@article{ČuklinaHahnImakaevetal.2016, author = {Čuklina, Jelena and Hahn, Julia and Imakaev, Maxim and Omasits, Ulrich and F{\"o}rstner, Konrad U. and Ljubimov, Nikolay and Goebel, Melanie and Pessi, Gabriella and Fischer, Hans-Martin and Ahrens, Christian H. and Gelfand, Mikhail S. and Evguenieva-Hackenberg, Elena}, title = {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}, series = {BMC Genomics}, volume = {17}, journal = {BMC Genomics}, doi = {10.1186/s12864-016-2602-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164565}, pages = {302}, year = {2016}, abstract = {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.}, language = {en} } @article{UeceylerSchaeferMackenrodtetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Sch{\"a}fer, Kristina A. and Mackenrodt, Daniel and Sommer, Claudia and M{\"u}llges, Wolfgang}, title = {High-Resolution Ultrasonography of the Superficial Peroneal Motor and Sural Sensory Nerves May Be a Non-invasive Approach to the Diagnosis of Vasculitic Neuropathy}, series = {Frontiers in Neurology}, volume = {7}, journal = {Frontiers in Neurology}, number = {48}, doi = {10.3389/fneur.2016.00048}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146671}, year = {2016}, abstract = {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.}, language = {en} } @article{UeceylerSchroeterKafkeetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia}, title = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856}, year = {2016}, abstract = {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.}, language = {en} } @article{UeceylerBikoHoseetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Biko, Lydia and Hose, Dorothea and Hoffmann, Lukas and Sommer, Claudia}, title = {Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development}, series = {Molecular Pain}, volume = {12}, journal = {Molecular Pain}, number = {1744806916646370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147562}, year = {2016}, abstract = {Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease. Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain.}, language = {en} } @phdthesis{Zott2016, author = {Zott, Maximilian}, title = {Extreme Value Theory in Higher Dimensions - Max-Stable Processes and Multivariate Records}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136614}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Die Extremwerttheorie behandelt die stochastische Modellierung seltener und extremer Ereignisse. W{\"a}hrend 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 unabh{\"a}ngigen 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 eingef{\"u}hrt und untersucht. Ferner werden 'verallgemeinerte max-lineare Modelle' eingef{\"u}hrt, um einen bekannten max-stabilen Zufallsvektor durch einen max-stabilen Prozess zu interpolieren. Dar{\"u}ber hinaus wird der Zusammenhang von extremwerttheoretischen Methoden mit der Theorie der multivariaten Rekorde hergestellt. Insbesondere werden sogenannte 'vollst{\"a}ndige' und 'einfache' Rekorde eingef{\"u}hrt, und deren asymptotisches Verhalten untersucht.}, subject = {Stochastischer Prozess}, language = {en} } @article{ZlamyAlmanzarParsonetal.2016, author = {Zlamy, Manuela and Almanzar, Giovanni and Parson, Walther and Schmidt, Christian and Leierer, Johannes and Weinberger, Birgit and Jeller, Verena and Unsinn, Karin and Eyrich, Matthias and W{\"u}rzner, Reinhard and Prelog, Martina}, title = {Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy}, series = {Immunity \& Ageing}, volume = {13}, journal = {Immunity \& Ageing}, number = {3}, doi = {10.1186/s12979-016-0058-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146497}, year = {2016}, abstract = {Background Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced) and the role of Interleukin-(IL)-7 and IL-7 receptor (CD127)-expressing T cells in thymectomized patients compared to young and old healthy controls. Results Decreased proportions of naive and CD31 + CD8+ T cells were demonstrated after thymectomy, with higher proliferative activity of CD127-expressing T cells and significantly shorter relative telomere lengths (RTLs) and lower T cell receptor excision circles (TRECs). Increased circulating CD103+ T cells and a skewed T cell receptor (TCR) repertoire were found after thymectomy similar to elderly persons. Naive T cells were influenced by age at thymectomy and further decreased by CMV. Conclusions After childhood thymectomy, the immune system demonstrated constant efforts of the peripheral CD8+ T cell compartment to maintain homeostasis. Supposedly it tries to fill the void of RTEs by peripheral T cell proliferation, by at least partly IL-7-mediated mechanisms and by proportional increase of circulating CD103+ T cells, reminiscent of immune aging in elderly. Although other findings were less significant compared to healthy elderly, early thymectomy demonstrated immunological alterations of CD8+ T cells which mimic features of premature immunosenescence in humans.}, language = {en} } @article{ZipfelEyrichSchlegeletal.2016, author = {Zipfel, Julian and Eyrich, Matthias and Schlegel, Paul-Gerhardt and Wiegering, Verena}, title = {Disturbed B cell and DC-Homeostasis in Pediatric cGVHD Patients-Cocultivation Experiments and Review of the Literature}, series = {Clinics in Oncology}, volume = {1}, journal = {Clinics in Oncology}, number = {1097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147914}, year = {2016}, abstract = {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 na{\"i}ve 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.}, language = {en} } @article{ZinnerMoralesAlamoOrtenbladetal.2016, author = {Zinner, Christoph and Morales-Alamo, David and {\O}rtenblad, Niels and Larsen, Filip J. and Schiffer, Tomas A. and Willis, Sarah J. and Gelabert-Rebato, Miriam and Perez-Valera, Mario and Boushel, Robert and Calbet, Jose A. L. and Holmberg, Hans-Christer}, title = {The Physiological Mechanisms of Performance Enhancement with Sprint Interval Training Differ between the Upper and Lower Extremities in Humans}, series = {Frontiers in Physiology}, volume = {7}, journal = {Frontiers in Physiology}, number = {426}, doi = {10.3389/fphys.2016.00426}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165257}, year = {2016}, abstract = {To elucidate the mechanisms underlying the differences in adaptation of arm and leg muscles to sprint training, over a period of 11 days 16 untrained men performed six sessions of 4-6 × 30-s all-out sprints (SIT) with the legs and arms, separately, with a 1-h interval of recovery. Limb-specific VO2peak, sprint performance (two 30-s Wingate tests with 4-min recovery), muscle efficiency and time-trial performance (TT, 5-min all-out) were assessed and biopsies from the m. vastus lateralis and m. triceps brachii taken before and after training. VO2peak and Wmax increased 3-11\% after training, with a more pronounced change in the arms (P < 0.05). Gross efficiency improved for the arms (+8.8\%, P < 0.05), but not the legs (-0.6\%). Wingate peak and mean power outputs improved similarly for the arms and legs, as did TT performance. After training, VO2 during the two Wingate tests was increased by 52 and 6\% for the arms and legs, respectively (P < 0.001). In the case of the arms, VO2 was higher during the first than second Wingate test (64 vs. 44\%, P < 0.05). During the TT, relative exercise intensity, HR, VO2, VCO2, VE, and Vt were all lower during arm-cranking than leg-pedaling, and oxidation of fat was minimal, remaining so after training. Despite the higher relative intensity, fat oxidation was 70\% greater during leg-pedaling (P = 0.017). The aerobic energy contribution in the legs was larger than for the arms during the Wingate tests, although VO2 for the arms was enhanced more by training, reducing the O2 deficit after SIT. The levels of muscle glycogen, as well as the myosin heavy chain composition were unchanged in both cases, while the activities of 3-hydroxyacyl-CoA-dehydrogenase and citrate synthase were elevated only in the legs and capillarization enhanced in both limbs. Multiple regression analysis demonstrated that the variables that predict TT performance differ for the arms and legs. The primary mechanism of adaptation to SIT by both the arms and legs is enhancement of aerobic energy production. However, with their higher proportion of fast muscle fibers, the arms exhibit greater plasticity.}, language = {en} } @article{ZinnerKruegerReedetal.2016, author = {Zinner, C. and Krueger, M. and Reed, J. L. and Kohl-Bareis, M. and Holmberg, H. C. and Sperlich, B.}, title = {Exposure to a combination of heat and hyperoxia during cycling at submaximal intensity does not alter thermoregulatory responses}, series = {Biology of Sport}, volume = {33}, journal = {Biology of Sport}, number = {1}, doi = {10.5604/20831862.1192041}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160993}, pages = {71-76}, year = {2016}, abstract = {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.}, language = {en} } @phdthesis{Ziegler2016, author = {Ziegler, Christiane}, title = {Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146815}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10\%. Panic disorder (PD) has a life time prevalence of 2-5\% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue. In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called "hidden heritability", which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders. In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD. The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as - applying a psychotherapy-epigenetic approach - its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD. Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively.}, subject = {Angst}, language = {en} }