pudlas, Marieke A1 - Walles, Heike A1 - Schenke-Layland, Katja T1 - Non-contact, Label-free Monitoring of Cells and Extracellular Matrix using Raman Spectroscopy JF - Journal of Visual Expression N2 - Non-destructive, non-contact and label-free technologies to monitor cell and tissue cultures are needed in the field of biomedical research.1-5 However, currently available routine methods require processing steps and alter sample integrity. Raman spectroscopy is a fast method that enables the measurement of biological samples without the need for further processing steps. This laser-based technology detects the inelastic scattering of monochromatic light.6 As every chemical vibration is assigned to a specific Raman band (wavenumber in cm-1), each biological sample features a typical spectral pattern due to their inherent biochemical composition.7-9 Within Raman spectra, the peak intensities correlate with the amount of the present molecular bonds.1 Similarities and differences of the spectral data sets can be detected by employing a multivariate analysis (e.g. principal component analysis (PCA)).10 Here, we perform Raman spectroscopy of living cells and native tissues. Cells are either seeded on glass bottom dishes or kept in suspension under normal cell culture conditions (37 °C, 5% CO2) before measurement. Native tissues are dissected and stored in phosphate buffered saline (PBS) at 4 °C prior measurements. Depending on our experimental set up, we then either focused on the cell nucleus or extracellular matrix (ECM) proteins such as elastin and collagen. For all studies, a minimum of 30 cells or 30 random points of interest within the ECM are measured. Data processing steps included background subtraction and normalization. KW - tissue engineering KW - label-free analysis KW - raman spectroscopy KW - bioengineering KW - living cells KW - extracellular matrix Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124569 VL - 63 IS - e3977 ER - TY - JOUR A1 - Vieira, Jacqueline A1 - Jones, Alex R. A1 - Danon, Antoine A1 - Sakuma, Michiyo A1 - Hoang, Nathalie A1 - Robles, David A1 - Tait, Shirley A1 - Heyes, Derren J. A1 - Picot, Marie A1 - Yoshii, Taishi A1 - Helfrich-Förster, Charlotte A1 - Soubigou, Guillaume A1 - Coppee, Jean-Yves A1 - Klarsfeld, André A1 - Rouyer, Francois A1 - Scrutton, Nigel S. A1 - Ahmad, Margaret T1 - Human Cryptochrome-1 Confers Light Independent Biological Activity in Transgenic Drosophila Correlated with Flavin Radical Stability JF - PLoS One N2 - Cryptochromes are conserved flavoprotein receptors found throughout the biological kingdom with diversified roles in plant development and entrainment of the circadian clock in animals. Light perception is proposed to occur through flavin radical formation that correlates with biological activity in vivo in both plants and Drosophila. By contrast, mammalian (Type II) cryptochromes regulate the circadian clock independently of light, raising the fundamental question of whether mammalian cryptochromes have evolved entirely distinct signaling mechanisms. Here we show by developmental and transcriptome analysis that Homo sapiens cryptochrome - 1 (HsCRY1) confers biological activity in transgenic expressing Drosophila in darkness, that can in some cases be further stimulated by light. In contrast to all other cryptochromes, purified recombinant HsCRY1 protein was stably isolated in the anionic radical flavin state, containing only a small proportion of oxidized flavin which could be reduced by illumination. We conclude that animal Type I and Type II cryptochromes may both have signaling mechanisms involving formation of a flavin radical signaling state, and that light independent activity of Type II cryptochromes is a consequence of dark accumulation of this redox form in vivo rather than of a fundamental difference in signaling mechanism. KW - arabidopsi KW - dependent magnetosensitvity KW - protein KW - clock KW - gene KW - mechanism KW - rhythm KW - oscillator KW - circadian photoreception KW - mammalian CRY1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134513 VL - 7 IS - 3 ER - TY - JOUR A1 - Vergho, Daniel Claudius A1 - Loeser, Andreas A1 - Kocot, Arkadius A1 - Spahn, Martin A1 - Riedmüller, Hubertus T1 - Tumor thrombus of inferior vena cava in patients with renal cell carcinoma - Clinical and oncological outcome of 50 patients after surgery N2 - Background: To evaluate oncological and clinical outcome in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC) treated with nephrectomy and thrombectomy. Methods: We identified 50 patients with a median age of 65 years, who underwent radical surgical treatment for RCC and tumor thrombus of the IVC between 1997 and 2010. The charts were reviewed for pathological and surgical parameters, as well as complications and oncological outcome. Results: The median follow-up was 26 months. In 21 patients (42%) distant metastases were already present at the time of surgery. All patients underwent radical nephrectomy, thrombectomy and lymph node dissection through a flank (15 patients/30%), thoracoabdominal (14 patients/28%) or midline abdominal approach (21 patients/42%), depending upon surgeon preference and upon the characteristics of tumor and associated thrombus. Extracorporal circulation with cardiopulmonary bypass (CPB) was performed in 10 patients (20%) with supradiaphragmal thrombus of IVC. Cancer-specific survival for the whole cohort at 5 years was 33.1%. Survival for the patients without distant metastasis at 5 years was 50.7%, whereas survival rate in the metastatic group at 5 years was 7.4%. Median survival of patients with metastatic disease was 16.4 months. On multivariate analysis lymph node invasion, distant metastasis and grading were independent prognostic factors. There was no statistically significant influence of level of the tumor thrombus on survival rate. Indeed, patients with supradiaphragmal tumor thrombus (n = 10) even had a better outcome (overall survival at 5 years of 58.33%) than the entire cohort. Conclusions: An aggressive surgical approach is the most effective therapeutic option in patients with RCC and any level of tumor thrombus and offers a reasonable longterm survival. Due to good clinical and oncological outcome we prefer the use of CPB with extracorporal circulation in patients with supradiaphragmal tumor thrombus. Cytoreductive surgery appears to be beneficial for patients with metastatic disease, especially when consecutive therapy is performed. Although sample size of our study cohort is limited consistent with some other studies lymph node invasion, distant metastasis and grading seem to have prognostic value. KW - Medizin KW - Renal cell carcinoma KW - Inferior vena cava KW - Thrombectomy KW - Tumor thrombus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75230 ER - TY - JOUR A1 - Varykhalov, A. A1 - Marchenko, D. A1 - Sánchez-Barriga, J. A1 - Scholz, M. R. A1 - Verberck, B. A1 - Trauzettel, B. A1 - Wehling, T. O. A1 - Carbone, C. A1 - Rader, O. T1 - Intact Dirac Cones at Broken Sublattice Symmetry: Photoemission Study of Graphene on Ni and Co JF - Physical Review X N2 - The appearance of massless Dirac fermions in graphene requires two equivalent carbon sublattices of trigonal shape. While the generation of an effective mass and a band gap at the Dirac point remains an unresolved problem for freestanding extended graphene, it is well established by breaking translational symmetry by confinement and by breaking sublattice symmetry by interaction with a substrate. One of the strongest sublattice-symmetry-breaking interactions with predicted and measured band gaps ranging from 400 meV to more than 3 eV has been attributed to the interfaces of graphene with Ni and Co, which are also promising spin-filter interfaces. Here, we apply angle-resolved photoemission to epitaxial graphene on Ni (111) and Co(0001) to show the presence of intact Dirac cones 2.8 eV below the Fermi level. Our results challenge the common belief that the breaking of sublattice symmetry by a substrate and the opening of the band gap at the Dirac energy are in a straightforward relation. A simple effective model of a biased bilayer structure composed of graphene and a sublattice-symmetry-broken layer, corroborated by density-functional-theory calculations, demonstrates the general validity of our conclusions. KW - NI(111) KW - ultrasoft pseudopotentials KW - monolayer graphite KW - electronic states KW - transistors KW - surface Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135732 VL - 2 IS - 041017 ER - TY - JOUR A1 - Vandenberg, Laura N. A1 - Chahoud, Ibrahim A1 - Heindel, Jerrold J. A1 - Padmanabhan, Vasantha A1 - Paumgartten, Francisco J. R. A1 - Schönfelder, Gilbert T1 - Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A T1 - Estudos de biomonitoração do sistema urinário, circulatório e tecidos indicam grande exposição ao Bisfenol A JF - Ciência & Saúde Coletiva N2 - Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. We examined many possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions. More than 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism were examined. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes. N2 - Bisfenol A (BPA) é um dos produtos químicos mais produzido em todo o mundo, e a exposição humana a ele é considerada onipresente. Assim, há preocupações de que a quantidade de BPA para o qual os seres humanos estão expostos podem causar efeitos adversos à saúde. Nós examinamos muitas possibilidades sobre o porquê estudos de biomonitorização e toxicocinética podem chegar a conclusões aparentemente conflitantes. Mais de 80 estudos publicados de biomonitorização humana que mediram a concentração de BPA em tecidos humanos, urina, sangue e outros fluidos, juntamente com dois estudos de toxicocinética do metabolismo humano BPA foram examinados. BPA não conjugado foi detectado no sangue (nonanogramas por mililitro gama), e BPA conjugado foi detectado na grande maioria das amostras de urina. Em contraste, estudos de toxico-cinética propuseram que os seres humanos não são internamente expostos ao BPA. Dados disponíveis de estudos de biomonitorização indicam que a população em geral está exposta ao BPA e em risco de exposição interna ao BPA não conjugado. Os dois estudos de toxicocinética, que sugeriram a exposição humana ao BPA é insignificante, têm deficiências significativas e estão diretamente refutados por outros estudos e, portanto não são confiáveis para fins de avaliação de risco. KW - human KW - performance liquid-chromatography KW - toxicocinética KW - serum KW - fluorescence detection KW - disrupting chemicals KW - endocrine disruptor KW - human exposure KW - PBPK/PBTK model KW - pregnancy KW - risk assessment KW - toxicokinetics KW - solid-phase extraction KW - tandem mass-spectrometry KW - HPLC-MS/MS method KW - environmental phenols KW - estrogen receptor KW - adipose tissue KW - disruptor endócrino KW - exposição humana KW - modelo PBPK/PBTK KW - gravidez KW - avaliação de risco Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134332 VL - 17 IS - 2 ER - TY - JOUR A1 - van Koolwijk, Leonieke M. E. A1 - Ramdas, Wishal D. A1 - Ikram, M. Kamran A1 - Jansonius, Nomdo M. A1 - Pasutto, Francesca A1 - Hys, Pirro G. A1 - Macgregor, Stuart A1 - Janssen, Sarah F. A1 - Hewitt, Alex W. A1 - Viswanathan, Ananth C. A1 - ten Brink, Jacoline B. A1 - Hosseini, S. Mohsen A1 - Amin, Najaf A1 - Despriet, Dominiek D. G. A1 - Willemse-Assink, Jacqueline J. M. A1 - Kramer, Rogier A1 - Rivadeneira, Fernando A1 - Struchalin, Maksim A1 - Aulchenko, Yurii S. A1 - Weisschuh, Nicole A1 - Zenkel, Matthias A1 - Mardin, Christian Y. A1 - Gramer, Eugen A1 - Welge-Lüssen, Ulrich A1 - Montgomery, Grant W. A1 - Carbonaro, Francis A1 - Young, Terri L. A1 - Bellenguez, Céline A1 - McGuffin, Peter A1 - Foster, Paul J. A1 - Topouzis, Fotis A1 - Mitchell, Paul A1 - Wang, Jie Jin A1 - Wong, Tien Y. A1 - Czudowska, Monika A. A1 - Hofman, Albert A1 - Uitterlinden, Andre G. A1 - Wolfs, Roger C. W. A1 - de Jong, Paulus T. V. M. A1 - Oostra, Ben A. A1 - Paterson, Andrew D. A1 - Mackey, David A. A1 - Bergen, Arthur A. B. A1 - Reis, Andre A1 - Hammond, Christopher J. A1 - Vingerling, Johannes R. A1 - Lemij, Hans G. A1 - Klaver, Caroline C. W. A1 - van Duijn, Cornelia M. T1 - Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma JF - PLoS Genetics N2 - Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation. KW - expression KW - goldmann applanation tonometer KW - central corneal thickness KW - genome-wide scan KW - beaver-dam eye KW - to-disc ratio KW - onset KW - association KW - identification KW - population Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131378 VL - 8 IS - 5 ER - TY - JOUR A1 - van de Kerkhof, Noortje W. A. A1 - van der Heijden, Frank M. M. A. A1 - Schneider, Marc K. F. A1 - Pfuhlmann, Bruno A1 - Stöber, Gerald A1 - Egger, Jos I. M. A1 - Verhoeven, Willem M. A. T1 - Cycloid psychoses: Leonhard's descriptions revisited JF - European Journal of Psychiatry N2 - Background and Objectives: Cycloid psychoses are characterized by polymorphic symptomatology with intraphasic bipolarity, a remitting and recurrent course and favourable prognosis. Perris and Brocicington (P&B) described the first set of operational criteria that were partly incorporated in ICD-10. The present study investigates psychopathological profiles according to the P&B criteria and the original descriptions by Leonhard, both against the background of the criteria from the prevailing international classification systems. Methods: Eighty patients with psychotic disorders were recruited and assessed with various psychometric instruments at baseline and after six weeks of antipsychotic treatment in order to investigate the presence of cycloid psychoses according to Leonhard (LCP) and the effect of treatment with antipsychotics. The overlap between LCP and DSM-IV Brief Psychotic Disorder (BPD), ICD Acute Polymorphic Psychotic Disorder (APP) and P&B criteria was calculated. Results: Using P&B criteria and a symptom checklist adapted from the original descriptions by Leonhard, 14 and 12 cases of cycloid psychosis were identified respectively reflecting a prevalence of 15-18%. Small though significant concordance rates were found between LCP and both DSM-BPD and ICD-APP. Concordance between LCP and P&B criteria was also significant, but modest. Conclusions: This study demonstrates that LCP can be identified in a substantial number of patients with psychotic disorders. Cycloid psychoses are not adequately covered in current classification systems and criteria. Since they are demonstrated to have a specific psychopathological profile, relapsing course and favourable prognosis, it is advocated to include these psychoses in daily differential diagnostic procedures. KW - P300 KW - endogenous psychoses KW - follow-up KW - schizophrenia KW - disorder KW - classification KW - validity KW - family Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134779 VL - 26 IS - 4 ER - TY - JOUR A1 - Van de Kerkhof, Noortje W. A. A1 - Feenstra, Ilse A1 - van der Heijden, Frank M. M. A. A1 - de Leeuw, Nicole A1 - Pfundt, Rolph A1 - Stöber, Gerald A1 - Egger, Jos I. M. A1 - Verhoeven, Willem M. A. T1 - Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice? JF - Neuropsychiatric Disease and Treatment N2 - With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment. KW - microarrays KW - spectrum disorders KW - schizophrenia KW - gene KW - psychopathology KW - polymorphisms KW - microdeletion KW - perspectives KW - association KW - environment KW - copy number variants KW - 1q21 KW - 7q11.2 KW - 1p13.3 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134769 VL - 8 ER - TY - JOUR A1 - Van Baelen, Anthony A1 - Mottet, Nicolas A1 - Spahn, Martin A1 - Briganti, Alberto A1 - Gontero, Paolo A1 - Joniau, Steven T1 - Sense and Nonsense of an Extended Pelvic Lymph Node Dissection in Prostate Cancer JF - Advances in Urology N2 - Lymph node metastases associated with prostate cancer (PCa) has been shown to be a poor prognostic factor. The role of pelvic lymph node dissection (PLND) itself in relation to survival remains unclear, however. A Medline search was conducted to address this issue. The following conclusions were drawn. Only recently, improved survival due to completion of radical prostatectomy (RP) (compared to abandoning RP) in known or presumed lymph-node-positive patients has been shown. Lymph node sampling can only be considered representative if an adequate number of nodes is removed. While several authors have suggested that a therapeutic benefit in patients undergoing RP is not provided by PLND, the reliability of these studies is uncertain. Contrary to this, several studies have indicated the possibility of long-term survival even in the presence of limited lymph node metastases. The role and timing of initiation of adjuvant androgen deprivation therapy (ADT) in patients who have node-positive disease after RP is controversial. Recent studies suggest that delaying ADT may not adversely impact survival. KW - Prostatakrebs Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123990 VL - 2012 IS - 983058 ER - TY - JOUR A1 - Tu, Xiaolin A1 - Chen, Jianquan A1 - Lim, Joohyun A1 - Karner, Courtney M. A1 - Lee, Seung-Yon A1 - Heisig, Julia A1 - Wiese, Cornelia A1 - Surendran, Kameswaran A1 - Kopan, Raphael A1 - Gessler, Manfred A1 - Long, Fanxin T1 - Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1 JF - PLoS Genetics N2 - Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo. KW - expression KW - axial skeletal defects KW - transcription factor KW - alagille syndrome KW - osteoblast differentiation KW - human jagged1 KW - aortic-valve KW - T cells KW - mutations KW - mice Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133490 VL - 8 IS - 3 ER - TY - JOUR A1 - Tretter, Verena A1 - Mukherjee, Jayanta A1 - Maric, Hans-Michael A1 - Schindelin, Hermann A1 - Sieghart, Werner A1 - Moss, Stephen J. T1 - Gephyrin, the enigmatic organizer at GABAergic synapses JF - Frontiers in Cellular Neuroscience N2 - GABA(A) receptors are clustered at synaptic sites to achieve a high density of postsynaptic receptors opposite the input axonal terminals. This allows for an efficient propagation of GABA mediated signals, which mostly result in neuronal inhibition. A key organizer for inhibitory synaptic receptors is the 93 kDa protein gephyrin that forms oligomeric superstructures beneath the synaptic area. Gephyrin has long been known to be directly associated with glycine receptor beta subunits that mediate synaptic inhibition in the spinal cord. Recently, synaptic GABA(A) receptors have also been shown to directly interact with gephyrin and interaction sites have been identified and mapped within the intracellular loops of the GABA(A) receptor alpha 1, alpha 2, and alpha 3 subunits. Gephyrin-binding to GABA(A) receptors seems to be at least one order of magnitude weaker than to glycine receptors (GlyRs) and most probably is regulated by phosphorylation. Gephyrin not only has a structural function at synaptic sites, but also plays a crucial role in synaptic dynamics and is a platform for multiple protein-protein interactions, bringing receptors, cytoskeletal proteins and downstream signaling proteins into close spatial proximity. KW - scaffolding protein gephyryrin KW - containing GABA(A) receptors KW - GABA(A) receptors KW - inhibitory synapse KW - gamma-aminobutyric-acid KW - receptor-beta subunits KW - molybdenum cofactor biosynthesis KW - temporal-lobe epilepsy KW - cultured hippocampal-neurons KW - exchange factor collybistin KW - rat spinal-cord KW - glycine KW - gephyrin KW - receptor clustering KW - synapse formation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133356 VL - 6 IS - 23 ER - TY - JOUR A1 - Tomei, Sara A1 - Adams, Sharon A1 - Uccellini, Lorenzo A1 - Bedognetti, Davide A1 - De Giorgi, Valeria A1 - Erdenebileg, Narnygerel A1 - Libera Ascierto, Maria A1 - Reinboth, Jennifer A1 - Liu, Qiuzhen A1 - Bevilacqua, Generoso A1 - Wang, Ena A1 - Mazzanti, Chiara A1 - Marincola, Francesco M. T1 - Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population JF - Medical Oncology N2 - HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case–control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690. KW - HRAS KW - polymorphism KW - melanoma KW - rs12628 KW - rs112587690 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126834 VL - 29 IS - 5 ER - TY - JOUR A1 - Toepfer, Regina T1 - Spielregeln für das Überleben: Dietrich von Bern im "Nibelungenlied" und in der "Nibelungenklage" JF - Zeitschrift für deutsches Altertum und deutsche Literatur N2 - Anknüpfend an Jan Dirk Müllers Studie ‘Spielregeln für den Untergang’ fragt der Beitrag nach jenen Verhaltensweisen im ‘Nibelungenlied’, mit denen die Katastrophe hätte verhindert werden können. Im Zentrum des Beitrags steht Dietrich von Bern, der wiederholt Handlungsalternativen aufzeigt, die eine andere Entwicklung des Geschehens ermöglicht hätten. Seine Spielregeln für ein Überleben funktionieren nur deshalb nicht, weil der Herr der Amelungen in der nibelungischen Welt keine Mitspieler findet, die sich dauerhaft an seine Regeln halten. Nach der Katastrophe werden seine Maximen jedoch bestätigt und anerkannt, wie die zeitgenössischen Reflexionen im Umfeld des Epos zeigen. In der ʻNibelungenklageʼ wird nicht nur rückblickend das Fehlverhalten einzelner Figuren getadelt, sondern ermöglichen die Anweisungen Dietrichs auch ein Weiterleben und die Gestaltung künftigen Geschehens. Um diese These zu stützen, werden zunächst die für Dietrich relevanten Episoden des ‘Nibelungenlieds’ in chronologischer Folge untersucht und die jeweiligen Handlungsmaximen bestimmt, anschließend die Bedeutung und Bewertung seiner Spielregeln in der ‘Klage’ untersucht. Flankierend werden auch die Werke der historischen Dietrichepik herangezogen. KW - Katastrophe KW - Spielregeln KW - historische Dietrichepik KW - Handlungsalternative KW - Nibelungenlied KW - Klage (Epos) KW - Dietrich, von Bern Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303049 UR - https://www.hirzel.de/zeitschrift-fuer-deutsches-altertum-und-deutsche-literatur/0044-2518 SN - 0044-2518 VL - 141 IS - 3 ER - TY - JOUR A1 - Tobias, Kaufmann A1 - Völker, Stefan A1 - Gunesch, Laura A1 - Kübler, Andrea T1 - Spelling is just a click away – a user-centered brain-computer interface including auto-calibration and predictive text entry N2 - Brain–computer interfaces (BCI) based on event-related potentials (ERP) allow for selection of characters from a visually presented character-matrix and thus provide a communica- tion channel for users with neurodegenerative disease. Although they have been topic of research for more than 20 years and were multiply proven to be a reliable communication method, BCIs are almost exclusively used in experimental settings, handled by qualified experts. This study investigates if ERP–BCIs can be handled independently by laymen without expert support, which is inevitable for establishing BCIs in end-user’s daily life situations. Furthermore we compared the classic character-by-character text entry against a predictive text entry (PTE) that directly incorporates predictive text into the character- matrix. N = 19 BCI novices handled a user-centered ERP–BCI application on their own without expert support. The software individually adjusted classifier weights and control parameters in the background, invisible to the user (auto-calibration). All participants were able to operate the software on their own and to twice correctly spell a sentence with the auto-calibrated classifier (once with PTE, once without). Our PTE increased spelling speed and, importantly, did not reduce accuracy. In sum, this study demonstrates feasi- bility of auto-calibrating ERP–BCI use, independently by laymen and the strong benefit of integrating predictive text directly into the character-matrix. KW - Psychologie KW - P300-Speller KW - ERP-BCI KW - brain–computerinterface KW - user-centered KW - auto-calibration KW - predictivetextentry KW - event-relatedpotentials KW - assisitvetechnology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75739 ER - TY - JOUR A1 - Thoma, Eva C. A1 - Wischmeyer, Erhard A1 - Offen, Nils A1 - Maurus, Katja A1 - Sirén, Anna-Leena A1 - Schartl, Manfred A1 - Wagner, Toni U. T1 - Ectopic expression of Neurogenin 2 alone is sufficient to induce differentiation of embryonic stem cells into mature neurons N2 - Recent studies show that combinations of defined key developmental transcription factors (TFs) can reprogram somatic cells to pluripotency or induce cell conversion of one somatic cell type to another. However, it is not clear if single genes can define a cells identity and if the cell fate defining potential of TFs is also operative in pluripotent stem cells in vitro. Here, we show that ectopic expression of the neural TF Neurogenin2 (Ngn2) is sufficient to induce rapid and efficient differentiation of embryonic stem cells (ESCs) into mature glutamatergic neurons. Ngn2-induced neuronal differentiation did not require any additional external or internal factors and occurred even under pluripotency-promoting conditions. Differentiated cells displayed neuron-specific morphology, protein expression, and functional features, most importantly the generation of action potentials and contacts with hippocampal neurons. Gene expression analyses revealed that Ngn2-induced in vitro differentiation partially resembled neurogenesis in vivo, as it included specific activation of Ngn2 target genes and interaction partners. These findings demonstrate that a single gene is sufficient to determine cell fate decisions of uncommitted stem cells thus giving insights into the role of key developmental genes during lineage commitment. Furthermore, we present a promising tool to improve directed differentiation strategies for applications in both stem cell research and regenerative medicine. KW - Physiologie Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75862 ER - TY - JOUR A1 - Thein, Marcus A1 - Bonde, Mari A1 - Bunikis, Ignas A1 - Denker, Katrin A1 - Sickmann, Albert A1 - Bergström, Sven A1 - Benz, Roland T1 - DipA, a Pore-Forming Protein in the Outer Membrane of Lyme Disease Spirochetes Exhibits Specificity for the Permeation of Dicarboxylates N2 - Lyme disease Borreliae are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography from Borrelia burgdorferi B31 and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borreliae. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a singlechannel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl) were obtained among the 11 tested anions for oxaloacetate, 2-oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75809 ER - TY - JOUR A1 - Thangaraj Selvaraj, Bhuvaneish A1 - Frank, Nicolas A1 - Bender, Florian L. P. A1 - Asan, Esther A1 - Sendtner, Michael T1 - Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease JF - The Journal of Cell Biology N2 - Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule-destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration. KW - Schwann cells KW - transcription-3 (STAT3) KW - ciliary neurotrophic factor (CNTF) KW - axonal degeneration Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154675 VL - 199 IS - 3 SP - 437 EP - 451 ER - TY - JOUR A1 - Tessmer, Ingrid A1 - Melikishvili, Manana A1 - Fried, Michael G. T1 - Cooperative cluster formation, DNA bending and base-flipping by O\(^6\)-alkylguanine-DNA alkyltransferase JF - Nucleic Acids Research N2 - O\(^6\)-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of 11 proteins. Longer clusters, predicted by the McGhee-von Hippel model, were not seen even at high [protein]. Interestingly, torsional stress due to DNA unwinding has the potential to limit cluster size to the observed range. DNA at cluster sites showed bend angles (similar to 0, similar to 30 and similar to 60 degrees) that are consistent with models in which each protein induces a bend of similar to 30 degrees. Distributions of complexes along the DNA are incompatible with sequence specificity but suggest modest preference for DNA ends. These properties tell us about environments in which AGT may function. Small cooperative clusters and the ability to accommodate a range of DNA bends allow function where DNA topology is constrained, such as near DNA-replication complexes. The low sequence specificity allows efficient and unbiased lesion search across the entire genome. KW - inactivation KW - nucleotide excision-repair KW - atomic-force microscopy KW - noncooperative binding KW - restricition enzymes KW - complex stability KW - stranded DNAs KW - protein KW - chemotherapy KW - AGT Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133949 VL - 40 IS - 17 ER - TY - JOUR A1 - Tempel, Jean-Sebastian A1 - Veit, Tempel A1 - Assmann, Marc A1 - Kreilkamp, Lars Erik A1 - Höfling, Sven A1 - Kamp, Martin A1 - Forchel, Alfred A1 - Bayer, Manfred T1 - Temperature dependence of pulsed polariton lasing in a GaAs microcavity JF - New Journal of Physics N2 - The second-order correlation function g\(^2\)(\(\tau\) = 0), input-output curves and pulse duration of the emission from a microcavity exciton-polariton system subsequent to picosecond-pulsed excitation are measured for different temperatures. At low temperatures a two-threshold behaviour emerges, which has been attributed to the onset of polariton lasing and conventional lasing at the first and the second threshold, respectively. We observe that polariton lasing is stable up to temperatures comparable with the exciton binding energy. At higher temperatures a single threshold displays the direct transition from thermal emission to photon lasing. KW - semiconductor microavity KW - quantized vortices KW - cavity polaritons KW - room temperature KW - excitons KW - time Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134022 VL - 14 IS - 083014 ER - TY - JOUR A1 - Sütterlin, Stefan A1 - Paap, Muirne C. S. A1 - Babic, Stana A1 - Kübler, Andrea A1 - Vögele, Claus T1 - Rumination and Age: Some Things Get Better JF - Journal of Aging Research N2 - Rumination has been defined as a mode of responding to distress that involves passively focusing one's attention on symptoms of distress without taking action. This dysfunctional response style intensifies depressed mood, impairs interpersonal problem solving, and leads to more pessimistic future perspectives and less social support. As most of these results were obtained from younger people, it remains unclear how age affects ruminative thinking. Three hundred members of the general public ranging in age from 15 to 87 years were asked about their ruminative styles using the Response Styles Questionnaire (RSQ), depression and satisfaction with life. A Mokken Scale analysis confirmed the two-factor structure of the RSQ with brooding and reflective pondering as subcomponents of rumination. Older participants (63 years and older) reported less ruminative thinking than other age groups. Life satisfaction was associated with brooding and highest for the earlier and latest life stages investigated in this study. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124356 VL - 2012 IS - 267327 ER - TY - JOUR A1 - Sweeney, Reinhart A. A1 - Seubert, Benedikt A1 - Stark, Silke A1 - Homann, Vanessa A1 - Müller, Gerd A1 - Flentje, Michael A1 - Guckenbeger, Matthias T1 - Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors N2 - Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1–3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 % and 7.1 % observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability. KW - Medizin KW - Lung cancer KW - Image-guidance KW - Cone-beam CT KW - Inter-observer variability KW - Respiration correlated imaging Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75698 ER - TY - JOUR A1 - Stölting, Miriam A1 - Wiesner, Christiane A1 - van Vliet, Vanessa A1 - Butt, Elke A1 - Pavenstädt, Hermann A1 - Linder, Stefan A1 - Kremerskothen, Joachim T1 - Lasp-1 Regulates Podosome Function JF - PLoS One N2 - Eukaryotic cells form a variety of adhesive structures to connect with their environment and to regulate cell motility. In contrast to classical focal adhesions, podosomes, highly dynamic structures of different cell types, are actively engaged in matrix remodelling and degradation. Podosomes are composed of an actin-rich core region surrounded by a ring-like structure containing signalling molecules, motor proteins as well as cytoskeleton-associated proteins. Lasp-1 is a ubiquitously expressed, actin-binding protein that is known to regulate cytoskeleton architecture and cell migration. This multidomain protein is predominantely present at focal adhesions, however, a second pool of Lasp-1 molecules is also found at lamellipodia and vesicle-like microdomains in the cytosol. In this report, we show that Lasp-1 is a novel component and regulator of podosomes. Immunofluorescence studies reveal a localization of Lasp-1 in the podosome ring structure, where it colocalizes with zyxin and vinculin. Life cell imaging experiments demonstrate that Lasp-1 is recruited in early steps of podosome assembly. A siRNA-mediated Lasp-1 knockdown in human macrophages affects podosome dynamics as well as their matrix degradation capacity. In summary, our data indicate that Lasp-1 is a novel component of podosomes and is involved in the regulation of podosomal function. KW - discrete KW - smooth muscle cells KW - microdomains KW - actin cytoskeleton KW - endothelial cells KW - epithelial cells KW - cancer cells KW - phosphorylation KW - invadopodia KW - dependent protein-kinase KW - camp signaling pathway Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134315 VL - 7 IS - 4 ER - TY - JOUR A1 - Sturm, Julia B. A1 - Hess, Michael A1 - Weibel, Stephanie A1 - Chen, Nanhei G. A1 - Yu, Yong A. A1 - Zhang, Quian A1 - Donat, Ulrike A1 - Reiss, Cora A1 - Gambaryan, Stepan A1 - Krohne, Georg A1 - Stritzker, Jochen A1 - Szalay, Aladar A. T1 - Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy N2 - Background: Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods: Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results: We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion: Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects. KW - Biologie KW - vaccinia virus KW - cancer KW - cytokine KW - hyper-IL-6 KW - oncolysis KW - chemotherapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75224 ER - TY - JOUR A1 - Strauss, Armin A1 - Moskalenko, Vasily A1 - Tiurbe, Christian A1 - Chodnevskaja, Irina A1 - Timm, Stephan A1 - Wiegering, Verena A. A1 - Germer, Chrioph Thomas A1 - Ulrichs, Karin T1 - Goettingen Minipigs (GMP): Comparison of Two Different Models for Inducing Diabetes N2 - Purpose: Preclinical experiments on large animals are indispensable for evaluating the effectiveness of diabetes therapies. Miniature swine are well suited for such studies due to their physiological and pathophysiological responses. Methods: We compare two methods for inducing diabetes in Goettingen minipigs (GMP), in five with the beta cell toxin streptozotocin (STZ) and in five other GMP by total pancreatectomy (PE). Glucose homeostasis was assessed with the intravenous glucose-tolerance test (IVGTT) and continual monitoring of interstitial glucose levels. At conclusion of the observation period, the pancreata were examined histologically. Three non-diabetic GMP served as control group. Results: The IVGTT revealed markedly diabetic profiles in both GMP groups. STZ-GMP were found to harbor residual C-peptides and scattered insulin-positive cells in the pancreas. PE-GMP survived the total pancreatectomy only with intensive postoperative care. Conclusions: Although both methods reliably induced diabetes in GMP, the PE-GMP clearly had more health problems and required a greater expenditure of time and resources. The PE-GMP model, however, was better at eliminating endogenous insulin and C-peptide than the STZ-GMP model. KW - Göttingen KW - Minischwein KW - diabetes KW - pig or swine KW - real-time glucose monitoring KW - intravenous glucose tolerance test KW - total pancreatectomy KW - streptozotocin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75119 ER - TY - JOUR A1 - Stolpmann, K. A1 - Brinkmann, J. A1 - Salzmann, S. A1 - Genkinger, D. A1 - Fritsche, E. A1 - Hutzler, C. A1 - Wajant, H. A1 - Luch, A. A1 - Henkler, F. T1 - Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis JF - Cell Death & Disease N2 - In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[ a] pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by beta-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure. KW - CD95 KW - HaCaT cells KW - growth-factor receptor KW - cell death KW - mitochondrial dysfunction KW - mediated apoptosis KW - FAS KW - dermatitis KW - pathways KW - skin KW - progression KW - aryl hydrocarbon receptor (AhR) KW - apoptosis KW - benzo[a]pyrene KW - human keratinocytes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133501 VL - 3 IS - e388 ER - TY - JOUR A1 - Stippekohl, Bastian A1 - Winkler, Markus H. A1 - Walter, Bertram A1 - Kagerer, Sabine A1 - Mucha, Ronald F. A1 - Pauli, Paul A1 - Vaitl, Dieter A1 - Stark, Rudolf T1 - Neural Responses to Smoking Stimuli Are Influenced by Smokers' Attitudes towards Their Own Smoking Behaviour JF - PLoS One N2 - An important feature of addiction is the high drug craving that may promote the continuation of consumption. Environmental stimuli classically conditioned to drug-intake have a strong motivational power for addicts and can elicit craving. However, addicts differ in the attitudes towards their own consumption behavior: some are content with drug taking (consonant users) whereas others are discontent (dissonant users). Such differences may be important for clinical practice because the experience of dissonance might enhance the likelihood to consider treatment. This fMRI study investigated in smokers whether these different attitudes influence subjective and neural responses to smoking stimuli. Based on self-characterization, smokers were divided into consonant and dissonant smokers. These two groups were presented smoking stimuli and neutral stimuli. Former studies have suggested differences in the impact of smoking stimuli depending on the temporal stage of the smoking ritual they are associated with. Therefore, we used stimuli associated with the beginning (BEGIN-smoking-stimuli) and stimuli associated with the terminal stage (END-smoking-stimuli) of the smoking ritual as distinct stimulus categories. Stimulus ratings did not differ between both groups. Brain data showed that BEGIN-smoking-stimuli led to enhanced mesolimbic responses (amygdala, hippocampus, insula) in dissonant compared to consonant smokers. In response to END-smoking-stimuli, dissonant smokers showed reduced mesocortical responses (orbitofrontal cortex, subcallosal cortex) compared to consonant smokers. These results suggest that smoking stimuli with a high incentive value (BEGIN-smoking-stimuli) are more appetitive for dissonant than consonant smokers at least on the neural level. To the contrary, smoking stimuli with low incentive value (END-smoking-stimuli) seem to be less appetitive for dissonant smokers than consonant smokers. These differences might be one reason why dissonant smokers experience difficulties in translating their attitudes into an actual behavior change. KW - smoking habits KW - addiction KW - amygdala KW - behavioral addiction KW - addicts KW - nicotine addiction KW - drug research and development KW - drug addiction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124393 VL - 7 IS - 11 ER - TY - JOUR A1 - Steinmann, Diana A1 - Paelecke-Habermann, Yvonne A1 - Geinitz, Hans A1 - Aschoff, Raimund A1 - Bayerl, Anja A1 - Bölling, Tobias A1 - Bosch, Elisabeth A1 - Bruns, Frank A1 - Eichenseder-Seiss, Ute A1 - Gerstein, Johanna A1 - Gharbi, Nadine A1 - Hagg, Juliane A1 - Hipp, Matthias A1 - Kleff, Irmgard A1 - Müller, Axel A1 - Schäfer, Christof A1 - Schleicher, Ursula A1 - Sehlen, Susanne A1 - Theodorou, Marilena A1 - Wypior, Hans-Joachim A1 - Zehentmayr, Franz A1 - van Oorschot, Birgitt A1 - Vordermark, Dirk T1 - Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases JF - BMC Cancer N2 - Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information. KW - breast cancer KW - brain tumours KW - survival KW - validation KW - symptoms KW - EORTC-QLQ-C15-PAL KW - EORTC-BN20 KW - whole-brain radiotherapy KW - partitioning analysis RPA KW - cancer patients KW - lung cancer KW - prognostic index KW - radiation oncology KW - clinical trials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135254 VL - 12 IS - 283 ER -