TY - JOUR
A1 - Čuklina, Jelena
A1 - Hahn, Julia
A1 - Imakaev, Maxim
A1 - Omasits, Ulrich
A1 - Förstner, Konrad U.
A1 - Ljubimov, Nikolay
A1 - Goebel, Melanie
A1 - Pessi, Gabriella
A1 - Fischer, Hans-Martin
A1 - Ahrens, Christian H.
A1 - Gelfand, Mikhail S.
A1 - Evguenieva-Hackenberg, Elena
T1 - Genome-wide transcription start site mapping of Bradyrhizobium japonicum grown free-living or in symbiosis - a rich resource to identify new transcripts, proteins and to study gene regulation
JF - BMC Genomics
N2 - Background
Differential RNA-sequencing (dRNA-seq) is indispensable for determination of primary transcriptomes. However, using dRNA-seq data to map transcriptional start sites (TSSs) and promoters genome-wide is a bioinformatics challenge. We performed dRNA-seq of Bradyrhizobium japonicum USDA 110, the nitrogen-fixing symbiont of soybean, and developed algorithms to map TSSs and promoters.
Results
A specialized machine learning procedure for TSS recognition allowed us to map 15,923 TSSs: 14,360 in free-living bacteria, 4329 in symbiosis with soybean and 2766 in both conditions. Further, we provide proteomic evidence for 4090 proteins, among them 107 proteins corresponding to new genes and 178 proteins with N-termini different from the existing annotation (72 and 109 of them with TSS support, respectively). Guided by proteomics evidence, previously identified TSSs and TSSs experimentally validated here, we assign a score threshold to flag 14 % of the mapped TSSs as a class of lower confidence. However, this class of lower confidence contains valid TSSs of low-abundant transcripts. Moreover, we developed a de novo algorithm to identify promoter motifs upstream of mapped TSSs, which is publicly available, and found motifs mainly used in symbiosis (similar to RpoN-dependent promoters) or under both conditions (similar to RpoD-dependent promoters). Mapped TSSs and putative promoters, proteomic evidence and updated gene annotation were combined into an annotation file.
Conclusions
The genome-wide TSS and promoter maps along with the extended genome annotation of B. japonicum represent a valuable resource for future systems biology studies and for detailed analyses of individual non-coding transcripts and ORFs. Our data will also provide new insights into bacterial gene regulation during the agriculturally important symbiosis between rhizobia and legumes.
KW - Bradyrhizobium
KW - RNA-seq
KW - Promoter prediction
KW - Genome re-annotation
KW - Internal transcription start site
KW - Nodule
KW - Transcription start site
KW - Proteogenomics
KW - Antisense RNA
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164565
VL - 17
ER -
TY - JOUR
A1 - Üçeyler, Nurcan
A1 - Schäfer, Kristina A.
A1 - Mackenrodt, Daniel
A1 - Sommer, Claudia
A1 - Müllges, Wolfgang
T1 - High-Resolution Ultrasonography of the Superficial Peroneal Motor and Sural Sensory Nerves May Be a Non-invasive Approach to the Diagnosis of Vasculitic Neuropathy
JF - Frontiers in Neurology
N2 - High-resolution ultrasonography (HRUS) is an emerging new tool in the investigation of peripheral nerves. We set out to assess the utility of HRUS performed at lower extremity nerves in peripheral neuropathies. Nerves of 26 patients with polyneuropathies of different etiologies and 26 controls were investigated using HRUS. Patients underwent clinical, laboratory, electrophysiological assessment, and a diagnostic sural nerve biopsy as part of the routine work-up. HRUS was performed at the sural, tibial, and the common, superficial, and deep peroneal nerves. The superficial peroneal nerve longitudinal diameter (LD) distinguished best between the groups: patients with immune-mediated neuropathies (n = 13, including six with histology-proven vasculitic neuropathy) had larger LD compared to patients with non-immune-mediated neuropathies (p < 0.05) and to controls (p < 0.001). Among all subgroups, patients with vasculitic neuropathy showed the largest superficial peroneal nerve LD (p < 0.001) and had a larger sural nerve cross-sectional area when compared with disease controls (p < 0.001). Enlargement of the superficial peroneal and sural nerves as detected by HRUS may be a useful additional finding in the differential diagnosis of vasculitic and other immune-mediated neuropathies.
KW - peripheral neuropathy
KW - nerve ultrasonography
KW - vasculitis
KW - sural nerve
KW - superficial peroneal nerve
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146671
VL - 7
IS - 48
ER -
TY - JOUR
A1 - Üçeyler, Nurcan
A1 - Schröter, Nils
A1 - Kafke, Waldemar
A1 - Kramer, Daniela
A1 - Wanner, Christoph
A1 - Weidemann, Frank
A1 - Sommer, Claudia
T1 - Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease
JF - PLoS ONE
N2 - Background
The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.
Methods
At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.
Results
We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.
Conclusions
Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.
KW - biopsy
KW - neuropathy
KW - Fabry disease
KW - renal system
KW - immunofluorescence
KW - enzyme replacement therapy
KW - skin diseases
KW - nerve fibers
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178856
VL - 11
IS - 11
ER -
TY - JOUR
A1 - Üçeyler, Nurcan
A1 - Biko, Lydia
A1 - Hose, Dorothea
A1 - Hoffmann, Lukas
A1 - Sommer, Claudia
T1 - Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development
JF - Molecular Pain
N2 - Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease.
Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.
KW - Fabry disease
KW - alpha-galactosidase A
KW - mouse model
KW - pain
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147562
VL - 12
IS - 1744806916646370
ER -
TY - THES
A1 - Zott, Maximilian
T1 - Extreme Value Theory in Higher Dimensions - Max-Stable Processes and Multivariate Records
T1 - Höherdimensionale Extremwerttheorie - Max-Stabile Prozesse und Multivariate Rekorde
N2 - Die Extremwerttheorie behandelt die stochastische Modellierung seltener und extremer Ereignisse. Während fundamentale Theorien in der klassischen Stochastik, wie etwa die Gesetze der großen Zahlen oder der zentrale Grenzwertsatz das asymptotische Verhalten der Summe von Zufallsvariablen untersucht, liegt in der Extremwerttheorie der Fokus auf dem Maximum oder dem Minimum einer Menge von Beobachtungen. Die Grenzverteilung des normierten Stichprobenmaximums unter einer Folge von unabhängigen und identisch verteilten Zufallsvariablen kann durch sogenannte max-stabile Verteilungen charakterisiert werden.
In dieser Dissertation werden verschiedene Aspekte der Theorie der max-stabilen Zufallsvektoren und stochastischen Prozesse behandelt. Insbesondere wird der Begriff der 'Differenzierbarkeit in Verteilung' eines max-stabilen Prozesses eingeführt und untersucht. Ferner werden 'verallgemeinerte max-lineare Modelle' eingeführt, um einen bekannten max-stabilen Zufallsvektor durch einen max-stabilen Prozess zu interpolieren. Darüber hinaus wird der Zusammenhang von extremwerttheoretischen Methoden mit der Theorie der multivariaten Rekorde hergestellt. Insbesondere werden sogenannte 'vollständige' und 'einfache' Rekorde eingeführt, und deren asymptotisches Verhalten untersucht.
N2 - Extreme value theory is concerned with the stochastic modeling of rare and extreme events. While fundamental theories of classical stochastics - such as the laws of small numbers or the central limit theorem - are used to investigate the asymptotic behavior of the sum of random variables, extreme value theory focuses on the maximum or minimum of a set of observations. The limit distribution of the normalized sample maximum among a sequence of independent and identically distributed random variables can be characterized by means of so-called max-stable distributions.
This dissertation concerns with different aspects of the theory of max-stable random vectors and stochastic processes. In particular, the concept of 'differentiability in distribution' of a max-stable process is introduced and investigated. Moreover, 'generalized max-linear models' are introduced in order to interpolate a known max-stable random vector by a max-stable process. Further, the connection between extreme value theory and multivariate records is established. In particular, so-called 'complete' and 'simple' records are introduced as well as it is examined their asymptotic behavior.
KW - Stochastischer Prozess
KW - Extremwertstatistik
KW - max-stable process
KW - max-linear model
KW - Wahrscheinlichkeitsrechnung
KW - Rekord
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136614
ER -
TY - JOUR
A1 - Zlamy, Manuela
A1 - Almanzar, Giovanni
A1 - Parson, Walther
A1 - Schmidt, Christian
A1 - Leierer, Johannes
A1 - Weinberger, Birgit
A1 - Jeller, Verena
A1 - Unsinn, Karin
A1 - Eyrich, Matthias
A1 - Würzner, Reinhard
A1 - Prelog, Martina
T1 - Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy
JF - Immunity & Ageing
N2 - Background
Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system.
The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls.
Results
Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV.
Conclusions
After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.
KW - thymectomy
KW - naive T cells
KW - TRECs
KW - TCR diversity
KW - CMV
KW - CD8
KW - telomeres
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146497
VL - 13
IS - 3
ER -
TY - JOUR
A1 - Zipfel, Julian
A1 - Eyrich, Matthias
A1 - Schlegel, Paul-Gerhardt
A1 - Wiegering, Verena
T1 - Disturbed B cell and DC-Homeostasis in Pediatric cGVHD Patients-Cocultivation Experiments and Review of the Literature
JF - Clinics in Oncology
N2 - B cells and DCs are suspected to play an important role in the pathogenesis of cGvHD, which is a serious complication of HSCT with high morbidity. It is characterized by immune responses of donor immune cells against recipient-derived antigens. athogenesis is not yet fully understood, however reconstitution of B cells after HSCT has similarities to physiologic ontogeny. Immunophenotyping and co-cultivation-experiments of B cells and DCs from pediatric patients with cGvHD as well as healthy donors were conducted. Significant differences between patients and healthy donors were observed with increased memory, transitional, CD69+ and CD86+ phenotype and lower levels of naïve B cells due to apoptosis. Co-cultivation revealed this to be primarily B cell-dependent without major effects of and with DCs. There was a decreased CD11c- phenotype in patients and less apoptosis of DCs. Our data suggest a disturbed homeostasis in B cells with increased memory phenotype in patients, whereas DCs could not influence these differences, therefore DCs are not imposing as promising targets. B cell-dependent approaches should be further investigated.
KW - B cell
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147914
VL - 1
IS - 1097
ER -
TY - JOUR
A1 - Zinner, Christoph
A1 - Morales-Alamo, David
A1 - Ørtenblad, Niels
A1 - Larsen, Filip J.
A1 - Schiffer, Tomas A.
A1 - Willis, Sarah J.
A1 - Gelabert-Rebato, Miriam
A1 - Perez-Valera, Mario
A1 - Boushel, Robert
A1 - Calbet, Jose A. L.
A1 - Holmberg, Hans-Christer
T1 - The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans
JF - Frontiers in Physiology
N2 - To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4–6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3–11% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8%, P < 0.05), but not the legs (−0.6%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.
KW - high-intensity training
KW - lower body
KW - performance
KW - triceps brachii
KW - upper body
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165257
VL - 7
IS - 426
ER -
TY - JOUR
A1 - Zinner, C.
A1 - Krueger, M.
A1 - Reed, J. L.
A1 - Kohl-Bareis, M.
A1 - Holmberg, H. C.
A1 - Sperlich, B.
T1 - Exposure to a combination of heat and hyperoxia during cycling at submaximal intensity does not alter thermoregulatory responses
JF - Biology of Sport
N2 - In this study, we tested the hypothesis that breathing hyperoxic air (F\(_{in}\)O\(_2\) = 0.40) while exercising in a hot environment exerts negative effects on the total tissue level of haemoglobin concentration (tHb); core (T\(_{core}\)) and skin (T\(_{skin}\)) temperatures; muscle activity; heart rate; blood concentration of lactate; pH; partial pressure of oxygen (P\(_a\)O\(_2\)) and carbon dioxide; arterial oxygen saturation (S\(_a\)O\(_2\)); and perceptual responses. Ten well-trained male athletes cycled at submaximal intensity at 21°C or 33°C in randomized order: first for 20 min while breathing normal air (FinO\(_2\) = 0.21) and then 10 min with F\(_{in}\)O\(_2\) = 0.40 (HOX). At both temperatures, S\(_a\)O\(_2\) and P\(_a\)O\(_2\), but not tHb, were increased by HOX. Tskin and perception of exertion and thermal discomfort were higher at 33°C than 21°C (p < 0.01), but independent of F\(_{in}\)O\(_2\). T\(_{core}\) and muscle activity were the same under all conditions (p > 0.07). Blood lactate and heart rate were higher at 33°C than 21°C. In conclusion, during 30 min of submaximal cycling at 21°C or 33°C, T\(_{core}\), T\(_{skin}\) and T\(_{body}\), tHb, muscle activity and ratings of perceived exertion and thermal discomfort were the same under normoxic and hyperoxic conditions. Accordingly, breathing hyperoxic air (F\(_{in}\)O\(_2\) = 0.40) did not affect thermoregulation under these conditions.
KW - heat stress
KW - hyperthermia
KW - skin blood flow
KW - thermoregulation
KW - vasoconstriction
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-160993
VL - 33
IS - 1
ER -
TY - THES
A1 - Ziegler, Christiane
T1 - Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders
T1 - Epigenetische Mechanismen in der Pathogenese und Therapie von Angsterkrankungen
N2 - Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10%. Panic disorder (PD) has a life time prevalence of 2-5% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue.
In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called “hidden heritability”, which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders.
In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD.
The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as – applying a psychotherapy-epigenetic approach – its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD.
Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively.
N2 - Angsterkrankungen sind die häufigsten psychischen Erkrankungen, welche in hohem Maße den Alltag der Betroffenen beeinträchtigen und eine große sozioökonomische Belastung darstellen. Eine der häufigsten Formen von Angsterkrankungen bildet die soziale Phobie, d.h. die Angst vor sozialen Situationen, in denen man im Mittelpunkt der Aufmerksamkeit steht, mit einer Lebenszeit-Prävalenz von circa 10%. Die Panikstörung, charakterisiert durch das wiederholte und unerwartete Auftreten von Panikattacken, ist eine weitere Form der Angsterkrankungen mit einer Lebenszeit-Prävalenz von circa 2-5%.
Epigenetische Mechanismen, wie zum Beispiel die DNA Methylierung, rücken in den letzten Jahren immer weiter in den Fokus der psychiatrischen Forschung. Hier werden sie als eine mögliche Lösung für das Problem der „hidden heritability“ (versteckte Heritabilität) angesehen.
Im ersten Teil dieser Arbeit wurde die DNA Methylierung des Oxytozinrezeptorgens (OXTR) hinsichtlich ihrer Rolle in der Pathogenese der sozialen Phobie untersucht. Hierbei konnte eine verringerte Methylierung des Gens, speziell an einem CpG-Dinukleotid (CpG3, Chr3: 8 809 437) innerhalb der protein-kodierenden Genregion, auf verschiedenen Ebenen mit der Erkrankung an sozialer Phobie, dimensionalen Maßen der Erkrankungsschwere sowie der Stressverarbeitung auf neuro-endokrinologischer und neuronaler Ebene in Verbindung gebracht werden.
Der zweite Teil dieser Arbeit beschäftigt sich mit der Rolle von DNA Methylierungsmustern des Monoaminooxidase A (MAOA) Gens in der Pathogenese und der Therapie der Panikstörung. Zum einen konnte gezeigt werden, dass eine verringerte MAOA Methylierung mit dem Auftreten von Panikstörung sowie mit einer erhöhten Symptomschwere assoziiert ist. Zum anderen zeigten Patienten, welche auf eine kognitive Verhaltenstherapie (KVT) ansprachen, eine signifikante Erhöhung der MAOA Methylierung nach der Therapie, welche zusätzlich in einer unabhängigen Stichprobe mit einer Verringerung der Symptomschwere assoziiert war. Diese Veränderung zeigte sich jedoch nicht in Patienten, welche nicht auf die KVT ansprachen.
Zusammenfassend können beide im Rahmen dieser Arbeit untersuchten epigenetischen Muster und deren Rolle in der Pathogenese der sozialen Phobie sowie der Panikstörung zur Etablierung personalisierter Therapiemöglichkeiten wie auch targetierter präventiver Interventionen beitragen.
KW - Angst
KW - Psychische Störung
KW - DNA-Methylierung
KW - Panikstörung
KW - Soziale Phobie
KW - Angsterkrankungen
KW - Epigenetische Mechanismen
KW - Epigenetik
KW - Methylierung
KW - DNS
KW - Angsterkrankungen
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146815
ER -
TY - JOUR
A1 - Ziegler, C.
A1 - Richter, J.
A1 - Mahr, M.
A1 - Gajewska, A.
A1 - Schiele, M.A.
A1 - Gehrmann, A.
A1 - Schmidt, B.
A1 - Lesch, K.-P.
A1 - Lang, T.
A1 - Helbig-Lang, S.
A1 - Pauli, P.
A1 - Kircher, T.
A1 - Reif, A.
A1 - Rief, W.
A1 - Vossbeck-Elsebusch, A.N.
A1 - Arolt, V.
A1 - Wittchen, H.-U.
A1 - Hamm, A.O.
A1 - Deckert, J.
A1 - Domschke, K.
T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy
JF - Translational Psychiatry
N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
KW - Adult
KW - Case-Control Studies
KW - Cognitive Therapy
KW - DNA Methylation
KW - Epigenesis
KW - Genetic
KW - Female
KW - Humans
KW - Monoamine Oxidase/genetics
KW - Panic Disorder/genetics
KW - Panic Disorder/therapy
KW - Sequence Analysis
KW - DNA
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422
IS - 6
ER -
TY - JOUR
A1 - Zhu, Min
A1 - Shabala, Lana
A1 - Cuin, Tracey A.
A1 - Huang, Xin
A1 - Zhou, Meixue
A1 - Munns, Rana
A1 - Shabala, Sergey
T1 - Nax loci affect SOS1-like Na\(^+\)/H\(^+\) exchanger expression and activity in wheat
JF - Journal of Experimental Botany
N2 - Salinity stress tolerance in durum wheat is strongly associated with a plant's ability to control Na\(^+\) delivery to the shoot. Two loci, termed Nax1 and Nax2, were recently identified as being critical for this process and the sodium transporters HKT1;4 and HKT1; 5 were identified as the respective candidate genes. These transporters retrieve Na\(^+\) from the xylem, thus limiting the rates of Na\(^+\) transport from the root to the shoot. In this work, we show that the Nax loci also affect activity and expression levels of the SOS1-like Na\(^+\)/H\(^+\) exchanger in both root cortical and stelar tissues. Net Na\(^+\) efflux measured in isolated steles from salt-treated plants, using the non-invasive ion flux measuring MIFE technique, decreased in the sequence: Tamaroi (parental line)>Nax1=Nax2>Nax1:Nax2 lines. This efflux was sensitive to amiloride (a known inhibitor of the Na\(^+\)/H\(^+\) exchanger) and was mirrored by net H\(^+\) flux changes. TdSOS1 relative transcript levels were 6-10-fold lower in Nax lines compared with Tamaroi. Thus, it appears that Nax loci confer two highly complementary mechanisms, both of which contribute towards reducing the xylem Na\(^+\) content. One enhances the retrieval of Na\(^+\) back into the root stele via HKT1;4 or HKT1;5, whilst the other reduces the rate of Na\(^+\) loading into the xylem via SOS1. It is suggested that such duality plays an important adaptive role with greater versatility for responding to a changing environment and controlling Na\(^+\) delivery to the shoot.
KW - HKT transporter
KW - potassium
KW - salinity stress
KW - sequestration
KW - sodium
KW - xylem loading
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190908
VL - 67
IS - 3
ER -
TY - JOUR
A1 - Zhu, Min
A1 - Shabala, Lana
A1 - Cuin, Tracey A
A1 - Huang, Xin
A1 - Zhou, Meixue
A1 - Munns, Rana
A1 - Shabala, Sergey
T1 - Nax loci affect SOS1-like Na\(^{+}\)/H\(^{+}\) exchanger expression and activity in wheat
JF - Journal of Experimental Botany
N2 - Salinity stress tolerance in durum wheat is strongly associated with a plant’s ability to control Na\(^{+}\) delivery to the shoot. Two loci, termed Nax1 and Nax2, were recently identified as being critical for this process and the sodium transporters HKT1;4 and HKT1;5 were identified as the respective candidate genes. These transporters retrieve Na\(^{+}\) from the xylem, thus limiting the rates of Na\(^{+}\) transport from the root to the shoot. In this work, we show that the Nax loci also affect activity and expression levels of the SOS1-like Na\(^{+}\)/H\(^{+}\) exchanger in both root cortical and stelar tissues. Net Na\(^{+}\) efflux measured in isolated steles from salt-treated plants, using the non-invasive ion flux measuring MIFE technique, decreased in the sequence: Tamaroi (parental line)>Nax1=Nax2>Nax1:Nax2 lines. This efflux was sensitive to amiloride (a known inhibitor of the Na\(^{+}\)/H\(^{+}\) exchanger) and was mirrored by net H\(^{+}\) flux changes. TdSOS1 relative transcript levels were 6–10-fold lower in Nax lines compared with Tamaroi. Thus, it appears that Nax loci confer two highly complementary mechanisms, both of which contribute towards reducing the xylem Na\(^{+}\) content. One enhances the retrieval of Na\(^{+}\) back into the root stele via HKT1;4 or HKT1;5, whilst the other reduces the rate of Na\(^{+}\) loading into the xylem via SOS1. It is suggested that such duality plays an important adaptive role with greater versatility for responding to a changing environment and controlling Na\(^{+}\) delivery to the shoot.
KW - HKT transporter
KW - potassium
KW - salinity stress
KW - sequestration
KW - sodium
KW - xylem loading
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150236
VL - 67
IS - 3
ER -
TY - JOUR
A1 - Zhou, Sijie
A1 - Allison, Brendan Z.
A1 - Kübler, Andrea
A1 - Cichocki, Andrzej
A1 - Wang, Xingyu
A1 - Jin, Jing
T1 - Effects of Background Music on Objective and Subjective Performance Measures in an Auditory BCI
JF - Frontiers in Computational Neuroscience
N2 - Several studies have explored brain computer interface (BCI) systems based on auditory stimuli, which could help patients with visual impairments. Usability and user satisfaction are important considerations in any BCI. Although background music can influence emotion and performance in other task environments, and many users may wish to listen to music while using a BCI, auditory, and other BCIs are typically studied without background music. Some work has explored the possibility of using polyphonic music in auditory BCI systems. However, this approach requires users with good musical skills, and has not been explored in online experiments. Our hypothesis was that an auditory BCI with background music would be preferred by subjects over a similar BCI without background music, without any difference in BCI performance. We introduce a simple paradigm (which does not require musical skill) using percussion instrument sound stimuli and background music, and evaluated it in both offline and online experiments. The result showed that subjects preferred the auditory BCI with background music. Different performance measures did not reveal any significant performance effect when comparing background music vs. no background. Since the addition of background music does not impair BCI performance but is preferred by users, auditory (and perhaps other) BCIs should consider including it. Our study also indicates that auditory BCIs can be effective even if the auditory channel is simultaneously otherwise engaged.
KW - brain computer interface
KW - event-related potentials
KW - auditory
KW - music background
KW - audio stimulus
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165101
VL - 10
IS - 105
ER -
TY - JOUR
A1 - Zayats, T
A1 - Jacobsen, KK
A1 - Kleppe, R
A1 - Jacob, CP
A1 - Kittel-Schneider, S
A1 - Ribasés, M
A1 - Ramos-Quiroga, JA
A1 - Richarte, V
A1 - Casas, M
A1 - Mota, NR
A1 - Grevet, EH
A1 - Klein, M
A1 - Corominas, J
A1 - Bralten, J
A1 - Galesloot, T
A1 - Vasquez, AA
A1 - Herms, S
A1 - Forstner, AJ
A1 - Larsson, H
A1 - Breen, G
A1 - Asherson, P
A1 - Gross-Lesch, S
A1 - Lesch, KP
A1 - Cichon, S
A1 - Gabrielsen, MB
A1 - Holmen, OL
A1 - Bau, CHD
A1 - Buitelaar, J
A1 - Kiemeney, L
A1 - Faraone, SV
A1 - Cormand, B
A1 - Franke, B
A1 - Reif, A
A1 - Haavik, J
A1 - Johansson, S
T1 - Exome chip analyses in adult attention deficit hyperactivity disorder
JF - Translational Psychiatry
N2 - Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.
KW - chip analyses
KW - ADHD
KW - adulthood
KW - Illumina Human Exome Bead Chip
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168297
VL - 6
IS - e923
ER -
TY - JOUR
A1 - Zahnert, Thomas
A1 - Löwenheim, Hubert
A1 - Beutner, Dirk
A1 - Hagen, Rudolf
A1 - Ernst, Arneborg
A1 - Pau, Hans-Wilhelm
A1 - Zehlicke, Thorsten
A1 - Kühne, Hilke
A1 - Friese, Natascha
A1 - Tropitzsch, Anke
A1 - Lüers, Jan-Christoffer
A1 - Mlynski, Robert
A1 - Todt, Ingo
A1 - Hüttenbrink, Karl-Bernd
T1 - Multicenter Clinical Trial of Vibroplasty Couplers to Treat Mixed/Conductive Hearing Loss: First Results
JF - Audiology and Neurotology
N2 - Objective: To evaluate the safety and effectiveness of round window (RW), oval window (OW), CliP and Bell couplers for use with an active middle ear implant. Methods: This is a multicenter, long-term, prospective trial with consecutive enrollment, involving 6 university hospitals in Germany. Bone conduction, air conduction, implant-aided warble-tone thresholds and Freiburger monosyllable word recognition scores were compared with unaided preimplantation results in 28 moderate-to-profound hearing-impaired patients after 12 months of follow-up. All patients had previously undergone failed reconstruction surgeries (up to 5 or more). In a subset of patients, additional speech tests at 12 months postoperatively were used to compare the aided with the unaided condition after implantation with the processor switched off. An established quality-of-life questionnaire for hearing aids was used to determine patient satisfaction. Results: Postoperative bone conduction remained stable. Mean functional gain for all couplers was 37 dB HL (RW = 42 dB, OW = 35 dB, Bell = 38 dB, CliP = 27 dB). The mean postoperative Freiburger monosyllable score was 71% at 65 dB SPL. The postimplantation mean SRT50 (speech reception in quiet for 50% understanding of words in sentences) improved on average by 23 dB over unaided testing and signal-to-noise ratios also improved in all patients. The International Outcome Inventory for Hearing Aids (IOI-HA)quality-of-life questionnaire was scored very positively by all patients. Conclusion: A significant improvement was seen with all couplers, and patients were satisfied with the device at 12 months postoperatively. These results demonstrate that an active implant is an advantage in achieving good hearing benefit in patients with prior failed reconstruction surgery.
KW - conductive hearing loss
KW - mixed hearing loss
KW - vibroplasty
KW - couplers
KW - middle ear implant
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199129
SN - 1420-3030
SN - 1421-9700
N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL - 21
IS - 4
ER -
TY - JOUR
A1 - Yadav, Preeti
A1 - Selvaraj, Bhuvaneish T.
A1 - Bender, Florian L. P.
A1 - Behringer, Marcus
A1 - Moradi, Mehri
A1 - Sivadasan, Rajeeve
A1 - Dombert, Benjamin
A1 - Blum, Robert
A1 - Asan, Esther
A1 - Sauer, Markus
A1 - Julien, Jean-Pierre
A1 - Sendtner, Michael
T1 - Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
JF - Acta Neuropathologica
N2 - In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.
KW - Amyotrophic-lateral-sclerosis
KW - Transgenic mice
KW - Mouse model
KW - Alzheimers disease
KW - Neurofilament
KW - Progressive motor neuronopathy
KW - Axonal transport
KW - Intermediate filaments
KW - Motoneuron disease
KW - Lacking neurofilaments
KW - Missense mutation
KW - Axon degeneration
KW - Microtubules
KW - Stathmin
KW - Stat3
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188234
VL - 132
IS - 1
ER -
TY - THES
A1 - Yadav, Preeti
T1 - Studying Neuronal Cytoskeleton Defects and Synaptic Defects in Mouse Model of Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy
T1 - Die Analyse des neuronalen Zytoskeletts und synaptischer Defekte im Mausmodel der Amyotrophen Lateralsklerose und der Spinalen Muskelatrophie
N2 - Amyotrophic lateral sclerosis and spinal muscular atrophy are the two most common motoneuron diseases. Both are characterized by destabilization of axon terminals, axon degeneration and alterations in neuronal cytoskeleton. Accumulation of neurofilaments has been observed in several neurodegenerative diseases but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, I show that increased neurofilament expression in motor nerves of pmn mutant mice causes disturbed microtubule dynamics. Depletion of neurofilament by Nefl knockout increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Depletion of neurofilament increases stathmin-Stat3 interaction and stabilizes the microtubules. Consequently, the axonal maintenance is improved and the pmn mutant mice survive longer. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation is a prominent feature.
Next, using Smn-/-;SMN2 mouse as a model, the molecular mechanism behind synapse loss in SMA is studied. SMA is characterized by degeneration of lower α-motoneurons in spinal cord; however, how reduction of ubiquitously expressed SMN leads to MN-specific degeneration remains unclear. SMN is involved in pre-mRNA splicing (Pellizzoni, Kataoka et al. 1998) and its deficiency in SMA affects the splicing machinery. Neuromuscular junction denervation precedes neurodegeneration in SMA. However, there is no evidence of a link between aberrant splicing of transcripts downstream of Smn and reduced presynaptic axon excitability observed in SMA. In this study, we observed that expression and splicing of Nrxn2, that encodes a presynaptic protein is affected in the SMA mouse and that Nrxn2 could be a candidate that relates aberrant splicing to synaptic motoneuron defects in SMA.
N2 - Die Amyotrophe Lateralsklerose und die spinale Muskelatrophie sind die beiden häufigsten Formen der Motoneuronerkrankungen. Sie sind charakterisiert durch eine Destabilisierung der Axonendigungen, durch Axondegeneration und durch Änderungen im neuronalen Zytoskelett. Eine Anhäufung von Neurofilamenten konnte in einigen neurodegenerativen Erkrankungen beobachtet werden. Der genaue Mechanismus, welcher zu einer Destabilisierung des Axons führt, ist bis heute jedoch unklar. Hiermit zeige ich, dass eine gesteigerte Expression von Neurofilamenten in motorischen Nerven von pmn mutierten Mäusen zu einer Störung der Mikrotubuli – Dynamik führt. Ein Neurofilamentabbau durch Nefl knockout steigert die Anzahl an neu wachsenden Mikrotubuli in pmn mutierten Motoneuronen und führt zu erneutem Axonwachstum. Dieser Effekt wird durch eine Interaktion zwischen dem Neurofilament und dem Stathmin Komplex vermittelt. Ein Abbau des Neurofilaments führt zu einer Erhöhung der Stathmin-Stat3 Interaktion und zu einer Stabilisierung der Mikrotubuli. Demzufolge ist die Versorgung der Axone verbessert und die pmn mutierten Mäuse überleben länger. Wir vermuten, dass dieser Mechanismus auch für andere neurodegenerative Erkrankungen, bei denen Neurofilamentanhäufung ein dominantes Merkmal ist, relevant sein könnte.
Des Weiteren studierte ich mit Hilfe des Smn-/-;SMN2 Mausmodels, den molekularen Mechanismus der sich hinter dem Synapsenverlust bei SMA verbirgt. SMA ist charakterisiert durch eine Degeneration der unteren -Motoneuronen im Rückenmark. Es ist jedoch unklar, wie ein Verlust des ubiquitär exprimierten SMN Proteins zu einer MN-spezifischen Degeneration führt. Smn ist involviert in den Prozess des pre-mRNA Splicing (Pellizzoni, Kataoka et al. 1998) und ein Verlust des Proteins führt zu einer Störung des Splicing. Eine Denervierung der motorischen Endplatte führt zu einer Neurodegeneration in SMA. Es gibt jedoch keinen Hinweis auf eine kausale Verbindung zwischen anomalem Splicen von stromabwärts gelegenen Transkripten des Smn und einer Reduktion präsynaptischer Axone, wie man es bei SMA beobachten kann. In dieser Studie konnten wir beobachten, dass Expression und Splicing von Nrxn2, welches für ein präsynaptisches Protein kodiert, in SMA Mäusen betroffen ist und dass Nrxn2 ein Kandidat sein könnte, der eine Verbindung zwischen Störungen im Splice Prozess und synaptischen Motoneuron-Defekten in der SMA herstellen könnte.
KW - Neurofilament
KW - Neurofilament
KW - Zellskelett
KW - Spinale Muskelatrophie
KW - Cytoskeleton
KW - Spinal muscular Atrophy
KW - Pmn mutant mouse
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138093
ER -
TY - JOUR
A1 - Xu, Li
A1 - He, Jianzheng
A1 - Kaiser, Andrea
A1 - Gräber, Nikolas
A1 - Schläger, Laura
A1 - Ritze, Yvonne
A1 - Scholz, Henrike
T1 - A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila
JF - PLoS ONE
N2 - Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling—the serotonin transporter–in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.
KW - attraction
KW - ethanol
KW - Drosophila melanogaster
KW - serotonin transporter
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166762
VL - 11
IS - 12
ER -
TY - JOUR
A1 - Wölfling, Mirko
A1 - Becker, Mira C.
A1 - Uhl, Britta
A1 - Traub, Anja
A1 - Fiedler, Konrad
T1 - How differences in the settling behaviour of moths (Lepidoptera) may contribute to sampling bias when using automated light traps
JF - European Journal of Entomology
N2 - Quantitative community-wide moth surveys frequently employ flight-interception traps equipped with UV-light emitting sources as attractants. It has long been known that moth species differ in their responsiveness to light traps. We studied how the settling behaviour of moths at a light trap may further contribute to sampling bias. We observed the behaviour of 1426 moths at a light tower. Moths were classified as either, settling and remaining still after arrival, or continually moving on the gauze for extended periods of time. Moths that did not move after settling may not end up in the sampling container of the light trap and therefore are under-represented in automated trap samples relative to their true proportions in the community. Our analyses revealed highly significant behavioural differences between moths that differed in body size. Small moths were more likely to remain stationary after settling. As a corollary, representatives of three taxa, which in Europe are predominantly small species (Nolidae, Geometridae: Eupitheciini, Erebidae: Lithosiini), usually settled down immediately, whereas most other moths remained active on or flying around the trap for some time. Moth behaviour was also modulated by ambient temperature. At high temperatures, they were less likely to settle down immediately, but this behavioural difference was most strongly apparent among medium-sized moths. These results indicate the likely extent of the sampling bias when analysing and interpreting automated light-trap samples. Furthermore, to control for temperature modulated sampling bias temperature should always be recorded when sampling moths using flight-interception traps.
KW - Lepidoptera
KW - moths
KW - biodiversity assessment
KW - sampling method
KW - light-trapping
KW - sampling bias
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191154
VL - 113
ER -
TY - JOUR
A1 - Wächtler, Maria
A1 - Kübel, Joachim
A1 - Barthelmes, Kevin
A1 - Winter, Andreas
A1 - Schmiedel, Alexander
A1 - Pascher, Torbjörn
A1 - Lambert, Christoph
A1 - Schubert, Ulrich S.
A1 - Dietzek, Benjamin
T1 - Energy transfer and formation of long-lived \(^3\)MLCT states in multimetallic complexes with extended highly conjugated bis-terpyridyl ligands
JF - Physical Chemistry Chemical Physics
N2 - Multimetallic complexes with extended and highly conjugated bis-2,2':6',2''-terpyridyl bridging ligands, which present building blocks for coordination polymers, are investigated with respect to their ability to act as light-harvesting antennae. The investigated species combine Ru(II)- with Os(II)- and Fe(II)-terpyridyl chromophores, the latter acting as energy sinks. Due to the extended conjugated system the ligands are able to prolong the lifetime of the \(^3\)MLCT states compared to unsubstituted terpyridyl species by delocalization and energetic stabilization of the \(^3\)MLCT states. This concept is applied for the first time to Fe(II) terpyridyl species and results in an exceptionally long lifetime of 23 ps for the Fe(II) \(^3\)MLCT state. While partial energy (>80%) transfer is observed between the Ru(II) and Fe(II) centers with a time-constant of 15 ps, excitation energy is transferred completely from the Ru(II) to the Os(II) center within the first 200 fs after excitation.
KW - polypyridyl complexes
KW - bis-terpyridyl ligands
KW - multimetallic complexes
KW - metal-to-ligand charge transfer (MLCT)
KW - RU-(II) complexes
KW - Ru(II)–Fe(II)–Ru(II) complex
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191041
VL - 18
IS - 4
ER -
TY - JOUR
A1 - Wunsch, Marie
A1 - Hohmann, Christopher
A1 - Milles, Bianca
A1 - Rostermund, Christina
A1 - Lehmann, Paul V.
A1 - Schroeter, Michael
A1 - Bayas, Antonios
A1 - Ulzheimer, Jochen
A1 - Mäurer, Mathias
A1 - Ergün, Süleyman
A1 - Kuerten, Stefanie
T1 - The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis
JF - Viruses
N2 - There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.
KW - B cells
KW - CMV
KW - EBV
KW - ELISPOT
KW - MS
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146946
VL - 8
IS - 4
ER -
TY - JOUR
A1 - Wunsch, Kathrin
A1 - Pfister, Roland
A1 - Henning, Anne
A1 - Aschersleben, Gisa
A1 - Weigelt, Matthias
T1 - No Interrelation of Motor Planning and Executive Functions across Young Ages
JF - Frontiers in Psychology
N2 - The present study examined the developmental trajectories of motor planning and executive functioning in children. To this end, we tested 217 participants with three motor tasks, measuring anticipatory planning abilities (i.e., the bar-transport-task, the sword-rotation-task and the grasp-height-task), and three cognitive tasks, measuring executive functions (i.e., the Tower-of-Hanoi-task, the Mosaic-task, and the D2-attention-endurance-task). Children were aged between 3 and 10 years and were separated into age groups by 1-year bins, resulting in a total of eight groups of children and an additional group of adults. Results suggested (1) a positive developmental trajectory for each of the sub-tests, with better task performance as children get older; (2) that the performance in the separate tasks was not correlated across participants in the different age groups; and (3) that there was no relationship between performance in the motor tasks and in the cognitive tasks used in the present study when controlling for age. These results suggest that both, motor planning and executive functions are rather heterogeneous domains of cognitive functioning with fewer interdependencies than often suggested.
KW - anticipatory planning
KW - end-state comfort effect
KW - developmental disorders
KW - child development
KW - motor development
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165281
VL - 7
IS - 1031
ER -
TY - JOUR
A1 - Wolf, Karen
A1 - Braun, Attila
A1 - Haining, Elizabeth J.
A1 - Tseng, Yu-Lun
A1 - Kraft, Peter
A1 - Schuhmann, Michael K.
A1 - Gotru, Sanjeev K.
A1 - Chen, Wenchun
A1 - Hermanns, Heike M.
A1 - Stoll, Guido
A1 - Lesch, Klaus-Peter
A1 - Nieswandt, Bernhard
T1 - Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice
JF - PLoS One
N2 - Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.
Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.
Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.
Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
KW - platelets
KW - serotonin
KW - integrins
KW - blood flow
KW - collagens
KW - platelet activation
KW - platelet aggregation
KW - ischemic stroke
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146399
VL - 11
IS - 1
ER -
TY - JOUR
A1 - Wohlgemuth, Matthias
A1 - Mitric, Roland
T1 - Photochemical Chiral Symmetry Breaking in Alanine
JF - Journal of Physical Chemistry A
N2 - We introduce a general theoretical approach for the simulation of photochemical dynamics under the influence of circularly polarized light to explore the possibility of generating enantiomeric enrichment through polarized-light-selective photochemistry. The method is applied to the simulation of the photolysis of alanine, a prototype chiral amino acid. We show that a systematic enantiomeric enrichment can be obtained depending on the helicity of the circularly polarized light that induces the excited-state photochemistry of alanine. By analyzing the patterns of the photoinduced fragmentation of alanine we find an inducible enantiomeric enrichment up to 1.7%, which is also in good correspondence to the experimental findings. Our method is generally applicable to complex systems and might serve to systematically explore the photochemical origin of homochirality.
KW - circularly-polarized light
KW - amino-acids
KW - homochirality
KW - molecular dynamics
KW - dichroism
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158557
UR - https://pubs.acs.org/doi/10.1021/acs.jpca.6b07611
N1 - This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Physical Chemistry A, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jpca.6b07611
VL - 45
IS - 120
ER -
TY - JOUR
A1 - Wittmann, Katharina
A1 - Sieber, Cornel
A1 - von Stengel, Simon
A1 - Kohl, Matthias
A1 - Freiberger, Ellen
A1 - Jakob, Franz
A1 - Lell, Michael
A1 - Engelke, Klaus
A1 - Kemmler, Wolfgang
T1 - Impact of whole body electromyostimulation on cardiometabolic risk factors in older women with sarcopenic obesity: the randomized controlled FORMOsA-sarcopenic obesity study
JF - Clinical Interventions in Aging
N2 - Background:
Sarcopenic obesity (SO) is characterized by a combination of low muscle and high fat mass with an additive negative effect of both conditions on cardiometabolic risk. The aim of the study was to determine the effect of whole-body electromyostimulation (WB-EMS) on the metabolic syndrome (MetS) in community-dwelling women aged ≥70 years with SO.
Methods:
The study was conducted in an ambulatory university setting. Seventy-five community-dwelling women aged ≥70 years with SO living in Northern Bavaria, Germany, were randomly allocated to either 6 months of WB-EMS application with (WB-EMS&P) or without (WB-EMS) dietary supplementation (150 kcal/day, 56% protein) or a non-training control group (CG). WB-EMS included one session of 20 min (85 Hz, 350 µs, 4 s of strain–4 s of rest) per week with moderate-to-high intensity. The primary study endpoint was the MetS Z-score with the components waist circumference (WC), mean arterial pressure (MAP), triglycerides, fasting plasma glucose, and high-density lipoprotein cholesterol (HDL-C); secondary study endpoints were changes in these determining variables.
Results:
MetS Z-score decreased in both groups; however, changes compared with the CG were significant (P=0.001) in the WB-EMS&P group only. On analyzing the components of the MetS, significant positive effects for both WB-EMS groups (P≤0.038) were identified for MAP, while the WB-EMS group significantly differed for WC (P=0.036), and the WB-EMS&P group significantly differed for HDL-C (P=0.006) from the CG. No significant differences were observed between the WB-EMS groups.
Conclusion:
The study clearly confirms the favorable effect of WB-EMS application on the MetS in community-dwelling women aged ≥70 years with SO. However, protein-enriched supplements did not increase effects of WB-EMS alone. In summary, we considered this novel technology an effective and safe method to prevent cardiometabolic risk factors and diseases in older women unable or unwilling to exercise conventionally.
KW - sarcopenia
KW - obesity
KW - whole-body electromyostimulation
KW - cardiovascular
KW - metabolic risk
KW - metabolic syndrome
KW - community-dwelling
KW - older people
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164930
VL - 11
ER -
TY - JOUR
A1 - Wilhelm, M.
A1 - Smetak, M.
A1 - Reimer, P.
A1 - Geissinger, E.
A1 - Ruediger, T.
A1 - Metzner, B.
A1 - Schmitz, N.
A1 - Engert, A.
A1 - Schaefer-Eckart, K.
A1 - Birkmann, J.
T1 - First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation
JF - Blood Cancer Journal
N2 - Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified (n=42) and angioimmunoblastic T-cell lymphoma (n=37). Seventy-five (68%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the complete response rate after myeloablative therapy was 59%. The estimated 5-year overall survival, disease-free survival and progression-free survival rates were 44%, 54% and 39%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible.
KW - Chemotherapy
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164506
VL - 6
ER -
TY - JOUR
A1 - Wildgruber, Moritz
A1 - Aschenbrenner, Teresa
A1 - Wendorff, Heiko
A1 - Czubba, Maria
A1 - Glinzer, Almut
A1 - Haller, Bernhard
A1 - Schiemann, Matthias
A1 - Zimmermann, Alexander
A1 - Berger, Hermann
A1 - Eckstein, Hans-Henning
A1 - Meier, Reinhard
A1 - Wohlgemuth, Walter A.
A1 - Libby, Peter
A1 - Zernecke, Alma
T1 - The "Intermediate" CD14\(^{++}\)CD16\(^{+}\) monocyte subset increases in severe peripheral artery disease in humans
JF - Scientific Reports
N2 - Monocytes are key players in atherosclerotic. Human monocytes display a considerable heterogeneity and at least three subsets can be distinguished. While the role of monocyte subset heterogeneity has already been well investigated in coronary artery disease (CAD), the knowledge about monocytes and their heterogeneity in peripheral artery occlusive disease (PAOD) still is limited. Therefore, we aimed to investigate monocyte subset heterogeneity in patients with PAOD. Peripheral blood was obtained from 143 patients suffering from PAOD (Rutherford stage I to VI) and three monocyte subsets were identified by flow cytometry: CD14\(^{++}\)CD16\(^{-}\) classical monocytes, CD14\(^{+}\)CD16\(^{++}\) non-classical monocytes and CD14\(^{++}\)CD16\(^{+}\) intermediate monocytes. Additionally the expression of distinct surface markers (CD106, CD162 and myeloperoxidase MPO) was analyzed. Proportions of CD14\(^{++}\)CD16\(^{+}\) intermediate monocyte levels were significantly increased in advanced stages of PAOD, while classical and non-classical monocytes displayed no such trend. Moreover, CD162 and MPO expression increased significantly in intermediate monocyte subsets in advanced disease stages. Likewise, increased CD162 and MPO expression was noted in CD14\(^{++}\)CD16\(^{-}\) classical monocytes. These data suggest substantial dynamics in monocyte subset distributions and phenotypes in different stages of PAOD, which can either serve as biomarkers or as potential therapeutic targets to decrease the inflammatory burden in advanced stages of atherosclerosis.
KW - peripheral artery occlusive disease
KW - monocyte subset
KW - humans
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167476
VL - 6
IS - 39483
ER -
TY - JOUR
A1 - Wieser, Matthias J.
A1 - Reicherts, Philipp
A1 - Juravle, Georgiana
A1 - von Leupoldt, Andreas
T1 - Attention mechanisms during predictable and unpredictable threat - a steady-state visual evoked potential approach
JF - NeuroImage
N2 - Fear is elicited by imminent threat and leads to phasic fear responses with selective attention, whereas anxiety is characterized by a sustained state of heightened vigilance due to uncertain danger. In the present study, we investigated attention mechanisms in fear and anxiety by adapting the NPU-threat test to measure steady-state visual evoked potentials (ssVEPs). We investigated ssVEPs across no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U), signaled by four-object arrays (30 s). In addition, central cues were presented during all conditions but predictably signaled imminent threat only during the P condition. Importantly, cues and context events were flickered at different frequencies (15 Hz vs. 20 Hz) in order to disentangle respective electrocortical responses. The onset of the context elicited larger electrocortical responses for U compared to P context. Conversely, P cues elicited larger electrocortical responses compared to N cues. Interestingly, during the presence of the P cue, visuocortical processing of the concurrent context was also enhanced. The results support the notion of enhanced initial hypervigilance to unpredictable compared to predictable threat contexts, while predictable cues show electrocortical enhancement of the cues themselves but additionally a boost of context processing.
KW - Event-related potential
KW - Contextual fear
KW - Conditioning evidence
KW - Sustained attention
KW - Selective attention
KW - Aversive events
KW - Time-course
KW - Virtual-reality
KW - Anxiety
KW - Humans
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187365
VL - 139
ER -
TY - JOUR
A1 - Wiedenmann, J.
A1 - Bocquillon, E.
A1 - Deacon, R.S.
A1 - Hartinger, S.
A1 - Herrmann, O.
A1 - Klapwijk, T.M.
A1 - Maier, L.
A1 - Ames, C.
A1 - Brüne, C.
A1 - Gould, C.
A1 - Oiwa, A.
A1 - Ishibashi, K.
A1 - Tarucha, S.
A1 - Buhmann, H.
A1 - Molenkamp, L.W.
T1 - 4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions
JF - Nature Communications
N2 - The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.
KW - Josephson effect
KW - supercurrent
KW - superconductors
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175353
VL - 7
ER -
TY - THES
A1 - Wiebusch, Dennis
T1 - Reusability for Intelligent Realtime Interactive Systems
T1 - Wiederverwendbarkeit für Intelligente Echtzeit-interaktive Systeme
N2 - Software frameworks for Realtime Interactive Systems (RIS), e.g., in the areas of Virtual, Augmented, and Mixed Reality (VR, AR, and MR) or computer games, facilitate a multitude of functionalities by coupling diverse software modules. In this context, no uniform methodology for coupling these modules does exist; instead various purpose-built solutions have been proposed. As a consequence, important software qualities, such as maintainability, reusability, and adaptability, are impeded.
Many modern systems provide additional support for the integration of Artificial Intelligence (AI) methods to create so called intelligent virtual environments. These methods exacerbate the above-mentioned problem of coupling software modules in the thus created Intelligent Realtime Interactive Systems (IRIS) even more. This, on the one hand, is due to the commonly applied specialized data structures and asynchronous execution schemes, and the requirement for high consistency regarding content-wise coupled but functionally decoupled forms of data representation on the other.
This work proposes an approach to decoupling software modules in IRIS, which is based on the abstraction of architecture elements using a semantic Knowledge Representation Layer (KRL). The layer facilitates decoupling the required modules, provides a means for ensuring interface compatibility and consistency, and in the end constitutes an interface for symbolic AI methods.
N2 - Software Frameworks zur Entwicklung Echtzeit-interaktiver Systeme (engl. Realtime Interactive Systems, RIS), z.B. mit Anwendungen in der Virtual, Augmented und Mixed Reality (VR, AR und MR) sowie in Computerspielen, integrieren vielfältige Funktionalitäten durch die Kopplung verschiedener Softwaremodule. Eine einheitliche Methodik einer Kopplung in diesen Systemen besteht dabei nicht, stattdessen existieren mannigfaltige individuelle Lösungen. Als Resultat sinken wichtige Softwarequalitätsfaktoren wie Wartbarkeit, Wiederverwendbarkeit und Anpassbarkeit.
Viele moderne Systeme setzen zusätzlich unterschiedliche Methoden der Künstlichen Intelligenz (KI) ein, um so intelligente virtuelle Umgebungen zu generieren. Diese KI-Methoden verschärfen in solchen Intelligenten Echtzeit-interaktiven Systemen (engl. Intelligent Realtime Interactive Systems, IRIS) das eingangs genannte Kopplungsproblem signifikant durch ihre spezialisierten Datenstrukturen und häufig asynchronen Prozessflüssen bei gleichzeitig hohen Konsistenzanforderungen bzgl. inhaltlich assoziierter, aber funktional entkoppelter Datenrepräsentationen in anderen Modulen.
Die vorliegende Arbeit beschreibt einen Lösungsansatz für das Entkopplungsproblem mittels Abstraktion maßgeblicher Softwarearchitekturelemente basierend auf einer erweiterbaren semantischen Wissensrepräsentationsschicht. Diese semantische Abstraktionsschicht erlaubt die Entkopplung benötigter Module, ermöglicht eine automatische Überprüfung von Schnittstellenkompatibiltät und Konsistenz und stellt darüber hinaus eine generische Schnittstelle zu symbolischen KI-Methoden bereit.
KW - Virtuelle Realität
KW - Ontologie
KW - Wissensrepräsentation
KW - Echtzeitsystem
KW - Framework
KW - Intelligent Realtime Interactive System
KW - Virtual Reality
KW - Knowledge Representation Layer
KW - Intelligent Virtual Environment
KW - Semantic Entity Model
KW - Erweiterte Realität
KW - Softwarewiederverwendung
KW - Modul
KW - Software Engineering
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121869
SN - 978-3-95826-040-5 (print)
SN - 978-3-95826-041-2 (online)
N1 - Parallel erschienen als Druckausg. in Würzburg University Press, ISBN 978-3-95826-040-5, 34,90 EUR
PB - Würzburg University Press
CY - Würzburg
ER -
TY - JOUR
A1 - Widmann, Annekathrin
A1 - Artinger, Marc
A1 - Biesinger, Lukas
A1 - Boepple, Kathrin
A1 - Peters, Christina
A1 - Schlechter, Jana
A1 - Selcho, Mareike
A1 - Thum, Andreas S.
T1 - Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae
JF - PLoS Genetics
N2 - Memory formation is a highly complex and dynamic process. It consists of different phases, which depend on various neuronal and molecular mechanisms. In adult Drosophila it was shown that memory formation after aversive Pavlovian conditioning includes—besides other forms—a labile short-term component that consolidates within hours to a longer-lasting memory. Accordingly, memory formation requires the timely controlled action of different neuronal circuits, neurotransmitters, neuromodulators and molecules that were initially identified by classical forward genetic approaches. Compared to adult Drosophila, memory formation was only sporadically analyzed at its larval stage. Here we deconstruct the larval mnemonic organization after aversive olfactory conditioning. We show that after odor-high salt conditioning larvae form two parallel memory phases; a short lasting component that depends on cyclic adenosine 3’5’-monophosphate (cAMP) signaling and synapsin gene function. In addition, we show for the first time for Drosophila larvae an anesthesia resistant component, which relies on radish and bruchpilot gene function, protein kinase C activity, requires presynaptic output of mushroom body Kenyon cells and dopamine function. Given the numerical simplicity of the larval nervous system this work offers a unique prospect for studying memory formation of defined specifications, at full-brain scope with single-cell, and single-synapse resolution.
KW - genetic dissection
KW - Drosophila
KW - memory formation
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166672
VL - 12
IS - 10
ER -
TY - JOUR
A1 - White, P. Lewis
A1 - Wiederhold, Nathan P.
A1 - Loeffler, Juergen
A1 - Najvar, Laura K.
A1 - Melchers, Willem
A1 - Herrera, Monica
A1 - Bretagne, Stephane
A1 - Wickes, Brian
A1 - Kirkpatrick, William R.
A1 - Barnes, Rosemary A.
A1 - Donnelly, J. Peter
A1 - Patterson, Thomas F.
T1 - Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model
JF - Journal of Clinical Microbiology
N2 - The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.
KW - high-risk hematology
KW - Guinea pig model
KW - real-time PCR
KW - fungal disease
KW - galactomannan
KW - pulmonary aspergillosis
KW - amphotericin B
KW - Aspergillus fumigatus
KW - beta-D-glucan
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189674
VL - 54
IS - 4
ER -
TY - JOUR
A1 - Wheeler, Nicole E.
A1 - Barquist, Lars
A1 - Kingsley, Robert A.
A1 - Gardner, Paul P.
T1 - A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes
JF - Bioinformatics
N2 - Motivation:
Next generation sequencing technologies have provided us with a wealth of information on genetic variation, but predi cting the functional significance of this variation is a difficult task. While many comparative genomics studies have focused on gene flux and large scale changes, relatively little attention has been paid to quantifying the effects of single nucleotide polymorphisms and indels on protein function, particularly in bacterial genomics.
Results:
We present a hidden Markov model based approach we call delta-bitscore (DBS) for identifying orthologous proteins that have diverged at the amino acid sequence level in a way that is likely to impact biological function. We benchmark this approach with several widely used datasets and apply it to a proof-of-concept study of orthologous proteomes in an investigation of host adaptation in Salmonella enterica. We highlight the value of the method in identifying functional divergence of genes, and suggest that this tool may be a better approach than the commonly used dN/dS metric for identifying functionally significant genetic changes occurring in recently diverged organisms.
KW - Host adaptation
KW - Salmonella-enteritidis
KW - Sequence identity
KW - Rapid evolution
KW - Variants
KW - Cystic-fibriosis
KW - Strains
KW - Pathogenicity
KW - Typhimurium
KW - Yersinia
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186502
VL - 32
IS - 23
ER -
TY - JOUR
A1 - Westermaier, Thomas
A1 - Linsenmann, Thomas
A1 - Homola, György A.
A1 - Loehr, Mario
A1 - Stetter, Christian
A1 - Willner, Nadine
A1 - Ernestus, Ralf-Ingo
A1 - Soymosi, Laszlo
A1 - Vince, Giles H.
T1 - 3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms – assessment of feasibility and image quality
JF - BMC Medical Imaging
N2 - Background
Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms.
Materials and methods
Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency.
Results
Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants.
Conclusion
This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality.
KW - aneurysm surgery
KW - clip control
KW - angiography
KW - 3D fluoroscopy
KW - image quality
KW - intraoperative
KW - vessel patency
KW - contrast
KW - post-processing
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146381
VL - 16
IS - 30
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Beykan, Seval
A1 - Higuchi, Takahiro
A1 - Lückerath, Katharina
A1 - Weich, Alexander
A1 - Scheurlen, Michael
A1 - Bluemel, Christina
A1 - Herrmann, Ken
A1 - Buck, Andreas K.
A1 - Lassmann, Michael
A1 - Lapa, Constantin
A1 - Hänscheid, Heribert
T1 - The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy
JF - Oncotarget
N2 - Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.
KW - renal scintigraphy
KW - neuroendocrine tumor
KW - 177Lu
KW - MAG3
KW - PRRT
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177318
VL - 7
IS - 27
ER -
TY - JOUR
A1 - Werner, R. A.
A1 - Lückerath, K.
A1 - Schmid, J. S.
A1 - Higuchi, T.
A1 - Kreissl, M. C.
A1 - Grelle, I.
A1 - Reiners, C.
A1 - Buck, A. K.
A1 - Lapa, C.
T1 - Thyroglobulin fluctuations in patients with iodine-refractory differentiated thyroid carcinoma on lenvatinib treatment – initial experience
JF - Scientific Reports
N2 - Tyrosine kinase inhibitors (TKI) have shown clinical effectiveness in iodine-refractory differentiated thyroid cancer (DTC). The corresponding role of serum thyroglobulin (Tg) in iodine-refractory DTC has not been investigated yet. 9 patients (3 female, 61 ± 8y) with progressive iodine-refractory DTC starting on lenvatinib were considered. Tumor restaging was performed every 2–3 months including contrast-enhanced computed tomography (CT, RECIST 1.1). Serum Tg was measured and compared to imaging findings. After treatment initiation, serum Tg levels dropped in all patients with a median reduction of 86.2%. During long-term follow-up (median, 25.2 months), fluctuations in Tg could be observed in 8/9 subjects. According to RECIST, 6/9 subjects achieved a partial response or stable disease with the remaining 3/9 experiencing progressive disease (2/3 with Tg levels rising above baseline). All of the patients with disease progression presented with a preceding continuous rise in serum Tg, whereas tumor marker oscillations in the subjects with controlled disease were only intermittent. Initiation of lenvatinib in iodine-refractory DTC patients is associated with a significant reduction in serum Tg levels as a marker of treatment response. In the course of treatment, transient Tg oscillations are a frequent phenomenon that may not necessarily reflect morphologic tumor progression.
KW - Thyroid cancer
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147407
VL - 6
ER -
TY - JOUR
A1 - Werner, Franziska
A1 - Kojonazarov, Baktybek
A1 - Gaßner, Birgit
A1 - Abeßer, Marco
A1 - Schuh, Kai
A1 - Völker, Katharina
A1 - Baba, Hideo A.
A1 - Dahal, Bhola K.
A1 - Schermuly, Ralph T.
A1 - Kuhn, Michaela
T1 - Endothelial actions of atrial natriuretic peptide prevent pulmonary hypertension in mice
JF - Basic Research in Cardiology
N2 - The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT(1)-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.
KW - Atrial natriuretic peptide
KW - Endothelium
KW - Guanylyl cyclase-A
KW - Cyclic GMP
KW - Pulmonary hypertension
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190664
VL - 111
IS - 2
ER -
TY - JOUR
A1 - Wente, Sarah
A1 - Schröder, Simone
A1 - Buckard, Johannes
A1 - Büttel, Hans-Martin
A1 - von Deimling, Florian
A1 - Diener, Wilfried
A1 - Häussler, Martin
A1 - Hübschle, Susanne
A1 - Kinder, Silvia
A1 - Kurlemann, Gerhard
A1 - Kretzschmar, Christoph
A1 - Lingen, Michael
A1 - Maroske, Wiebke
A1 - Mundt, Dirk
A1 - Sánchez-Albisua, Iciar
A1 - Seeger, Jürgen
A1 - Toelle, Sandra P.
A1 - Boltshauser, Eugen
A1 - Brockmann, Knut
T1 - Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study
JF - Orphanet Journal of Rare Diseases
N2 - Background
The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom.
Methods
We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA.
Results
Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups.
Conclusions
Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.
KW - congenital ocular motor apraxia
KW - molar tooth sign
KW - Joubert syndrome
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166534
VL - 11
IS - 104
ER -
TY - JOUR
A1 - Weisschuh, Nicole
A1 - Mayer, Anja K.
A1 - Strom, Tim M.
A1 - Kohl, Susanne
A1 - Glöckle, Nicola
A1 - Schubach, Max
A1 - Andreasson, Sten
A1 - Bernd, Antje
A1 - Birch, David G.
A1 - Hamel, Christian P.
A1 - Heckenlively, John R.
A1 - Jacobson, Samuel G.
A1 - Kamme, Christina
A1 - Kellner, Ulrich
A1 - Kunstmann, Erdmute
A1 - Maffei, Pietro
A1 - Reiff, Charlotte M.
A1 - Rohrschneider, Klaus
A1 - Rosenberg, Thomas
A1 - Rudolph, Günther
A1 - Vámos, Rita
A1 - Varsányi, Balázs
A1 - Weleber, Richard G.
A1 - Wissinger, Bernd
T1 - Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing
JF - PLoS ONE
N2 - Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.
KW - mutation detection
KW - retinal dystrophies
KW - next generation sequencing
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167398
VL - 11
IS - 1
ER -
TY - JOUR
A1 - Weismann, Dirk
A1 - Schneider, Andreas
A1 - Höybye, Charlotte
T1 - Clinical aspects of symptomatic hyponatremia
JF - Endocrine Connections
N2 - Hyponatremia (HN) is a common condition, with a large number of etiologies and a complicated treatment. Although chronic HN has been shown to be a predictor of poor outcome, sodium-increasing treatments in chronic stable and asymptomatic HN have not proven to increase life expectancy. For symptomatic HN, in contrast, the necessity for urgent treatment has broadly been accepted to avoid the development of fatal cerebral edema. On the other hand, a too rapid increase of serum sodium in chronic HN may result in cerebral damage due to osmotic demyelinisation. Recently, administration of hypertonic saline bolus has been recommended as first-line treatment in patients with moderate-to-severe symptomatic HN. This approach is easy to memorize and holds the potential to greatly facilitate the initial treatment of symptomatic HN. First-line treatment of chronic HN is fluid restriction and if ineffective treatment with tolvaptan or in some patients other agents should be considered. A number of recommendations and guidelines have been published on HN. In the present review, the management of patients with HN in relation to everyday clinical practice is summarized with focus on the acute management.
KW - hyponatremia
KW - clinical
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162936
VL - 5
IS - 5
ER -
TY - JOUR
A1 - Weigand, Annika
A1 - Boos, Anja M.
A1 - Tasbihi, Kereshmeh
A1 - Beier, Justus P.
A1 - Dalton, Paul D.
A1 - Schrauder, Michael
A1 - Horch, Raymund E.
A1 - Beckmann, Matthias W.
A1 - Strissel, Pamela L.
A1 - Strick, Reiner
T1 - Selective isolation and characterization of primary cells from normal breast and tumors reveal plasticity of adipose derived stem cells
JF - Breast Cancer Research
N2 - Background
There is a need to establish more cell lines from breast tumors in contrast to immortalized cell lines from metastatic effusions in order to represent the primary tumor and not principally metastatic biology of breast cancer. This investigation describes the simultaneous isolation, characterization, growth and function of primary mammary epithelial cells (MEC), mesenchymal cells (MES) and adipose derived stem cells (ADSC) from four normal breasts, one inflammatory and one triple-negative ductal breast tumors.
Methods
A total of 17 cell lines were established and gene expression was analyzed for MEC and MES (n = 42) and ADSC (n = 48) and MUC1, pan-KRT, CD90 and GATA-3 by immunofluorescence. DNA fingerprinting to track cell line identity was performed between original primary tissues and isolates. Functional studies included ADSC differentiation, tumor MES and MEC invasion co-cultured with ADSC-conditioned media (CM) and MES adhesion and growth on 3D-printed scaffolds.
Results
Comparative analysis showed higher gene expression of EPCAM, CD49f, CDH1 and KRTs for normal MEC lines; MES lines e.g. Vimentin, CD10, ACTA2 and MMP9; and ADSC lines e.g. CD105, CD90, CDH2 and CDH11. Compared to the mean of all four normal breast cell lines, both breast tumor cell lines demonstrated significantly lower ADSC marker gene expression, but higher expression of mesenchymal and invasion gene markers like SNAI1 and MMP2. When compared with four normal ADSC differentiated lineages, both tumor ADSC showed impaired osteogenic and chondrogenic but enhanced adipogenic differentiation and endothelial-like structures, possibly due to high PDGFRB and CD34. Addressing a functional role for overproduction of adipocytes, we initiated 3D-invasion studies including different cell types from the same patient. CM from ADSC differentiating into adipocytes induced tumor MEC 3D-invasion via EMT and amoeboid phenotypes. Normal MES breast cells adhered and proliferated on 3D-printed scaffolds containing 20 fibers, but not on 2.5D-printed scaffolds with single fiber layers, important for tissue engineering.
Conclusion
Expression analyses confirmed successful simultaneous cell isolations of three different phenotypes from normal and tumor primary breast tissues. Our cell culture studies support that breast-tumor environment differentially regulates tumor ADSC plasticity as well as cell invasion and demonstrates applications for regenerative medicine.
KW - Normal breast
KW - Breast cancer
KW - Stem cells plasticity
KW - Primary cell lines
KW - Tissue engineering
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164759
VL - 18
IS - 32
ER -
TY - JOUR
A1 - Weidner, Christopher
A1 - Rousseau, Morten
A1 - Plauth, Annabell
A1 - Wowro, Sylvia J.
A1 - Fischer, Cornelius
A1 - Abdel-Aziz, Heba
A1 - Sauer, Sascha
T1 - Iberis amara Extract Induces Intracellular Formation of Reactive Oxygen Species and Inhibits Colon Cancer
JF - PLoS ONE
N2 - Massively increasing global incidences of colorectal cancer require efficient treatment and prevention strategies. Here, we report unexpected anticancerogenic effects of hydroethanolic Iberis amara extract (IAE), which is known as a widely used phytomedical product for treating gastrointestinal complaints. IAE significantly inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC\(_{50}\)) of 6 and 9 μg/ml, respectively, and further generated inhibitory effects in PC-3 prostate and MCF7 breast cancer cells. Inhibition of proliferation in HT-29 cells was associated with a G2/M phase cell cycle arrest including reduced expression of various regulatory marker proteins. Notably, in HT-29 cells IAE further induced apoptosis by intracellular formation of reactive oxygen species (ROS). Consistent with predictions derived from our in vitro experiments, bidaily oral gavage of 50 mg/kg of IAE over 4 weeks resulted in significant inhibition of tumor growth in a mouse HT-29 tumor xenograft model. Taken together, Iberis amara extracts could become useful alternatives for preventing and treating the progression of colon cancer.
KW - iberis amara extract
KW - colorectal cancer
KW - treatment
KW - prevention
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167044
VL - 11
IS - 4
ER -
TY - JOUR
A1 - Weidemann, Frank
A1 - Maier, Sebastian K. G.
A1 - Störk, Stefan
A1 - Brunner, Thomas
A1 - Liu, Dan
A1 - Hu, Kai
A1 - Seydelmann, Nora
A1 - Schneider, Andreas
A1 - Becher, Jan
A1 - Canan-Kühl, Sima
A1 - Blaschke, Daniela
A1 - Bijnens, Bart
A1 - Ertl, Georg
A1 - Wanner, Christoph
A1 - Nordbeck, Peter
T1 - Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy
JF - The American Journal of Cardiology
N2 - Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.
KW - Cardiovascular magnetic-resonance
KW - Coronary artery disease
KW - Ventricular-arrhythmias
KW - Task force
KW - Management
KW - Enzyme replacement therapy
KW - Hypertrophic cardiomyopathy
KW - Myocardial fibrosis
KW - Guidelines
KW - Manifestation
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188093
VL - 118
IS - 2
ER -
TY - THES
A1 - Weber, Stefan
T1 - Simulation Studies on the New Small Wheel Shielding of the ATLAS Experiment and Design and Construction of a Test Facility for Gaseous Detectors
T1 - Simulationsstudien zur New Small Wheel Abschirmung des ATLAS Experiments und Entwurf und Konstruktion eines Teststandes für Gasdetektoren
N2 - In this thesis two main projects are presented, both aiming at the overall goal
of particle detector development. In the first part of the thesis detailed shielding
studies are discussed, focused on the shielding section of the planned New Small
Wheel as part of the ATLAS detector upgrade. Those studies supported the discussions
within the upgrade community and decisions made on the final design of
the New Small Wheel. The second part of the thesis covers the design, construction
and functional demonstration of a test facility for gaseous detectors at the
University of Würzburg. Additional studies on the trigger system of the facility are
presented. Especially the precision and reliability of reference timing signals were
investigated.
N2 - In dieser Arbeit werden zwei Projekte vorgestellt, welche beide das gemeinsame
Ziel der Entwicklung von Teilchendetektoren verfolgen. Im ersten Teil der Arbeit
werden ausführliche Simulationsstudien zur Abschirmung behandelt, die sich auf
die Abschirmungsbereiche des geplanten New Small Wheels als Teil der ATLAS-Detektor
Verbesserungen konzentrieren. Diese Studien unterstützten die Diskussionen
innerhalb der Upgrade-Gemeinschaft und Entscheidungen, welche für die
endgültige Kostruktionsplanung des New Small Wheels getroffen wurden. Der
zweite Teil der Arbeit umfasst die Konstruktion, den Aufbau sowie den Funktionsnachweis
eines Teststandes für Gasdetektoren an der Universität Würzburg.
Ebenfalls werden Studien über das Triggersystems des Teststandes dargestellt. Insbesondere
wurden die Präzision und Verlässlichkeit von Referenzzeitsignalen untersucht.
KW - Teilchendetektor
KW - Abschirmung
KW - Simulation
KW - test facility
KW - New Small Wheel
KW - Teststand
KW - Gasionisationsdetektor
KW - European Organization for Nuclear Research. ATLAS Collaboration
KW - Computersimulation
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133084
ER -
TY - JOUR
A1 - Wawra, Stephan
A1 - Fesel, Philipp
A1 - Widmer, Heidi
A1 - Timm, Malte
A1 - Seibel, Jürgen
A1 - Leson, Lisa
A1 - Kesseler, Leona
A1 - Nostadt, Robin
A1 - Hilbert, Magdalena
A1 - Langen, Gregor
A1 - Zuccaro, Alga
T1 - The fungal-specific beta-glucan-binding lectin FGB1 alters cell-wall composition and suppresses glucan-triggered immunity in plants
JF - Nature Communications
N2 - β-glucans are well-known modulators of the immune system in mammals but little is known about β-glucan triggered immunity in planta. Here we show by isothermal titration calorimetry, circular dichroism spectroscopy and nuclear magnetic resonance spectroscopy that the FGB1 gene from the root endophyte Piriformospora indica encodes for a secreted fungal-specific β-glucan-binding lectin with dual function. This lectin has the potential to both alter fungal cell wall composition and properties, and to efficiently suppress β-glucan-triggered immunity in different plant hosts, such as Arabidopsis, barley and Nicotiana benthamiana. Our results hint at the existence of fungal effectors that deregulate innate sensing of β-glucan in plants.
KW - Effectors in plant pathology
KW - Fungal host response
KW - Lectins
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165945
VL - 7
ER -
TY - THES
A1 - Wanzek, Katharina
T1 - The investigation of the function of repair proteins at G-quadruplex structures in \(Saccharomyces\) \(cerevisiae\) revealed that Mms1 promotes genome stability
T1 - Die Untersuchung der Funktion von Reparaturproteinen an G-Quadruplex Strukturen in \(Saccharomyces\) \(cerevisiae\) zeigte, dass Mms1 Genomstabilität fördert
N2 - G-quadruplex structures are highly stable alternative DNA structures that can, when not properly regulated, impede replication fork progression and cause genome instability (Castillo Bosch et al, 2014; Crabbe et al, 2004; Koole et al, 2014; Kruisselbrink et al, 2008; London et al, 2008; Lopes et al, 2011; Paeschke et al, 2013; Paeschke et al, 2011; Piazza et al, 2015; Piazza et al, 2010; Piazza et al, 2012; Ribeyre et al, 2009; Sabouri et al, 2014; Sarkies et al, 2012; Sarkies et al, 2010; Schiavone et al, 2014; Wu & Spies, 2016; Zimmer et al, 2016). The aim of this thesis was to identify novel G-quadruplex interacting proteins in Saccharomyces cerevisiae and to unravel their regulatory function at these structures to maintain genome integrity. Mms1 and Rtt101 were identified as G-quadruplex binding proteins in vitro via a pull-down experiment with subsequent mass spectrometry analysis. Rtt101, Mms1 and Mms22, which are all components of an ubiquitin ligase (Rtt101Mms1/Mms22), are important for the progression of the replication fork following fork stalling (Luke et al, 2006; Vaisica et al, 2011; Zaidi et al, 2008). The in vivo binding of endogenously tagged Mms1 to its target regions was analyzed genome-wide using chromatin-immunoprecipitation followed by deep-sequencing. Interestingly, Mms1 bound independently of Mms22 and Rtt101 to G-rich regions that have the potential to form G-quadruplex structures. In vitro, formation of G-quadruplex structures could be shown for the G-rich regions Mms1 bound to. This binding was observed throughout the cell cycle. Furthermore, the deletion of MMS1 caused replication fork stalling as evidenced by increased association of DNA Polymerase 2 at Mms1 dependent sites. A gross chromosomal rearrangement assay revealed that deletion of MMS1 results in a significantly increased genome instability at G-quadruplex motifs compared to G-rich or non-G-rich regions. Additionally, binding of the helicase Pif1, which unwinds G4 structures in vitro (Paeschke et al, 2013; Ribeyre et al, 2009; Sanders, 2010; Wallgren et al, 2016), to Mms1 binding sites was reduced in mms1 cells. The data presented in this thesis, together with published data, suggests a novel mechanistic model in which Mms1 binds to G-quadruplex structures and enables Pif1 association. This allows for replication fork progression and genome integrity.
N2 - Bei G-quadruplex Strukturen handelt es sich um stabile Sekundärstrukturen der DNA, welche das Fortschreiten der Replikationsgabel behindern und Genominstabilität verursachen können, falls sie nicht konsequent reguliert werden (Castillo Bosch et al, 2014; Crabbe et al, 2004; Koole et al, 2014; Kruisselbrink et al, 2008; London et al, 2008; Lopes et al, 2011; Paeschke et al, 2013; Paeschke et al, 2011; Piazza et al, 2015; Piazza et al, 2010; Piazza et al, 2012; Ribeyre et al, 2009; Sabouri et al, 2014; Sarkies et al, 2012; Sarkies et al, 2010; Schiavone et al, 2014; Wu & Spies, 2016; Zimmer et al, 2016). Ziel dieser Doktorarbeit war es, neue Proteininteraktionspartner dieser Strukturen in Saccharomyces cerevisiae zu identifizieren und zu untersuchen, wie diese Proteine die Strukturen regulieren um Genomstabilität zu gewährleisten. Mit Hilfe eines Pulldown Assays und anschließender massenspektrometrischer Analyse wurden Mms1 und Rtt101 in vitro als Interaktionspartner von G-quadruplex Strukturen identifiziert. Rtt101, Mms1 und Mms22, Komponenten der Ubiquitinligase Rtt101Mms1/Mms22, spielen eine wichtige Rolle beim Fortschreiten der Replikationsgabel, falls dieses durch Agenzien gehemmt wurde (Luke et al, 2006; Vaisica et al, 2011; Zaidi et al, 2008). Durch Chromatin-Immunpräzipitation mit anschließender Hochdurchsatzsequenzierung wurden die Bindestellen von Mms1 identifiziert. Interessanterweise hat Mms1 genomweit an G-reiche Sequenzen gebunden. Diese G-reichen Sequenzen bildeten G-quadruplex Strukturen in vitro aus. Die Bindung von Mms1 erfolgte unabhängig von Rtt101 und Mms22 sowie während des gesamten Zellzyklus. Außerdem kam es zu einer Verlangsamung der Replikationsgabel in mms1 Zellen, was durch eine verstärkte Bindung der DNA Polymerase 2 nachgewiesen wurde. Ein gross chromsomal rearrangement assay zeigte, dass die Genominstabilität in mms1 Zellen signifikant erhöht ist, wenn G-quadruplex Motive, im Vergleich zu nicht-G-reichen oder G-reichen Kontrollregionen, vorhanden sind. Zudem war die Bindung der Helikase Pif1, welche G-quadruplex Strukturen in vitro entwindet (Paeschke et al, 2013; Ribeyre et al, 2009; Sanders, 2010; Wallgren et al, 2016), stark reduziert, wenn Mms1 fehlte. Mit Hilfe der in dieser Doktorarbeit gewonnenen Ergebnisse, sowie mit Hilfe publizierter Daten, lässt sich ein Model postulieren, in welchem Mms1 an G-quadruplexe bindet und somit die Bindung von Pif1 ermöglicht. Dadurch werden das Fortschreiten der Replikationsgabel und die Genomstabilität gewährleistet.
KW - Quadruplex-DNS
KW - DNS-Reparatur
KW - genome stability
KW - Bierhefe
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142547
ER -
TY - JOUR
A1 - Wandrey, Georg
A1 - Wurzel, Joel
A1 - Hoffmann, Kyra
A1 - Ladner, Tobias
A1 - Büchs, Jochen
A1 - Meinel, Lorenz
A1 - Lühmann, Tessa
T1 - Probing unnatural amino acid integration into enhanced green fluorescent protein by genetic code expansion with a high-throughput screening platform
JF - Journal of Biological Engineering
N2 - Background
Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation.
Results
We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP). Two uAA, propargyl-L-lysine (Plk) and (S)-2-amino-6-((2-azidoethoxy) carbonylamino) hexanoic acid (Alk), were incorporated at the same site into eGFP co-expressing the native PylRS/tRNAPyl CUA pair originating from Methanosarcina barkeri in E. coli. The site-specific uAA functionalization was confirmed by LC-MS/MS analysis. uAA-eGFP production and biomass growth in parallelized E. coli cultivations was correlated to (i) uAA concentration and the (ii) time of uAA addition to the expression medium as well as to induction parameters including the (iii) time and (iv) amount of IPTG supplementation. The online measurements of the HTMS were consolidated by end point-detection using standard enzyme-linked immunosorbent procedures.
Conclusion
The developed HTMS is powerful tool for parallelized and rapid screening. In light of uAA integration, future applications may include parallelized screening of different PylRS/tRNAPyl CUA pairs as well as further optimization of culture conditions.
KW - protein engineering
KW - amber codon suppression
KW - online monitoring system
KW - high-throughput screening
KW - unnatural amino acid
KW - bio-orthogonal chemistry
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166304
VL - 10
IS - 11
ER -
TY - JOUR
A1 - Walz, Nora
A1 - Mühlberger, Andreas
A1 - Pauli, Paul
T1 - A human open field test reveals thigmotaxis related to agoraphobic fear
JF - Biological Psychiatry
N2 - BACKGROUND:
Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia.
METHODS:
A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. RESULTS: Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia.
CONCLUSIONS:
This study is the first to our knowledge to verify the translational validity of the OFT and to reveal that thigmotaxis, an evolutionarily adaptive behavior shown by most species, is related to agoraphobia, a pathologic fear of open spaces, and anxiety sensitivity, a risk factor for agoraphobia.
KW - Agoraphobia
KW - Animal models
KW - Anxiety sensitivity
KW - Avoidance behavior
KW - Openfield test
KW - Thigmotaxis
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187607
VL - 80
IS - 5
ER -
TY - JOUR
A1 - Walter, T.
A1 - Collenburg, L.
A1 - Japtok, L.
A1 - Kleuser, B.
A1 - Schneider-Schaulies, S.
A1 - Müller, N.
A1 - Becam, J.
A1 - Schubert-Unkmeir, A.
A1 - Kong, J. N.
A1 - Bieberich, E.
A1 - Seibel, J.
T1 - Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells
JF - Chemical Communications
N2 - The synthesis and biological evaluation of azido-N-oleoyl serinol is reported. It mimicks biofunctional lipid ceramides and has shown to be capable of click reactions for cell membrane imaging in Jurkat and human brain microvascular endothelial cells.
KW - Ceramide
KW - Apoptosis
KW - Golgi
KW - N-oleoyl serinol
KW - Jurkat cells
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191263
VL - 52
IS - 55
ER -