@article{GuederBrennerAngermannetal.2012, author = {G{\"u}der, G{\"u}lmisal and Brenner, Susanne and Angermann, Christiane E. and Ertl, Georg and Held, Matthias and Sachs, Alfred P. and Lammers, Jan Willem and Zanen, Peter and Hoes, Arno W. and St{\"o}rk, Stefan and Rutten, Frans H.}, title = {"GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study"}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75193}, year = {2012}, abstract = {Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner's diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, 'GOLD-COPD' misclassified 69 (28\%) patients, and the three LLNs misclassified 114 (46\%), 96 (39\%), and 98 (40\%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 \% predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50\% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice.}, subject = {Medizin}, language = {en} } @article{KlotzMentrupRegensburgeretal.2012, author = {Klotz, Barbara and Mentrup, Birgit and Regensburger, Martina and Zeck, Sabine and Schneidereit, Jutta and Schupp, Nicole and Linden, Christian and Merz, Cornelia and Ebert, Regina and Jakob, Franz}, title = {1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity}, series = {PLoS ONE}, volume = {7}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0029959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133392}, pages = {e29959}, year = {2012}, abstract = {1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence-and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.}, language = {en} } @article{FinzeReissFrohn2012, author = {Finze, Maik and Reiss, Guido J. and Frohn, Hermann-Josef}, title = {2,3,5,6-Tetrafluoro-1,4-bis(trimethylsilyl)benzene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75401}, year = {2012}, abstract = {no abstract available}, subject = {Chemie}, language = {en} } @article{LiSamnickLapaetal.2012, author = {Li, Xiang and Samnick, Samuel and Lapa, Constantin and Israel, Ina and Buck, Andreas K. and Kreissl, Michael C. and Bauer, Wolfgang}, title = {68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with18F-FDG, calcium burden and risk factors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76231}, year = {2012}, abstract = {Background: Ga-[1,4,7,10-tetraazacyclododecane-N,N0,N00,N000-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. Methods: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. Results: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2\%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2\%) had a colocalized 68Ga-DOTATATE accumulation. Conclusions: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions.}, subject = {Medizin}, language = {en} } @article{HomolaJbabdiBeckmannetal.2012, author = {Homola, Gy{\"o}rgy A. and Jbabdi, Saad and Beckmann, Christian F. and Bartsch, Andreas J.}, title = {A Brain Network Processing the Age of Faces}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75513}, year = {2012}, abstract = {Age is one of the most salient aspects in faces and of fundamental cognitive and social relevance. Although face processing has been studied extensively, brain regions responsive to age have yet to be localized. Using evocative face morphs and fMRI, we segregate two areas extending beyond the previously established face-sensitive core network, centered on the inferior temporal sulci and angular gyri bilaterally, both of which process changes of facial age. By means of probabilistic tractography, we compare their patterns of functional activation and structural connectivity. The ventral portion of Wernicke's understudied perpendicular association fasciculus is shown to interconnect the two areas, and activation within these clusters is related to the probability of fiber connectivity between them. In addition, post-hoc age-rating competence is found to be associated with high response magnitudes in the left angular gyrus. Our results provide the first evidence that facial age has a distinct representation pattern in the posterior human brain. We propose that particular face-sensitive nodes interact with additional object-unselective quantification modules to obtain individual estimates of facial age. This brain network processing the age of faces differs from the cortical areas that have previously been linked to less developmental but instantly changeable face aspects. Our probabilistic method of associating activations with connectivity patterns reveals an exemplary link that can be used to further study, assess and quantify structure-function relationships.}, subject = {Medizin}, language = {en} } @phdthesis{Platt2012, author = {Platt, Christian}, title = {A Common Thread in Unconventional Superconductivity: The Functional Renormalization Group in Multi-Band Systems}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-78824}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Die supraleitenden Eigenschaften von komplexen Materialsystemen, wie den erst k{\"u}rzlich entdeckten Eisen-Pniktiden oder den Strontium-Ruthenaten, sind oftmals durch das Zusammenspiel vieler elektronischer Orbitale bestimmt. Um die Supraleitung in derartigen Systemen besser zu verstehen, entwickeln wir in dieser Arbeit eine Multi-Orbital-Implementierung der funktionalen Renormierungsgruppe und untersuchen die Elektronenpaarung in verschiedenen charakteristischen Materialverbindungen. In den Eisen-Pniktiden finden wir hierbei mehrere Spinfluktuationskan{\"a}le, die eine Elektronenpaarung hervorrufen, sofern die Paarwellenfunktion einen Vorzeichenwechsel zwischen den verschiedenen genesteten Bereichen der Fermifl{\"a}che aufweist. Abh{\"a}ngig von den spezifischen Materialeigenschaften, wie der Dotierung oder der Position des Pniktogenatoms, f{\"u}hren diese Spinfluktuationen dann zu \$s_{\pm}\$-wellenartiger Paarung mit durchg{\"a}ngiger Energiel{\"u}cke oder mit Knoten auf der Fermifl{\"a}che. In manchen F{\"a}llen wird zudem auch \$d\$-wellenartige Paarung induziert, die in der N{\"a}he des {\"U}bergangs zur \$s_{\pm}\$-Symmetrie einen gemischten \$(s+id)\$-Zustand mit gebrochener Zeitinversionssymmetrie aufweist. Diese neuartige Phase zeigt faszinierende Eigenschaften, wie zum Beispiel das spontane Entstehen von Suprastr{\"o}men am Probenrand und um nichtmagnetische St{\"o}rstellen. Auf Grund der durchg{\"a}ngigen Energiel{\"u}cke ist dieser \$(s+id)\$-Zustand energetisch beg{\"u}nstigt. Im Folgenden untersuchen wir zudem auch die elektronischen Instabilit{\"a}ten eines weiteren außergew{\"o}hnlichen Materials -- dotiertes Graphen. Diese rein zweidimensionale Kohlenstoffverbindung ist schon seit mehreren Jahren im Fokus der Festk{\"o}rperforschung und wurde mittlerweile auch durch neuartige experimentelle Verfahren dotiert, ohne die zugrundeliegende hexagonale Gittersturktur merklich zu st{\"o}ren. Eine theoretische Beschreibung dieses Systems erfordert die Ber{\"u}cksichtigung zweier nicht-equivalenter Gitterpl{\"a}tze, was wiederum effektiv als Zwei-Orbital-System aufgefasst werden kann. Durch die besondere Symmetrie der hexagonalen Gitterstruktur sind beide \$d\$-wellenartigen Paarungskan{\"a}le entartet und ahnlich der \$(s+id)\$-Paarung in den Pniktiden finden wir hier eine chirale \$(d+id)\$-Paarung in einem weiten Dotierungsbereich um van-Hove F{\"u}llung. Des Weiteren identifizieren wir Spin-Triplet-Paarung und eine exotische Form der Spindichtewelle, welche beide durch leichte Ver{\"a}nderung der langreichweitigen H{\"u}pfamplituden und Wechselwirkungensparameter realisiert werden k{\"o}nnen. Als drittes Beispiel betrachten wir die Supraleitung in dem Strontium-Ruthenat Sr\$_2\$RuO\$_4\$. Die Besonderheit dieser Materialverbindung liegt in der m{\"o}glichen Realisierung einer chiralen Spin-Triplet Paarung, die wiederum faszinierende Eigenschaften wie die Existenz von halbganzzahligen Flussvortizes mit nicht-Abelscher Vertauschungsstatistik aufweisen w{\"u}rde. Mittels eines mikroskopischen Drei-Orbital-Modells und der Ber{\"u}cksichtigung von Spin-Bahn-Kopplung finden wir hierbei, dass moderate ferromagnetische Spinfluktuationen immer noch ausreichen, um diesen speziellen Paarungszustand anzutreiben. Die berechnete Energiel{\"u}cke zeigt im Weiteren sehr starke Anisotropien auf dem \$d_{xy}\$-Orbital-dominierten Bereich der Fermifl{\"a}che und verschwindet nahezu vollst{\"a}ndig auf den anderen beiden Fermifl{\"a}chen.}, subject = {Supraleitung}, language = {en} } @article{HagemannAnackerErnestusetal.2012, author = {Hagemann, Carsten and Anacker, Jelena and Ernestus, Ralf-Ingo and Vince, Giles H.}, title = {A complete compilation of matrix metalloproteinase expression in human malignant gliomas}, series = {World Journal of Clinical Oncology}, volume = {3}, journal = {World Journal of Clinical Oncology}, number = {5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123982}, pages = {67-79}, year = {2012}, abstract = {Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy.}, language = {en} } @article{FroehlichPapenfortBergeretal.2012, author = {Fr{\"o}hlich, Kathrin S. and Papenfort, Kai and Berger, Allison A. and Vogel, J{\"o}rg}, title = {A conserved RpoS-dependent small RNA controls the synthesis of major porin OmpD}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {8}, doi = {10.1093/nar/gkr1156}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134230}, pages = {3623-3640}, year = {2012}, abstract = {A remarkable feature of many small non-coding RNAs (sRNAs) of Escherichia coli and Salmonella is their accumulation in the stationary phase of bacterial growth. Several stress response regulators and sigma factors have been reported to direct the transcription of stationary phase-specific sRNAs, but a widely conserved sRNA gene that is controlled by the major stationary phase and stress sigma factor, Sigma(S) (RpoS), has remained elusive. We have studied in Salmonella the conserved SdsR sRNA, previously known as RyeB, one of the most abundant stationary phase-specific sRNAs in E. coli. Alignments of the sdsR promoter region and genetic analysis strongly suggest that this sRNA gene is selectively transcribed by Sigma(S). We show that SdsR down-regulates the synthesis of the major Salmonella porin OmpD by Hfq-dependent base pairing; SdsR thus represents the fourth sRNA to regulate this major outer membrane porin. Similar to the InvR, MicC and RybB sRNAs, SdsR recognizes the ompD mRNA in the coding sequence, suggesting that this mRNA may be primarily targeted downstream of the start codon. The SdsR-binding site in ompD was localized by 3'-RACE, an experimental approach that promises to be of use in predicting other sRNA-target interactions in bacteria.}, language = {en} } @article{JainVelezAcostaetal.2012, author = {Jain, M. and V{\´e}lez, J. I. and Acosta, M. T. and Palacio, L. G. and Balog, J. and Roessler, E. and Pineda, D. and Londo{\~n}o, A. C. and Palacio, J. D. and Arbelaez, A. and Lopera, F. and Elia, J. and Hakonarson, H. and Seitz, C. and Freitag, C. M. and Palmason, H. and Meyer, J. and Romanos, M. and Walitza, S. and Hemminger, U. and Warnke, A. and Romanos, J. and Renner, T. and Jacob, C. and Lesch, K.-P. and Swanson, J. and Castellanos, F. X. and Bailey-Wilson, J. E. and Arcos-Burgos, M. and Muenke, M.}, title = {A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD}, series = {Molecular Psychiatry}, volume = {17}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2011.59}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125128}, pages = {741-747}, year = {2012}, abstract = {In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10-8) and 11q and 17p (P<1 × 10-6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.}, language = {en} } @article{StaigerCadotKooteretal.2012, author = {Staiger, Christine and Cadot, Sidney and Kooter, Raul and Dittrich, Marcus and M{\"u}ller, Tobias and Klau, Gunnar W. and Wessels, Lodewyk F. A.}, title = {A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0034796}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131323}, pages = {e34796}, year = {2012}, abstract = {Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer.}, language = {en} } @article{ReussKieselKundeetal.2012, author = {Reuss, Heiko and Kiesel, Andrea and Kunde, Wilfried and W{\"u}hr, Peter}, title = {A cue from the unconscious - masked symbols prompt spatial anticipation}, series = {Frontiers in Psychology}, volume = {3}, journal = {Frontiers in Psychology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123971}, pages = {397}, year = {2012}, abstract = {Anticipating where an event will occur enables us to instantaneously respond to events that occur at the expected location. Here we investigated if such spatial anticipations can be triggered by symbolic information that participants cannot consciously see. In two experiments involving a Posner cueing task and a visual search task, a central cue informed participants about the likely location of the next target stimulus. In half of the trials, this cue was rendered invisible by pattern masking. In both experiments, visible cues led to cueing effects, that is, faster responses after valid compared to invalid cues. Importantly, even masked cues caused cueing effects, though to a lesser extent. Additionally, we analyzed effects on attention that persist from one trial to the subsequent trial. We found that spatial anticipations are able to interfere with newly formed spatial anticipations and influence orienting of attention in the subsequent trial. When the preceding cue was visible, the corresponding spatial anticipation persisted to an extent that prevented a noticeable effect of masked cues. The effects of visible cues were likewise modulated by previous spatial anticipations, but were strong enough to also exert an impact on attention themselves. Altogether, the results suggest that spatial anticipations can be formed on the basis of unconscious stimuli, but that interfering influences like still active spatial anticipations can suppress this effect.}, language = {en} } @book{FalkMarohnMicheletal.2012, author = {Falk, Michael and Marohn, Frank and Michel, Ren{\´e} and Hofmann, Daniel and Macke, Maria and Spachmann, Christoph and Englert, Stefan}, title = {A First Course on Time Series Analysis : Examples with SAS [Version 2012.August.01]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72617}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The analysis of real data by means of statistical methods with the aid of a software package common in industry and administration usually is not an integral part of mathematics studies, but it will certainly be part of a future professional work. The present book links up elements from time series analysis with a selection of statistical procedures used in general practice including the statistical software package SAS. Consequently this book addresses students of statistics as well as students of other branches such as economics, demography and engineering, where lectures on statistics belong to their academic training. But it is also intended for the practician who, beyond the use of statistical tools, is interested in their mathematical background. Numerous problems illustrate the applicability of the presented statistical procedures, where SAS gives the solutions. The programs used are explicitly listed and explained. No previous experience is expected neither in SAS nor in a special computer system so that a short training period is guaranteed. This book is meant for a two semester course (lecture, seminar or practical training) where the first three chapters can be dealt within the first semester. They provide the principal components of the analysis of a time series in the time domain. Chapters 4, 5 and 6 deal with its analysis in the frequency domain and can be worked through in the second term. In order to understand the mathematical background some terms are useful such as convergence in distribution, stochastic convergence, maximum likelihood estimator as well as a basic knowledge of the test theory, so that work on the book can start after an introductory lecture on stochastics. Each chapter includes exercises. An exhaustive treatment is recommended. Chapter 7 (case study) deals with a practical case and demonstrates the presented methods. It is possible to use this chapter independent in a seminar or practical training course, if the concepts of time series analysis are already well understood. This book is consecutively subdivided in a statistical part and an SAS-specific part. For better clearness the SAS-specific parts are highlighted. This book is an open source project under the GNU Free Documentation License.}, subject = {Zeitreihenanalyse}, language = {en} } @article{RaslanAlbertWeissenbergerWestermaieretal.2012, author = {Raslan, Furat and Albert-Weißenberger, Christiane and Westermaier, Thomas and Saker, Saker and Kleinschmitz, Christoph and Lee, Jin-Yul}, title = {A modified double injection model of cisterna magna for the study of delayed cerebral vasospasm following subarachnoid hemorrhage in rats}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76038}, year = {2012}, abstract = {Delayed cerebral vasospasm following subarachnoid hemorrhage (SAH) is a serious medical complication, characterized by constriction of cerebral arteries leading to varying degrees of cerebral ischemia. Numerous clinical and experimental studies have been performed in the last decades; however, the pathophysiologic mechanism of cerebral vasospasm after SAH still remains unclear. Among a variety of experimental SAH models, the double hemorrhage rat model involving direct injection of autologous arterial blood into the cisterna magna has been used most frequently for the study of delayed cerebral vasospasm following SAH in last years. Despite the simplicity of the technique, the second blood injection into the cisterna magna may result in brainstem injury leading to high mortality. Therefore, a modified double hemorrhage model of cisterna magna has been developed in rat recently. We describe here step by step the surgical technique to induce double SAH and compare the degree of vasospasm with other cisterna magna rat models using histological assessment of the diameter and cross-sectional area of the basilar artery}, subject = {Medizin}, language = {en} } @article{MolochnikovRabeyDobronevskyetal.2012, author = {Molochnikov, Leonid and Rabey, Jose M. and Dobronevsky, Evgenya and Bonuccelli, Ubaldo and Ceravolo, Roberto and Frosini, Daniela and Gr{\"u}nblatt, Edna and Riederer, Peter and Jacob, Christian and Aharon-Peretz, Judith and Bashenko, Yulia and Youdim, Moussa B. H. and Mandel, Silvia A.}, title = {A molecular signature in blood identifies early Parkinson's disease}, series = {Molecular Neurodegeneration}, volume = {7}, journal = {Molecular Neurodegeneration}, number = {26}, doi = {10.1186/1750-1326-7-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134508}, year = {2012}, abstract = {Background: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. Results: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95\% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95\% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95\% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95\% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100\% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). Conclusions: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134845}, year = {2012}, abstract = {Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8.15.7 +/- 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95\% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124052}, year = {2012}, abstract = {Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8. 15.7 ± 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95\%CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{HardcastleTomeCannonetal.2012, author = {Hardcastle, Nicholas and Tom{\´e}, Wolfgang A. and Cannon, Donald M. and Brouwer, Charlotte L. and Wittendorp, Paul W. H. and Dogan, Nesrin and Guckenberger, Matthias and Allaire, St{\´e}phane and Mallya, Yogish and Kumar, Prashant and Oechsner, Markus and Richter, Anne and Song, Shiyu and Myers, Michael and Polat, B{\"u}lent and Bzdusek, Karl}, title = {A multi-institution evaluation of deformable image registration algorithms for automatic organ delineation in adaptive head and neck radiotherapy}, series = {Radiation Oncology}, volume = {7}, journal = {Radiation Oncology}, number = {90}, doi = {10.1186/1748-717X-7-90}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134756}, year = {2012}, abstract = {Background: Adaptive Radiotherapy aims to identify anatomical deviations during a radiotherapy course and modify the treatment plan to maintain treatment objectives. This requires regions of interest (ROIs) to be defined using the most recent imaging data. This study investigates the clinical utility of using deformable image registration (DIR) to automatically propagate ROIs. Methods: Target (GTV) and organ-at-risk (OAR) ROIs were non-rigidly propagated from a planning CT scan to a per-treatment CT scan for 22 patients. Propagated ROIs were quantitatively compared with expert physician-drawn ROIs on the per-treatment scan using Dice scores and mean slicewise Hausdorff distances, and center of mass distances for GTVs. The propagated ROIs were qualitatively examined by experts and scored based on their clinical utility. Results: Good agreement between the DIR-propagated ROIs and expert-drawn ROIs was observed based on the metrics used. 94\% of all ROIs generated using DIR were scored as being clinically useful, requiring minimal or no edits. However, 27\% (12/44) of the GTVs required major edits. Conclusion: DIR was successfully used on 22 patients to propagate target and OAR structures for ART with good anatomical agreement for OARs. It is recommended that propagated target structures be thoroughly reviewed by the treating physician.}, language = {en} } @phdthesis{Walter2012, author = {Walter, Martina}, title = {A new methodological approach to assess drug driving - The German Smartphone Survey}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75283}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The aim of the present piece of work was to give information about the frequency of psychoactive substances within the German driver population and to identify preventive and promotive circumstances of drug driving. Furthermore, a new methodological approach to gather and link data about the consumption of psychoactive substances and the mobility of drug users is shown. Traditionally, roadside surveys are conducted to estimate the prevalence of drug driving within a population. By the present study, an alternative method is introduced. In total, 195 drug users (mainly cannabis users) and 100 controls out of the normal driving population were queried for four weeks about their driving and drug consumption behaviour by a questionnaire that was deployed on smartphones. The prevalences of drug driving within the sample were extrapolated into representative values. Because the subjects reported all daily activities within the study-period, it was also possible to describe situations in which the subjects decided against driving under influence. Besides, relevant previous experiences, attitudes, the approval of legal regulations, other traffic-specific parameters, social influences and personality variables were queried. So, individual factors that are associated with drug driving can be specified. The results are integrated in a model that shows dependencies of different societal, behavioural and legal variables. They can serve as major input to the discussion on drug driving and can be of practical use for rehabilitation and prevention purposes. The results can be summarised as follows: - Compared to the results of a German roadside survey from 1994, the prevalences that are found within the present study seem pretty low. This finding is discussed and possible explanations for the described trend are lined out. Furthermore, the prevalences that were calculated in the present study are compared to current data from other European countries. - The results show differences between users and controls on several variables. The differences indicate that substance use impacts on the structuring of day-to-day life. Overall, the controls' days proceed more along a daily working routine than the users' (e.g. less mobility at night, more mobility at rush-hour, alcohol consumption mainly at nights out). - The individual extent to which drugs are consumed differs dependent on daytime, day of the week and kind of substance. Of course, these dependencies also influence the occurrence of drug driving. Other factors of influence on drug driving are the distance, the availability of alternative modes of transport as well as the presence of female companions. - Not everybody who uses drugs drives under the influence of drugs. A striking predictor for frequent drug driving and highly intoxicated driving is a high consumption, associated with risky consumption patterns and a low subjective feeling of impairment after drug consumption. - The subjects' attitudes towards drug driving and their beliefs about social norms largely go in line with the behaviour they engage in. Drug users have rather liberal attitudes towards drug use and driving under influence. - A possible deterrence effect of sanctioning and police enforcement and its dependence on the acceptance and awareness of the measures is delineated. - Only small effects are found when examining the objective impairment that is caused by drug use by a computer-based test battery. This result is critically discussed with regards to the operationalisation of the study groups. - Except from driving under influence, there is no evidence to suggest that DUI offenders also show problematic behaviour according to other traffic-related measures. - Parents and peers may have an influence as role models on the development of problematic behaviour. A good relationship between parents and children may have a positive impact on the development of conventional values and behaviour. - Drug use is associated with some crucial personality dimensions and drugs are often used to solve personal problems. A less precise but similar difference was found for users who commit many drives under influence compared to users who never or only sometimes drive under influence. Moreover, users marginally more often have psychological problems compared to controls. Finally, the strengths and weaknesses of the new methodological approach of data collection are discussed as well as the challenges that are faced when implementing it. All in all, it has proved to be a promising method and should serve as a standard to which future studies should aspire.}, subject = {Verkehrspsychologie}, language = {en} } @article{GavvovidisRostTrimbornetal.2012, author = {Gavvovidis, Ioannis and Rost, Isabell and Trimborn, Marc and Kaiser, Frank J. and Purps, Josephine and Wiek, Konstanze and Haneberg, Helmut and Neitzel, Heidemarie and Schindler, Detlev}, title = {A Novel MCPH1 Isoform Complements the Defective Chromosome Condensation of Human MCPH1-Deficient Cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75050}, year = {2012}, abstract = {Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 39 exons (MCPH1De9-14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1De9-14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level.}, subject = {MCPH1}, language = {en} } @article{HofgaardJodalBommertetal.2012, author = {Hofgaard, Peter O. and Jodal, Henriette C. and Bommert, Kurt and Huard, Bertrand and Caers, Jo and Carlsen, Harald and Schwarzer, Rolf and Sch{\"u}nemann, Nicole and Jundt, Franziska and Lindeberg, Mona M. and Bogen, Bjarne}, title = {A Novel Mouse Model for Multiple Myeloma (MOPC315.BM) That Allows Noninvasive Spatiotemporal Detection of Osteolytic Disease}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0051892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131117}, pages = {e51892}, year = {2012}, abstract = {Multiple myeloma (MM) is a lethal human cancer characterized by a clonal expansion of malignant plasma cells in bone marrow. Mouse models of human MM are technically challenging and do not always recapitulate human disease. Therefore, new mouse models for MM are needed. Mineral-oil induced plasmacytomas (MOPC) develop in the peritoneal cavity of oil-injected BALB/c mice. However, MOPC typically grow extramedullary and are considered poor models of human MM. Here we describe an in vivo-selected MOPC315 variant, called MOPC315.BM, which can be maintained in vitro. When injected i.v. into BALB/c mice, MOPC315.BM cells exhibit tropism for bone marrow. As few as 10\(^4\) MOPC315.BM cells injected i.v. induced paraplegia, a sign of spinal cord compression, in all mice within 3-4 weeks. MOPC315.BM cells were stably transfected with either firefly luciferase (MOPC315.BM.Luc) or DsRed (MOPC315.BM.DsRed) for studies using noninvasive imaging. MOPC315.BM.Luc cells were detected in the tibiofemoral region already 1 hour after i.v. injection. Bone foci developed progressively, and as of day 5, MM cells were detected in multiple sites in the axial skeleton. Additionally, the spleen (a hematopoietic organ in the mouse) was invariably affected. Luminescent signals correlated with serum myeloma protein concentration, allowing for easy tracking of tumor load with noninvasive imaging. Affected mice developed osteolytic lesions. The MOPC315.BM model employs a common strain of immunocompetent mice (BALB/c) and replicates many characteristics of human MM. The model should be suitable for studies of bone marrow tropism, development of osteolytic lesions, drug testing, and immunotherapy in MM.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126845}, pages = {573-579}, year = {2012}, abstract = {RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{ConzelmannReifJacobetal.2012, author = {Conzelmann, Annette and Reif, Andreas and Jacob, Christian and Weyers, Peter and Lesch, Klaus-Peter and Lutz, Beat and Pauli, Paul}, title = {A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity}, series = {Psychopharmacology}, volume = {224}, journal = {Psychopharmacology}, number = {4}, doi = {10.1007/s00213-012-2785-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129936}, pages = {573-579}, year = {2012}, abstract = {Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.}, language = {en} } @article{WeisseHeddergottHeydtetal.2012, author = {Weiße, Sebastian and Heddergott, Niko and Heydt, Matthias and Pfl{\"a}sterer, Daniel and Maier, Timo and Haraszti, Tamas and Grunze, Michael and Engstler, Markus and Rosenhahn, Axel}, title = {A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0037296}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130666}, pages = {e37296}, year = {2012}, abstract = {We present a quantitative 3D analysis of the motility of the blood parasite Trypanosoma brucei. Digital in-line holographic microscopy has been used to track single cells with high temporal and spatial accuracy to obtain quantitative data on their behavior. Comparing bloodstream form and insect form trypanosomes as well as mutant and wildtype cells under varying external conditions we were able to derive a general two-state-run-and-tumble-model for trypanosome motility. Differences in the motility of distinct strains indicate that adaption of the trypanosomes to their natural environments involves a change in their mode of swimming.}, language = {en} } @article{DupuisDenglerHenekaetal.2012, author = {Dupuis, Luc and Dengler, Reinhard and Heneka, Michael T. and Meyer, Thomas and Zierz, Stephan and Kassubek, Jan and Fischer, Wilhelm and Steiner, Franziska and Lindauer, Eva and Otto, Markus and Dreyhaupt, Jens and Grehl, Torsten and Hermann, Andreas and Winkler, Andrea S. and Bogdahn, Ulrich and Benecke, Reiner and Schrank, Bertold and Wessig, Carsten and Grosskreutz, Julian and Ludolph, Albert C.}, title = {A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0037885}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130255}, pages = {e37885}, year = {2012}, abstract = {Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95\% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.}, language = {en} } @article{IsaiasMarzeganPezzolietal.2012, author = {Isaias, Ioannis U. and Marzegan, Alberto and Pezzoli, Gianni and Marotta, Giorgio and Canesi, Margherita and Biella, Gabriele E. M. and Volkmann, Jens and Cavallari, Paolo}, title = {A role for locus coeruleus in Parkinson tremor}, series = {Frontiers in Human Neuroscience}, volume = {5}, journal = {Frontiers in Human Neuroscience}, number = {179}, doi = {10.3389/fnhum.2011.00179}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133955}, year = {2012}, abstract = {We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease(PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [\(^{123}\)I] N-\(\omega\)-fluoropropyl-2 \(\beta\)-carbomethoxy-3 \(\beta\)-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.}, language = {en} } @phdthesis{Tuchscherer2012, author = {Tuchscherer, Philip}, title = {A Route to Optical Spectroscopy on the Nanoscale}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72228}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Time-resolved optical spectroscopy has become an important tool to investigate the dynamics of quantum mechanical processes in matter. In typical applications, a first "pump" pulse excites the system under investigation from the thermal equilibrium to an excited state, and a second variable time-delayed "probe" pulse then maps the dynamics of the excited system. Although advanced nonlinear techniques have been developed to investigate, e.g., coherent quantum effects, all of these techniques are limited in their spatial resolution. The laser focus diameter has a lower bound given by Abbe's diffraction limit, which is roughly half the optical excitation wavelength—corresponding to about 400nm in the presented experiments. In the time-resolved experiments that have been suggested so far, averaging over the sample volume within this focus cannot be avoided. In this thesis, two approaches were developed to overcome the diffraction limit in optical spectroscopy and to enable the investigation of coherent processes on the nanoscale. In the first approach, analytic solutions were found to calculate optimal polarizationshaped laser pulses that provide optical near-field pump-probe pulse sequences in the vicinity of a nanostructure. These near-field pulse sequences were designed to allow excitation of a quantum system at one specific position at a certain time and probing at a different position at a later time. In the second approach, the concept of coherent two-dimensional (2D) spectroscopy, which has had great impact on the investigation of coherent quantum effects in recent years, was combined with photoemission electron microscopy, which yields a spatial resolution well below the optical diffraction limit. Using the analytic solutions, optical near fields were investigated in terms of spectroscopic applications. Near fields that are excited with polarization-shaped femtosecond laser pulses in the vicinity of appropriate nanostructures feature two properties that are especially interesting in the view of spectroscopic applications: On the one hand, control of the spatial distribution of the optical fields is achieved on the order of nanometers. On the other hand, the temporal evolution of these fields can be adjusted on the order of femtoseconds. In this thesis, solutions were found to calculate the optimal polarizationshaped laser pulses that control the near field in a general manner. The main idea to achieve this deterministic control was to disentangle the spatial and temporal near-field control. First, the spatial distribution of the optical near field was controlled by assigning the correct state of polarization for each frequency within the polarization-shaped laser pulse independently. The remaining total phase—not employed for spatial control—was then used for temporal near-field compression, which, in experimental applications, would lead to an enhancement of the nonlinear signal at the respective location. In contrast to the use of optical near fields, where pump-probe sequences themselves are localized below the diffraction limit and the detection does not have to provide the spatial resolution, a different approach was suggested in this thesis to gain spectroscopic information on the nanoscale. The new method was termed "Coherent two-dimensional (2D) nanoscopy" and transfers the concept of "conventional" coherent 2D spectroscopy to photoemission electron microscopy. The pulse sequences used for the investigation of quantum systems in this method are still limited by diffraction. However, the new key concept is to detect locally generated photoelectrons instead of optical signals. This yields a spatial resolution that is well below the optical diffraction limit. In "conventional" 2D spectroscopy a triple-pulse sequence initiates a four wave mixing process that creates a coherence. In a quantum mechanical process, this coherence is converted into a population by emission of an electric field, which is measured in the experiment. Contrarily, in the developed 2D nanoscopy, four-wave mixing is initiated by a quadruple-pulse sequence, which leaves the quantum system in an electronic population. This electronic population carries coherent information about the investigated quantum system and can be mapped with a spatial resolution down to a few nanometers given by the spatial resolution of the photoemission electron microscope. Hence, 2D nanoscopy can be considered a generalization of time-resolved photoemission experiments. In the future, it may be of similar beneficial value for the field of photoemission research as "conventional" 2D spectroscopy has proven to be for optical spectroscopy and nuclear magnetic resonance experiments. In a first experimental implementation of coherent 2D nanoscopy coherent processes on a corrugated silver surface were measured and unexpected long coherence lifetimes could be determined.}, subject = {Ultrakurzzeitspektroskopie}, language = {en} } @article{OPUS4-12955, title = {A search for \(t\overline t\) resonances in lepton+jets events with highly boosted top quarks collected in pp collisions at √s=7 TeV with the ATLAS detector}, series = {Journal of High Energy Physics}, volume = {09}, journal = {Journal of High Energy Physics}, number = {41}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP09(2012)041}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129555}, year = {2012}, abstract = {A search for resonant production of high-mass top-quark pairs is performed on 2.05 fb\(^{-1}\) of proton-proton collisions at √s=7 TeV collected in 2011 with the ATLAS experiment at the Large Hadron Collider. This analysis of the lepton+jets final state is specifically designed for the particular topology that arises from the decay of highly boosted top quarks. The observed \(t\overline t\) invariant mass spectrum is found to be compatible with the Standard Model prediction and 95\% credibility level upper limits are derived on the \(t\overline t\) production rate through new massive states. An upper limit of 0.7 pb is set on the production cross section times branching fraction of a narrow 1 TeV resonance. A Kaluza-Klein gluon with a mass smaller than 1.5 TeV is excluded.}, language = {en} } @article{OPUS4-12795, title = {A search for \(t\overline t\) resonances with the ATLAS detector in 2.05 fb\(^{-1}\) of proton-proton collisions at √s=7 TeV}, series = {European Physical Journal C}, volume = {72}, journal = {European Physical Journal C}, number = {2083}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2083-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127959}, year = {2012}, abstract = {A search for top quark pair resonances in final states containing at least one electron or muon has been performed with the ATLAS experiment at the CERN Large Hadron Collider. The search uses a data sample corresponding to an integrated luminosity of 2.05 fb\(^{-1}\), which was recorded in 2011 at a proton-proton centre-of-mass energy of 7 TeV. No evidence for a resonance is found and limits are set on the production cross-section times branching ratio to \(t\overline t\) for narrow and wide resonances. For narrow Z′ bosons, the observed 95 \% Bayesian credibility level limits range from 9.3 pb to 0.95 pb for masses in the range of m Z′=500 GeV to m\(_{Z′}\)=1300 GeV. The corresponding excluded mass region for a leptophobic topcolour Z′ boson (Kaluza-Klein gluon excitation in the Randall-Sundrum model) is m\(_{Z′}\)<880 GeV (m\(_{gKK}\)<1130 GeV).}, language = {en} } @article{OPUS4-12915, title = {A search for flavour changing neutral currents in top-quark decays in pp collision data collected with the ATLAS detector at √s=7 TeV}, series = {Journal of High Energy Physics}, volume = {9}, journal = {Journal of High Energy Physics}, number = {139}, organization = {ATLAS Collaboration}, doi = {10.1007/JHEP09(2012)139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129152}, year = {2012}, abstract = {A search for flavour changing neutral current (FCNC) processes in top-quark decays by the ATLAS Collaboration is presented. Data collected from pp collisions at the LHC at a centre-of-mass energy of √s=7TeV during 2011, corresponding to an integrated luminosity of 2.1 fb\(^{-1}\), were used. A search was performed for top-quark pair-production events, with one top quark decaying through the t → Zq FCNC (q = u, c) channel, and the other through the Standard Model dominant mode t → W b. Only the decays of the Z boson to charged leptons and leptonic W -boson decays were considered as signal. Consequently, the final-state topology is characterised by the presence of three isolated charged leptons, at least two jets and missing transverse momentum from the undetected neutrino. No evidence for an FCNC signal was found. An upper limit on the t → Zq branching ratio of BR(t → Zq) < 0.73\% is set at the 95\% confidence level.}, language = {en} } @article{WeisschuhWissingerGramer2012, author = {Weisschuh, Nicole and Wissinger, Bernd and Gramer, Eugen}, title = {A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia}, series = {Molecular Vision}, volume = {18}, journal = {Molecular Vision}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124379}, pages = {751-757}, year = {2012}, abstract = {Purpose: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. Methods: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. Results: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a 'run on' translation past the normal translational stop codon. Conclusions: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein.}, language = {en} } @article{JahnSchrammSchnoelzeretal.2012, author = {Jahn, Daniel and Schramm, Sabine and Schn{\"o}lzer, Martina and Heilmann, Clemens J. and de Koster, Chris G. and Sch{\"u}tz, Wolfgang and Benavente, Ricardo and Alsheimer, Manfred}, title = {A truncated lamin A in the Lmna\(^{-/-}\) mouse line: Implications for the understanding of laminopathies}, series = {Nucleus}, volume = {3}, journal = {Nucleus}, number = {5}, doi = {10.4161/nucl.21676}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127281}, pages = {463-474}, year = {2012}, abstract = {During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna\(^{-/-}\)) by Sullivan and others,1 which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna\(^{-/-}\) mice and the concept of human laminopathies.}, language = {en} } @article{SweeneySeubertStarketal.2012, author = {Sweeney, Reinhart A. and Seubert, Benedikt and Stark, Silke and Homann, Vanessa and M{\"u}ller, Gerd and Flentje, Michael and Guckenbeger, Matthias}, title = {Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75698}, year = {2012}, abstract = {Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1-3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 \% and 7.1 \% observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability.}, subject = {Medizin}, language = {en} } @article{StolpmannBrinkmannSalzmannetal.2012, author = {Stolpmann, K. and Brinkmann, J. and Salzmann, S. and Genkinger, D. and Fritsche, E. and Hutzler, C. and Wajant, H. and Luch, A. and Henkler, F.}, title = {Activation of the aryl hydrocarbon receptor sensitises human keratinocytes for CD95L-and TRAIL-induced apoptosis}, series = {Cell Death \& Disease}, volume = {3}, journal = {Cell Death \& Disease}, number = {e388}, doi = {10.1038/cddis.2012.127}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133501}, year = {2012}, abstract = {In this study, we have analysed the apoptotic effects of the ubiquitous environmental toxin benzo[ a] pyrene (BP) in HaCaT cells and human keratinocytes. Although prolonged exposure to BP was not cytotoxic on its own, a strong enhancement of CD95 (Fas)-mediated apoptosis was observed with BP at concentrations activating the aryl hydrocarbon receptor (AhR). Importantly, the ultimately mutagenic BP-metabolite, that is, (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE), failed to enhance CD95-mediated cell death, suggesting that the observed pro-apoptotic effect of BP is neither associated with DNA adducts nor DNA-damage related signalling. CD95-induced apoptosis was also enhanced by beta-naphtoflavone, a well-known agonist of the AhR that does not induce DNA damage, thus suggesting a crucial role for AhR activation. Consistently, BP failed to sensitise for CD95L-induced apoptosis in AhR knockdown HaCaT cells. Furthermore, inhibition of CYP1A1 and/or 1B1 expression did not affect the pro-apoptotic crosstalk. Exposure to BP did not increase expression of CD95, but led to augmented activation of caspase-8. Enhancement of apoptosis was also observed with the TRAIL death receptors that activate caspase-8 and apoptosis by similar mechanisms as CD95. Together, these observations indicate an interference of AhR signalling with the activity of receptor-associated signalling intermediates that are shared by CD95 and TRAIL receptors. Our data thus suggest that AhR agonists can enhance cytokine-mediated adversity upon dermal exposure.}, language = {en} } @article{HafnerHoubenBaeurleetal.2012, author = {Hafner, Christian and Houben, Roland and Baeurle, Anne and Ritter, Cathrin and Schrama, David and Landthaler, Michael and Becker, J{\"u}rgen C.}, title = {Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {2}, doi = {10.1371/journal.pone.0031255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131398}, pages = {e31255}, year = {2012}, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88\% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4\%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.}, language = {en} } @article{NeubauerWirthRufetal.2012, author = {Neubauer, Henning and Wirth, Clemens and Ruf, Katharina and Hebestreit, Helge and Beer, Meinrad}, title = {Acute Muscle Trauma due to Overexercise in an Otherwise Healthy Patient with Cystic Fibrosis}, series = {Case Reports in Pediatrics}, volume = {2012}, journal = {Case Reports in Pediatrics}, number = {527989}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123967}, year = {2012}, abstract = {Cystic fibrosis (CF) is one of the most common inherited diseases and is caused by mutations in the CFTR gene. Although the pulmonary and gastrointestinal manifestations of the disease remain in the focus of treatment, recent studies have shown expression of the CFTR gene product in skeletal muscle cells and observed altered intramuscular \(Ca^{2+}\) release dynamics in CFTR-deficient animal models. Physical exercise is beneficial for maintaining fitness and well-being in CF patients and constitutes one aspect of modern multimodal treatment, which has considerably increased life span and reduced morbidity. We report on a case of acute muscle trauma resulting from excessive dumbbell exercise in a young adult with cystic fibrosis and describe clinical, laboratory and imaging characteristics of acute exercise-induced muscle injury.}, language = {en} } @article{NeuhausBurekDjuzenovaetal.2012, author = {Neuhaus, Winfried and Burek, Malgorzata and Djuzenova, Cholpon C and Thal, Serge C and Koepsell, Hermann and Roewer, Norbert and F{\"o}rster, Carola Y}, title = {Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the up-regulation of glucose uptake after subsequent reoxygenation in brain endothelial cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67241}, year = {2012}, abstract = {During stroke the blood-brain barrier (BBB) is damaged which can result in vasogenic brain edema and inflammation. The reduced blood supply leads to decreased delivery of oxygen and glucose to affected areas of the brain. Oxygen and glucose deprivation (OGD) can cause upregulation of glucose uptake of brain endothelial cells. In this letter, we investigated the influence of MK801, a non-competitive inhibitor of the NMDA-receptor, on the regulation of the glucose uptake and of the main glucose transporters glut1 and sglt1 in murine BBB cell line cerebEND during OGD. mRNA expression of glut1 was upregulated 68.7- fold after 6 h OGD, which was significantly reduced by 10 μM MK801 to 28.9-fold. Sglt1 mRNA expression decreased during OGD which was further reduced by MK801. Glucose uptake was significantly increased up to 907\% after 6 h OGD and was still higher (210\%) after the 20 h reoxygenation phase compared to normoxia. Ten micromolar MK801 during OGD was able to reduce upregulated glucose uptake after OGD and reoxygenation significantly. Presence of several NMDAR subunits was proven on the mRNA level in cerebEND cells. Furthermore, it was shown that NMDAR subunit NR1 was upregulated during OGD and that this was inhibitable by MK801. In conclusion, the addition of MK801 during the OGD phase reduced significantly the glucose uptake after the subsequent reoxygenation phase in brain endothelial cells.}, subject = {Blut-Hirn-Schranke}, language = {en} } @article{MuellerBroeckerKlinkeretal.2012, author = {M{\"u}ller, P.A. and Br{\"o}cker, E.B. and Klinker, E. and Stoevesandt, J. and Benoit, S.}, title = {Adjuvant treatment of recalcitrant Bullous pemphigoid with immunoadsorption}, series = {Dermatology}, volume = {224}, journal = {Dermatology}, number = {3}, issn = {1018-8665}, doi = {10.1159/000339071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196620}, pages = {224 -- 227}, year = {2012}, abstract = {Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.}, language = {en} } @phdthesis{Baunach2012, author = {Baunach, Marcel}, title = {Advances in Distributed Real-Time Sensor/Actuator Systems Operation - Operating Systems, Communication, and Application Design Concepts -}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76489}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {This work takes a close look at several quite different research areas related to the design of networked embedded sensor/actuator systems. The variety of the topics illustrates the potential complexity of current sensor network applications; especially when enriched with actuators for proactivity and environmental interaction. Besides their conception, development, installation and long-term operation, we'll mainly focus on more "low-level" aspects: Compositional hardware and software design, task cooperation and collaboration, memory management, and real-time operation will be addressed from a local node perspective. In contrast, inter-node synchronization, communication, as well as sensor data acquisition, aggregation, and fusion will be discussed from a rather global network view. The diversity in the concepts was intentionally accepted to finally facilitate the reliable implementation of truly complex systems. In particular, these should go beyond the usual "sense and transmit of sensor data", but show how powerful today's networked sensor/actuator systems can be despite of their low computational performance and constrained hardware: If their resources are only coordinated efficiently!}, subject = {Eingebettetes System}, language = {en} } @article{KlaukeWinterGajewskaetal.2012, author = {Klauke, Benedikt and Winter, Bernward and Gajewska, Agnes and Zwanzger, Peter and Reif, Andreas and Herrmann, Martin J. and Dlugos, Andrea and Warrings, Bodo and Jacob, Christian and M{\"u}hlberger, Andreas and Arolt, Volker and Pauli, Paul and Deckert, J{\"u}rgen and Domschke, Katharina}, title = {Affect-Modulated Startle: Interactive Influence of Catechol-O-Methyltransferase Val158Met Genotype and Childhood Trauma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {6}, doi = {10.1371/journal.pone.0039709}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132184}, pages = {e39709}, year = {2012}, abstract = {The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system - partly conferred by catechol-O-methyltransferase (COMT) gene variation - for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.}, language = {en} } @phdthesis{Nwandu2012, author = {Nwandu, McDonald Kelechi}, title = {Akọ na Uche (Wisdom and Justifiability) of Preemptive-strike in Self-defense and Alternative Conflict Resolutions}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-94846}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The "Akọ na Uche" (Wisdom and Justifiability) of Preemptive-strike in Self-defense and Alternative Conflict Resolutions is an ethical examine on man's inherent right of self-defense, not only as a right that is innate, but also as an individual's or a nation's right enshrined in, and guaranteed by the Charter provisions of the United Nations. Stemming from the painful experience of the First and Second World Wars, nations wishing never again to engage one another in such full scale wars of destruction, met in San Francisco, California, accepted the formation of a new organization, the United Nations, to replace the League of Nations considered as ineffectual. The participating nations articulated a set of guiding principles in the form of rules, rights and responsibilities endorsed by all the early member-nations on June 26, 1945, but effective from October 24, same year. This is the birth of the United Nations Charter. With the endorsement of the Charter, all member-nations assumed the responsibility of making the world a better place, peaceful and secure for humanity. They vowed never again to engage in unethical wars, they accepted to respect and foster human rights, to fight poverty, to spread democracy and to promote more healthy and robust international relations through a more vibrant cooperation and aggressive diplomacy. The Charter also reaffirmed the intrinsic right of self-defense of the victim of an armed attack, which sometimes has been utilized as well as exploited.}, subject = {Internationaler Konflikt}, language = {en} } @phdthesis{Zidorn2012, author = {Zidorn, Wilfried}, title = {Alliances and R\&D activites in the Biotechnology Industry}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75483}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {This dissertation is divided into three studies by addressing the following constitutive research questions in the context of the biotechnology industry: (1) How do different types of inter-firm alliances influence a firm's R\&D activity? (2) How does an increasing number and diversity of alliances in a firm's alliance portfolio affect its R\&D activity? (3) What is the optimal balance between exploration and exploitation? (1) To answer these research questions the first main chapter analyzes the impact of different types of alliances on the R\&D activities of successful firms in the biotechnology industry. Following the use of a new approach to measuring changes in research activities, the results show that alliances are used to specialize in a certain research field, rather than to enter a completely new market. This effect becomes smaller when the equity involvement of the partners in the alliance project increases. (2) The second main chapter analyzes the impact on innovation output of having heterogeneous partners in a biotechnology firm's alliance portfolio. Previous literature has stressed that investment in the heterogeneity of partners in an alliance portfolio is more important than merely engaging in multiple collaborative agreements. The analysis of a unique panel dataset of 20 biotechnology firms and their 8,602 alliances suggests that engaging in many alliances generally has a positive influence on a firm's innovation output. Furthermore, maintaining diverse alliance portfolios has an inverted U-shaped influence on a firm's innovation output, as managerial costs and complexity levels become too high. (3) And the third main chapter investigates whether there is an optimal balance to be found between explorative and exploitative innovation strategies. Previous literature states that firms that are ambidextrous (i.e., able to focus on exploration and exploitation simultaneously) tend to be more successful. Using a unique panel dataset of 20 leading biotechnology firms and separating their explorative and exploitative research, the chapter suggests that firms seeking to increase their innovation output should avoid imbalances between their explorative and exploitative innovation strategies. Furthermore, an inverted U-shaped relationship between a firm's relative research attention on exploration and its innovation output is found. This dissertation concludes with the results of the dissertation, combines the findings, gives managerial implications and proposes areas for potential further research.}, subject = {Biotechnologische Industrie}, language = {en} } @phdthesis{Wippel2012, author = {Wippel, Carolin}, title = {Alterations of brain dendrite and synapse structure by the Streptococcus pneumoniae neurotoxin pneumolysin - Insights and pharmacological modulation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72016}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Streptococcus pneumoniae (Pneumococcus) is one of the leading causes of childhood meningitis,pneumonia and sepsis. Despite the availability of childhood vaccination programs and antimicrobial agents, childhood pneumococcal meningitis is still a devastating illness with mortality rates among the highest of any cause of bacterial meningitis. Especially in low-income countries, where medical care is less accessible, mortality rates up to 50 \% have been reported. In surviving patients, neurological sequelae, including hearing loss, focal neurological deficits and cognitive impairment, is reported in 30 to 50 \%. Growing resistance of pneumococci towards conventional antibiotics emphasize the need for effective therapies and development of effective vaccines against Streptococcus pneumoniae. One major virulence factor of Streptococcus pneumoniae is the protein toxin Pneumolysin (PLY). PLY belongs to a family of structurally related toxins, the so-called cholesterol-dependent cytolysins (CDCs). Pneumolysin is produced by almost all clinical isolates of the bacterium. It is expressed during the late log phase of bacterial growth and gets released mainly through spontaneous autolysis of the bacterial cell. After binding to cholesterol in the host cell membranes, oligomerization of up to 50 toxin monomers and rearrangement of the protein structure, PLY forms large pores, leading to cell lysis in higher toxin concentrations. At sub-lytic concentrations, however, PLY mediates several other effects, such as activation of the classic complement pathway and the induction of apoptosis. First experiments with pneumococcal strains, deficient in pneumolysin, showed a reduced virulence of the organism, which emphasizes the contribution of this toxin to the course of bacterial meningitis and the urgent need for the understanding of the multiple mechanisms leading to invasive pneumococcal disease. The aim of this thesis was to shed light on the contribution of pneumolysin to the course of the disease as well as to the mental illness patients are suffering from after recovery from pneumococcal meningitis. Therefore, we firstly investigated the effects of sub-lytic pneumolysin concentrations onto primary mouse neurons, transfected with a GFP construct and imaged with the help of laser scanning confocal microscopy. We discovered two major morphological changes in the dendrites of primary mouse neurons: The formation of focal swellings along the dendrites (so-called varicosities) and the reduction of dendritic spines. To study these effects in a more complex system, closer to the in vivo situation, we established a reproducible method for acute brain slice culturing. With the help of this culturing method, we were able to discover the same morphological changes in dendrites upon challenge with sub-lytic concentrations of pneumolysin. We were able to reverse the seen alterations in dendritic structure with the help of two antagonists of the NMDA receptor, connecting the toxin´s mode of action to a non-physiological stimulation of this subtype of glutamate receptors. The loss of dendritic spines (representing the postsynapse) in our brain slice model could be verified with the help of brain slices from adult mice, suffering from pneumococcal meningitis. By immunohistochemical staining with an antibody against synapsin I, serving as a presynaptic marker, we were able to identify a reduction of synapsin I in the cortex of mice, infected with a pneumococcal strain which is capable of producing pneumolysin. The reduction of synapsin I was higher in these brain slices compared to mice infected with a pneumococcal strain which is not capable of producing pneumolysin, illustrating a clear role for the toxin in the reduction of dendritic spines. The fact that the seen effects weren´t abolished under calcium free conditions clarifies that not only the influx of calcium through the pneumolysin-pore is responsible for the alterations. These findings were further supported by calcium imaging experiments, where an inhibitor of the NMDA receptor was capable of delaying the time point, when the maximum of calcium influx upon PLY challenge was reached. Additionally, we were able to observe the dendritic beadings with the help of immunohistochemistry with an antibody against MAP2, a neuron-specific cytoskeletal protein. These observations also connect pneumolysin´s mode of action to excitotoxicity, as several studies mention the aggregation of MAP2 in dendritic beadings in response to excitotoxic stimuli. All in all, this is the first study connecting pneumolysin to excitotoxic events, which might be a novel chance to tie in other options of treatment for patients suffering from pneumococcal meningitis.}, subject = {Nervenzelle}, language = {en} } @article{JaegerPernitzschRichteretal.2012, author = {J{\"a}ger, Dominik and Pernitzsch, Sandy R. and Richter, Andreas S. and Backofen, Rolf and Sharma, Cynthia M. and Schmitz, Ruth A.}, title = {An archaeal sRNA targeting cis- and trans-encoded mRNAs via two distinct domains}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {21}, doi = {10.1093/nar/gks847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134972}, pages = {10964-10979}, year = {2012}, abstract = {We report on the characterization and target analysis of the small (s) RNA\(_{162}\) in the methanoarchaeon Methanosarcina mazei. Using a combination of genetic approaches, transcriptome analysis and computational predictions, the bicistronic MM2441-MM2440 mRNA encoding the transcription factor MM2441 and a protein of unknown function was identified as a potential target of this sRNA, which due to processing accumulates as three stabile 5' fragments in late exponential growth. Mobility shift assays using various mutants verified that the non-structured single-stranded linker region of sRNA\(_{162}\) (SLR) base-pairs with the MM2440-MM2441 mRNA internally, thereby masking the predicted ribosome binding site of MM2441. This most likely leads to translational repression of the second cistron resulting in dis-coordinated operon expression. Analysis of mutant RNAs in vivo confirmed that the SLR of sRNA\(_{162}\) is crucial for target interactions. Furthermore, our results indicate that sRNA\(_{162}\)-controlled MM2441 is involved in regulating the metabolic switch between the carbon sources methanol and methylamine. Moreover, biochemical studies demonstrated that the 50 end of sRNA\(_{162}\) targets the 5'-untranslated region of the cis-encoded MM2442 mRNA. Overall, this first study of archaeal sRNA/mRNA-target interactions unraveled that sRNA\(_{162}\) acts as an antisense (as) RNA on cis- and trans-encoded mRNAs via two distinct domains, indicating that cis-encoded asRNAs can have larger target regulons than previously anticipated.}, language = {en} } @article{AlbertWeissenbergerVarrallyayRaslanetal.2012, author = {Albert-Weißenberger, Christiane and V{\´a}rrallyay, Csan{\´a}d and Raslan, Furat and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena}, title = {An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75368}, year = {2012}, abstract = {Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI.}, subject = {Medizin}, language = {en} } @phdthesis{Neuenkirchen2012, author = {Neuenkirchen, Nils}, title = {An in vitro system for the biogenesis of small nuclear ribonucleoprotein particles}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71300}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Most protein-encoding genes in Eukaryotes are separated into alternating coding and non-coding sequences (exons and introns). Following the transcription of the DNA into pre-messenger RNA (pre-mRNA) in the nucleus, a macromolecular complex termed spliceosome removes the introns and joins the exons to generate mature mRNA that is exported to the cytoplasm. There, it can be interpreted by ribosomes to generate proteins. The spliceosome consists of five small nuclear ribonucleic acids (snRNAs) and more than 150 proteins. Integral components of this complex are RNA-protein particles (RNPs) composed of one or two snRNAs, seven common (Sm) and a various number of snRNP-specific proteins. The Sm proteins form a ring-structure around a conserved site of the snRNA called Sm site. In vitro, Sm proteins (B/B', D1, D2, D3, E, F, G) and snRNA readily assemble to form snRNPs. In the context of the cell, however, two macromolecular trans-acting factors, the PRMT5 (protein arginine methyltransferases type 5) and the SMN (survival motor neuron) complex, are needed to enable this process. Initially, the Sm proteins in the form of heterooligomers D1/D2, D3/B and F/E/G are sequestered by the type II methyltransferase PRMT5. pICln, a component of the PRMT5 complex, readily interacts with Sm proteins to form two distinct complexes. Whereas the first one comprises pICln and D3/B the second one forms a ring consisting of pICln, D1/D2 and F/E/G (6S). It has been found that pICln prevents the premature interaction of snRNAs with the Sm proteins in these complexes and thus functions as an assembly chaperone imposing a kinetic trap upon the further assembly of snRNPs. PRMT5 catalyzes the symmetrical dimethylation of arginine residues in B/B', D1 and D3 increasing their affinity towards the SMN complex. Finally, the SMN complex interacts with the pICln-Sm protein complexes, expels pICln and mediates snRNP assembly in an ATP-dependent reaction. So far, only little is known about the action of PRMT5 in the early phase of snRNP assembly and especially how the 6S complex is formed. Studies of this have so far been hampered by the unavailability of soluble and biologically active PRMT5 enzyme. The composition of the SMN complex and possible functions of individual subunits have been elucidated or hypothesized in recent years. Still, the exact mechanism of the entire machinery forming snRNPs is poorly understood. In vivo, reduced production of functional SMN protein results in the neurodegenerative disease spinal muscular atrophy (SMA). How specific SMN mutations that have been found in SMA patients cause the disease remains elusive, yet, are likely to interfere with either SMN complex stability or snRNP assembly. The aim of this work was to establish an in vitro system to recapitulate the cytoplasmic assembly of snRNPs. This was enabled by the recombinant production of all PRMT5 and SMN complex components as well as Sm proteins in a combination of bacterial and insect cell expression systems. Co-expression of human PRMT5 and its direct interaction partner WD45 (WD-repeat domain 45) in Sf21 (Spodoptera frugiperda 21) insect cells resulted for the first time in soluble and biologically active enzyme. Recombinant PRMT5/WD45 formed complexes with Sm protein heterooligomers as well as pICln-Sm protein complexes but not with F/E/G alone. Also, the enzyme exhibited a type II methyltransferase activity catalyzing the mono- (MMA) and symmetrical dimethylation (sDMA) of Sm proteins B, D1 and D3. Two experimental setups were devised to quantitatively analyze the overall methylation of substrates as well as to identify the type and relative abundance of specific methylation types. Methylation of Sm proteins followed Michaelis-Menten kinetics. Complex reconstitutions and competition of the methylation reaction indicate that 6S is formed in a step-wise manner on the PRMT5 complex. The analysis of the methylation type could be applied to deduce a model of sequential MMA and sDMA formation. It was found that large Sm protein substrate concentrations favored monomethylation. Following a distributive mechanism this leads to the conclusion that PRMT5 most likely confers partial methylation of several different substrate proteins instead of processing a single substrate iteratively until it is completely dimethylated. Finally, the human SMN complex was reconstituted from recombinant sources and was shown to be active in snRNP formation. The introduction of a modified SMN protein carrying a mutation (E134K) present in spinal muscular atrophy (SMA) proved that mutated complexes can be generated in vitro and that these might be applied to elucidate the molecular etiology of this devastating disease.}, subject = {Biogenese}, language = {en} } @phdthesis{Nilla2012, author = {Nilla, Jaya Santosh Chakravarthy}, title = {An Integrated Knowledgebase and Network Analysis Applied on Platelets and Other Cell Types}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85730}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Systems biology looks for emergent system effects from large scale assemblies of molecules and data, for instance in the human platelets. However, the computational efforts in all steps before such insights are possible can hardly be under estimated. In practice this involves numerous programming tasks, the establishment of new database systems but as well their maintenance, curation and data validation. Furthermore, network insights are only possible if strong algorithms decipher the interactions, decoding the hidden system effects. This thesis and my work are all about these challenges. To answer this requirement, an integrated platelet network, PlateletWeb, was assembled from different sources and further analyzed for signaling in a systems biological manner including multilevel data integration and visualization. PlateletWeb is an integrated network database and was established by combining the data from recent platelet proteome and transcriptome (SAGE) studies. The information on protein-protein interactions and kinase-substrate relationships extracted from bioinformatical databases as well as published literature were added to this resource. Moreover, the mass spectrometry-based platelet phosphoproteome was combined with site-specific phosphorylation/ dephosphorylation information and then enhanced with data from Phosphosite and complemented by bioinformatical sequence analysis for site-specific kinase predictions. The number of catalogued platelet proteins was increased by over 80\% as compared to the previous version. The integration of annotations on kinases, protein domains, transmembrane regions, Gene Ontology, disease associations and drug targets provides ample functional tools for platelet signaling analysis. The PlateletWeb resource provides a novel systems biological workbench for the analysis of platelet signaling in the functional context of protein networks. By comprehensive exploration, over 15000 phosphorylation sites were found, out of which 2500 have the corresponding kinase associations. The network motifs were also investigated in this anucleate cell and characterize signaling modules based on integrated information on phosphorylation and protein-protein interactions. Furthermore, many algorithmic approaches have been introduced, including an exact approach (heinz) based on integer linear programming. At the same time, the concept of semantic similarities between two genes using Gene Ontology (GO) annotations has become an important basis for many analytical approaches in bioinformatics. Assuming that a higher number of semantically similar gene functional annotations reflect biologically more relevant interactions, an edge score was devised for functional network analysis. Bringing these two approaches together, the edge score, based on the GO similarity, and the node score, based on the expression of the proteins in the analyzed cell type (e.g. data from proteomic studies), the functional module as a maximum-scoring sub network in large protein-protein interaction networks was identified. This method was applied to various proteome datasets (different types of blood cells, embryonic stem cells) to identify protein modules that functionally characterize the respective cell type. This scalable method allows a smooth integration of data from various sources and retrieves biologically relevant signaling modules.}, subject = {Systembiologie}, language = {en} } @phdthesis{Kaiser2012, author = {Kaiser, Fabian Marc Philipp}, title = {Analysis of Cross-Clade Neutralizing Antibodies against HIV-1 Env Induced by Immunofocusing}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75494}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Despite intense research efforts, a safe and effective HIV-1/AIDS vaccine still remains far away. HIV-1 escapes the humoral immune response through various mechanisms and until now, only a few nAbs have been identified. A promising strategy to identify new epitopes that may elicit such nAbs is to dissect and analyze the humoral immune response of sera with broadly reactive nAbs. The identified epitopes recognized by these antibodies might then be incorporated into a vaccine to elicit similar nAbs and thus provide protection from HIV-1 infection. Using random peptide phage display libraries, the Ruprecht laboratory has identified the epitopes recognized by polyclonal antibodies of a rhesus monkey with high-titer, broadly reactive nAbs that had been induced after infection with a SHIV encoding env of a recently transmitted HIV-1 clade C. The laboratory analyzed phage peptide inserts for conformational and linear homology with computational assistance. Several of the identified peptides mimicked domains of the original HIV-1 clade Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. As part of this work, these mimotopes were analyzed for cross-reactivity with other sera obtained from rhesus monkeys with nAbs and antibody recognition was shown for several mimotopes, particularly those representing the V3 loop. In addition, these mimotopes were incorporated into a novel DNA prime/phage boost strategy to analyze the immunogenicity of such phage-displayed peptides. Mice were primed only once with HIV-1 clade C gp160 DNA and subsequently boosted with mixtures of recombinant phages. This strategy was designed to focus the humoral immune response on a few, selected Env epitopes (immunofocusing) and induced HIV-1 clade C gp160 binding antibodies and cross-clade nAbs. Furthermore, the C-terminus of gp120, a conserved HIV Env region, was linked to the induction of nAbs for the first time. The identification of such conserved antigens may lead to the development of a vaccine that is capable of inducing broadly reactive nAbs that might confer protection form HIV-1 infection.}, subject = {Antik{\"o}rper}, language = {en} } @article{FernandezRodriguezQuilesBlancoetal.2012, author = {Fern{\´a}ndez-Rodr{\´i}guez, Juana and Quiles, Francisco and Blanco, Ignacio and Teul{\´e}, Alex and Feliubadal{\´o}, L{\´i}dia and del Valle, Jes{\´u}s and Salinas, M{\´o}nica and Izquierdo, {\´A}ngel and Darder, Esther and Schindler, Detlev and Capell{\´a}, Gabriel and Brunet, Joan and L{\´a}zaro, Conxi and Angel Pujana, Miguel}, title = {Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {84}, doi = {10.1186/1471-2407-12-84}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131772}, year = {2012}, abstract = {Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.}, language = {en} } @article{ZirkelCecilSchaeferetal.2012, author = {Zirkel, J. and Cecil, A. and Sch{\"a}fer, F. and Rahlfs, S. and Ouedraogo, A. and Xiao, K. and Sawadogo, S. and Coulibaly, B. and Becker, K. and Dandekar, T.}, title = {Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling}, series = {Bioinformatics and Biology Insights}, volume = {6}, journal = {Bioinformatics and Biology Insights}, doi = {10.4137/BBI.S10193}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123751}, pages = {287-302}, year = {2012}, abstract = {BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data. RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs. CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.}, language = {en} } @article{AbdelmohsenSzesnyOthmanetal.2012, author = {Abdelmohsen, Usama Ramadan and Szesny, Matthias and Othman, Eman Maher and Schirmeister, Tanja and Grond, Stepanie and Stopper, Helga and Hentschel, Ute}, title = {Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76279}, year = {2012}, abstract = {Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70-90 μM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 μM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate.}, subject = {Biologie}, language = {en} } @article{KannenHintzscheZanetteetal.2012, author = {Kannen, Vinicius and Hintzsche, Henning and Zanette, Dalila L. and Silva Jr., Wilson A. and Garcia, Sergio B. and Waaga-Gasser, Anna Maria and Stopper, Helga}, title = {Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75879}, year = {2012}, abstract = {The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G0/G1 phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy.}, subject = {Medizin}, language = {en} } @phdthesis{BasseLuesebrink2012, author = {Basse-L{\"u}sebrink, Thomas Christian}, title = {Application of 19F MRI for in vivo detection of biological processes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77188}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {This thesis focuses on various aspects and techniques of 19F magnetic resonance (MR). The first chapters provide an overview of the basic physical properties, 19F MR and MR sequences related to this work. Chapter 5 focuses on the application of 19F MR to visualize biological processes in vivo using two different animal models. The dissimilar models underlined the wide applicability of 19F MR in preclinical research. A subsection of Chapter 6 shows the application of compressed sensing (CS) to 19F turbo-spin-echo chemical shift imaging (TSE-CSI), which leads to reduced measurement time. CS, however, can only be successfully applied when a sufficient signal-to-noise ratio (SNR) is available. When the SNR is low, so-called spike artifacts occur with the CS algorithm used in the present work. However, it was shown in an additional subsection that these artifacts can be reduced using a CS-based post processing algorithm. Thus, CS might help overcome limitations with time consuming 19F CSI experiments. Chapter 7 deals with a novel technique to quantify the B+1 profile of an MR coil. It was shown that, using a specific application scheme of off resonant pulses, Bloch-Siegert (BS)-based B+1 mapping can be enabled using a Carr Purcell Meiboom Gill (CPMG)-based TSE sequence. A fast acquisition of the data necessary for B+1 mapping was thus enabled. In the future, the application of BS-CPMG-TSE B+1 mapping to improve quantification using 19F MR could therefore be possible.}, subject = {Kernspintomografie}, language = {en} } @article{JazbutyteStumpnerRedeletal.2012, author = {Jazbutyte, Virginija and Stumpner, Jan and Redel, Andreas and Lorenzen, Johan M. and Roewer, Norbert and Thum, Thomas and Kehl, Franz}, title = {Aromatase Inhibition Attenuates Desflurane-Induced Preconditioning against Acute Myocardial Infarction in Male Mouse Heart In Vivo}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151258}, pages = {e42032}, year = {2012}, abstract = {The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17b- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9\% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94615.5\% vs. 17.163.62\%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model.}, language = {en} } @phdthesis{Schaub2012, author = {Schaub, Kerstin}, title = {As Written in the Flesh. The Human Body as Medium of Cultural Identity and Memory in Fiction from New Zealand}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-78336}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {This dissertation focuses on selected novels written by contemporary indigenous authors from Aotearoa/New Zealand and examines the fictional imagination of the human body as a medium of cultural identity and memory. The novels discussed are Keri Hulme's »The Bone People« (1984), »Nights in the Gardens of Spain« (1995) and »The Uncle's Story« (2000) by Witi Ihimaera as well as James George's »Hummingbird« (2003). In order to further decolonisation processes and to come to terms with the colonial past and the complexity of present realities, the fictional works position the human body as an active entity in the negotiation of specific cultural epistemologies. This project explores the narrative translation of corporeality that is used to locate alternative concepts of identity and cultural memory. Taking into account indigenous perspectives, this thesis makes use of the current theoretical approaches presented by pragmatism and affect theory in order to analyse the investment of the novels in feeling and the reciprocal relationship between text and corporeality depicted by the narratives. On the one hand, the novels aim to undermine oppressive and marginalising categories by placing particular emphasis on »sensuous gaps« in the text. On the other hand, the narratives intend to construct alternative identities and evoke specific aspects of indigenous histories and knowledge by imagining the human body in terms of »sensuous inscription«. The novels portray individuals who act from a place in-between different cultures, and articulate a desire to dissolve polarities and emphasise individual and cultural transformation as a formative element in the creation of complex identities and new perspectives.}, subject = {Postkoloniale Literatur}, language = {en} } @article{SchreiberKlughammerKolbowski2012, author = {Schreiber, Ulrich and Klughammer, Christof and Kolbowski, J{\"o}rg}, title = {Assessment of wavelength-dependent parameters of photosynthetic electron transport with a new type of multi-color PAM chlorophyll fluorometer}, series = {Photosynthesis Research}, volume = {113}, journal = {Photosynthesis Research}, number = {1}, doi = {10.1007/s11120-012-9758-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127003}, pages = {127-144}, year = {2012}, abstract = {Technical features of a novel multi-color pulse amplitude modulation (PAM) chlorophyll fluorometer as well as the applied methodology and some typical examples of its practical application with suspensions of Chlorella vulgaris and Synechocystis PCC 6803 are presented. The multi-color PAM provides six colors of pulse-modulated measuring light (peak-wavelengths at 400, 440, 480, 540, 590, and 625 nm) and six colors of actinic light (AL), peaking at 440, 480, 540, 590, 625 and 420-640 nm (white). The AL can be used for continuous illumination, maximal intensity single-turnover pulses, high intensity multiple-turnover pulses, and saturation pulses. In addition, far-red light (peaking at 725 nm) is provided for preferential excitation of PS I. Analysis of the fast fluorescence rise kinetics in saturating light allows determination of the wavelength- and sample-specific functional absorption cross section of PS II, Sigma(II)λ, with which the PS II turnover rate at a given incident photosynthetically active radiation (PAR) can be calculated. Sigma(II)λ is defined for a quasi-dark reference state, thus differing from σPSII used in limnology and oceanography. Vastly different light response curves for Chlorella are obtained with light of different colors, when the usual PAR-scale is used. Based on Sigma(II)λ the PAR, in units of μmol quanta/(m2 s), can be converted into PAR(II) (in units of PS II effective quanta/s) and a fluorescence-based electron transport rate ETR(II) = PAR(II) · Y(II)/Y(II)max can be defined. ETR(II) in contrast to rel.ETR qualifies for quantifying the absolute rate of electron transport in optically thin suspensions of unicellular algae and cyanobacteria. Plots of ETR(II) versus PAR(II) for Chlorella are almost identical using either 440 or 625 nm light. Photoinhibition data are presented suggesting that a lower value of ETR(II)max with 440 nm possibly reflects photodamage via absorption by the Mn-cluster of the oxygen-evolving complex.}, language = {en} } @phdthesis{Froehlich2012, author = {Fr{\"o}hlich, Kathrin}, title = {Assigning functions to Hfq-dependent small RNAs in the model pathogen Salmonella Typhimurium}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85488}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Non-coding RNAs constitute a major class of regulators involved in bacterial gene expression. A group of riboregulators of heterogeneous size and shape referred to as small regulatory RNAs (sRNAs) control trans- or cis-encoded genes through direct base-pairing with their mRNAs. Although mostly inhibiting their target mRNAs, several sRNAs also induce gene expression. An important co-factor for sRNA activity is the RNA chaperone, Hfq, which is able to rearrange intramolecular secondary structures and to promote annealing of complementary RNA sequences. In addition, Hfq protects unpaired RNA from degradation by ribonucleases and thus increases sRNA stability. Co-immunoprecipitation of RNA with the Hfq protein, and further experimental as well as bioinformatical studies performed over the last decade suggested the presence of more than 150 different sRNAs in various Enterobacteria including Escherichia coli and Salmonellae. So-called core sRNAs are considered to fulfill central cellular activities as deduced from their high degree of conservation among different species. Approximately 25 core sRNAs have been implicated in gene regulation under a variety of environmental responses. However, for the majority of sRNAs, both the riboregulators' individual biological roles as well as modes of action remain to be elucidated. The current study aimed to define the cellular functions of the two highly conserved, Hfq-dependent sRNAs, SdsR and RydC, in the model pathogen Salmonella Typhimurium. SdsR had been known as one of the most abundant sRNAs during stationary growth phase in E. coli. Examination of the conservation patterns in the sdsR promoter region in combination with classic genetic analyses revealed SdsR as the first sRNA under direct transcriptional control of the alternative σ factor σS. In Salmonella, over-expression of SdsR down-regulates the synthesis of the major porin OmpD, and the interaction site in the ompD mRNA coding sequence was mapped by a 3'RACE-based approach. At the post-transcriptional level, expression of ompD is controlled by three additional sRNAs, but SdsR plays a specific role in porin regulation during the stringent response. Similarly, RydC, the second sRNA adressed in this study, was initially discovered in E. coli but appeared to be conserved in many related γ-proteobacteria. An interesting aspect of this Hfq-dependent sRNAs is its secondary structure involving a pseudo-knot configuration, while the 5' end remains single stranded. A transcriptomic approach combining RydC pulse-expression and scoring of global mRNA changes on microarrays was employed to identify the targets of this sRNA. RydC specifically activated expression of the longer of two versions of the cfa mRNA encoding for the phospholipid-modifying enzyme cyclopropane fatty acid synthase. Employing its conserved single-stranded 5' end, RydC acts as a positive regulator and masks a recognition site of the endoribonuclease, RNase E, in the cfa leader.}, subject = {Small RNA}, language = {en} } @article{ZwinkJenetzkySchmiedekeetal.2012, author = {Zwink, Nadine and Jenetzky, Ekkehart and Schmiedeke, Eberhard and Schmidt, Dominik and M{\"a}rzheuser, Schmidt and Grasshoff-Derr, Sabine and Holland-Cunz, Stefan and Weih, Sandra and Hosie, Stuart and Reifferscheid, Peter and Ameis, Helen and Kujath, Christina and Rissmann, Anke and Obermayr, Florian and Schwarzer, Nicole and Bartels, Enrika and Reutter, Heiko and Brenner, Hermann}, title = {Assisted reproductive techniques and the risk of anorectal malformations: a German case-control study}, series = {Orphanet Journal of Rare Diseases}, volume = {7}, journal = {Orphanet Journal of Rare Diseases}, number = {65}, organization = {CURE-Net Consortium}, doi = {10.1186/1750-1172-7-65}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134036}, year = {2012}, abstract = {Background: The use of assisted reproductive techniques (ART) for treatment of infertility is increasing rapidly worldwide. However, various health effects have been reported including a higher risk of congenital malformations. Therefore, we assessed the risk of anorectal malformations (ARM) after in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: Data of the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared to nationwide data of the German IVF register and the Federal Statistical Office (DESTATIS). Odds ratios (95\% confidence intervals) were determined to quantify associations using multivariable logistic regression accounting for potential confounding or interaction by plurality of births. Results: In total, 295 ARM patients born between 1997 and 2011 in Germany, who were recruited through participating pediatric surgeries from all over Germany and the German self-help organisation SoMA, were included. Controls were all German live-births (n = 10,069,986) born between 1997 and 2010. Overall, 30 cases (10\%) and 129,982 controls (1\%) were born after IVF or ICSI, which translates to an odds ratio (95\% confidence interval) of 8.7 (5.9-12.6) between ART and ARM in bivariate analyses. Separate analyses showed a significantly increased risk for ARM after IVF (OR, 10.9; 95\% CI, 6.2-19.0; P < 0.0001) as well as after ICSI (OR, 7.5; 95\% CI, 4.6-12.2; P < 0.0001). Furthermore, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed strong associations with ART (ORs 4.9, 11.9 and 7.9, respectively). After stratification for plurality of birth, the corresponding odds ratios (95\% confidence intervals) were 7.7 (4.6-12.7) for singletons and 4.9 (2.4-10.1) for multiple births. Conclusions: There is a strongly increased risk for ARM among children born after ART. Elevations of risk were seen after both IVF and ICSI. Further, separate analyses of patients with isolated ARM, ARM with associated anomalies and those with a VATER/VACTERL association showed increased risks in each group. An increased risk of ARM was also seen among both singletons and multiple births.}, language = {en} } @phdthesis{Heidbreder2012, author = {Heidbreder, Meike}, title = {Association and Activation of TNF-Receptor I Investigated with Single-Molecule Tracking and Super-Resolution Microscopy in Live Cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73191}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Cellular responses to outer stimuli are the basis for all biological processes. Signal integration is achieved by protein cascades, recognizing and processing molecules from the environment. Factors released by pathogens or inflammation usually induce an inflammatory response, a signal often transduced by Tumour Necrosis Factor alpha (TNF). TNFα receptors TNF-R1 and TNF-R2 can in turn lead to apoptosis or proliferation via NF-B. These processes are closely regulated by membrane compartimentalization, protein interactions and trafficking. Fluorescence microscopy offers a reliable and non-invasive method to probe these cellular events. However, some processes on a native membrane are not resolvable, as they are well below the diffraction limit of microscopy. The recent development of super-resolution fluorescence microscopy methods enables the observation of these cellular players well below this limit: by localizing, tracking and counting molecules with high spatial and temporal resolution, these new fluorescence microscopy methods offer a previously unknown insight into protein interactions at the near-molecular level. Direct stochastic optical reconstruction microscopy (dSTORM) utilizes the reversible, stochastic blinking events of small commercially available fluorescent dyes, while photoactivated localization microscopy (PALM) utilizes phototransformation of genetically encoded fluorescent proteins. By photoactivating only a small fraction of the present fluorophores in each observation interval, single emitters can be localized with high precision and a super-resolved image can be reconstructed. Quantum Dot Triexciton imaging (QDTI) utilizes the three-photon absorption (triexcitonic) properties of quantum dots (QD) and to achieve a twofold resolution increase using conventional confocal microscopes. In this thesis, experimental approaches were implemented to achieve super-resolution microscopy in fixed and live-cells to study the spatial and temporal dynamics of TNF and other cellular signaling events. We introduce QDTI to study the three-dimensional cellular distribution of biological targets, offering an easy method to achieve resolution enhancement in combination with optical sectioning, allowing the preliminary quantification of labeled proteins. As QDs are electron dense, QDTI can be used for correlative fluorescence and transmission electron microscopy, proving the versatility of QD probes. Utilizing the phototransformation properties of fluorescent proteins, single-receptor tracking on live cells was achieved, applying the concept of single particle tracking PALM (sptPALM) to track the dynamics of a TNF-R1-tdEos chimera on the membrane. Lateral receptor dynamics can be tracked with high precision and the influences of ligand addition or lipid disruption on TNF-R1 mobility was observed. The results reveal complex receptor dynamics, implying internalization processes in response to TNFα stimulation and a role for membrane domains with reduced fluidity, so-called lipid raft domains, in TNF-R1 compartimentalization prior or post ligand induction. Comparisons with previously published FCS data show a good accordance, but stressing the increased data depth available in sptPALM experiments. Additionally, the active transport of NF-κB-tdEos fusions was observed in live neurons under chemical stimulation and/or inhibition. Contrary to phototransformable proteins that need no special buffers to exhibit photoconversion or photoactivation, dSTORM has previously been unsuitable for in vivo applications, as organic dyes relied on introducing the probes via immunostaining in concert with a reductive, oxygen-free medium for proper photoswitching behaviour. ATTO655 had been previously shown to be suitable for live-cell applications, as its switching behavior can be catalyzed by the reductive environment of the cytoplasm. By introducing the cell-permeant organic dye via a chemical tag system, a high specificity and low background was achieved. Here, the labeled histone H2B complex and thus single nucleosome movements in a live cell can be observed over long time periods and with ~20 nm resolution. Implementing these new approaches for imaging biological processes with high temporal and spatial resolution provides new insights into the dynamics and spatial heterogeneities of proteins, further elucidating their function in the organism and revealing properties that are usually only detectable in vitro.  }, subject = {Fluoreszenzmikrosopie}, language = {en} } @article{TomeiAdamsUccellinietal.2012, author = {Tomei, Sara and Adams, Sharon and Uccellini, Lorenzo and Bedognetti, Davide and De Giorgi, Valeria and Erdenebileg, Narnygerel and Libera Ascierto, Maria and Reinboth, Jennifer and Liu, Qiuzhen and Bevilacqua, Generoso and Wang, Ena and Mazzanti, Chiara and Marincola, Francesco M.}, title = {Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population}, series = {Medical Oncology}, volume = {29}, journal = {Medical Oncology}, number = {5}, doi = {dx.doi.org/10.1007/s12032-012-0255-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126834}, pages = {3456-3461}, year = {2012}, abstract = {HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.}, language = {en} } @article{OPUS4-12888, title = {ATLAS search for a heavy gauge boson decaying to a charged lepton and a neutrino in pp collisions at √s=7 TeV}, series = {The European Physical Journal C}, volume = {72}, journal = {The European Physical Journal C}, number = {2241}, organization = {ATLAS Collaboration}, doi = {10.1140/epjc/s10052-012-2241-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128888}, year = {2012}, abstract = {The ATLAS detector at the LHC is used to search for high-mass states, such as heavy charged gauge bosons (W′), decaying to a charged lepton (electron or muon) and a neutrino. Results are presented based on the analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.7 fb\(^{-1}\). No excess beyond Standard Model expectations is observed. A W′ with Sequential Standard Model couplings is excluded at the 95 \% credibility level for masses up to 2.55 TeV. Excited chiral bosons (W∗) with equivalent coupling strength are excluded for masses up to 2.42 TeV.}, language = {en} } @article{ChenGassnerBoerneretal.2012, author = {Chen, Wen and Gaßner, Birgit and B{\"o}rner, Sebastian and Nikolaev, Viacheslav O. and Schlegel, Nicolas and Waschke, Jens and Steinbronn, Nadine and Strasser, Ruth and Kuhn, Michaela}, title = {Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway}, series = {Cardiovascular Research}, volume = {93}, journal = {Cardiovascular Research}, number = {1}, doi = {10.1093/cvr/cvr279}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126562}, pages = {141-151}, year = {2012}, abstract = {Aims Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP. Methods and results Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1-/- mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains. Conclusion ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume.}, language = {en} } @article{WolffRutter2012, author = {Wolff, Alexander and Rutter, Iganz}, title = {Augmenting the Connectivity of Planar and Geometric Graphs}, series = {Journal of Graph Algorithms and Applications}, journal = {Journal of Graph Algorithms and Applications}, doi = {10.7155/jgaa.00275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97587}, year = {2012}, abstract = {In this paper we study connectivity augmentation problems. Given a connected graph G with some desirable property, we want to make G 2-vertex connected (or 2-edge connected) by adding edges such that the resulting graph keeps the property. The aim is to add as few edges as possible. The property that we consider is planarity, both in an abstract graph-theoretic and in a geometric setting, where vertices correspond to points in the plane and edges to straight-line segments. We show that it is NP-hard to � nd a minimum-cardinality augmentation that makes a planar graph 2-edge connected. For making a planar graph 2-vertex connected this was known. We further show that both problems are hard in the geometric setting, even when restricted to trees. The problems remain hard for higher degrees of connectivity. On the other hand we give polynomial-time algorithms for the special case of convex geometric graphs. We also study the following related problem. Given a planar (plane geometric) graph G, two vertices s and t of G, and an integer c, how many edges have to be added to G such that G is still planar (plane geometric) and contains c edge- (or vertex-) disjoint s{t paths? For the planar case we give a linear-time algorithm for c = 2. For the plane geometric case we give optimal worst-case bounds for c = 2; for c = 3 we characterize the cases that have a solution.}, language = {en} } @article{ElKeredySchleyerKoenigetal.2012, author = {El-Keredy, Amira and Schleyer, Michael and K{\"o}nig, Christian and Ekim, Aslihan and Gerber, Bertram}, title = {Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040525}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130811}, pages = {e40525}, year = {2012}, abstract = {Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant.}, language = {en} } @article{GrossHennardMasourisetal.2012, author = {Gross, Henrik and Hennard, Christine and Masouris, Ilias and Cassel, Christian and Barth, Stephanie and Stober-Gr{\"a}sser, Ute and Mamiani, Alfredo and Moritz, Bodo and Ostareck, Dirk and Ostareck-Lederer, Antje and Neuenkirchen, Nils and Fischer, Utz and Deng, Wen and Leonhardt, Heinrich and Noessner, Elfriede and Kremmer, Elisabeth and Gr{\"a}sser, Friedrich A.}, title = {Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0042106}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133707}, year = {2012}, abstract = {The Epstein-Barr Virus (EBV) -encoded EBNA2 protein, which is essential for the in vitro transformation of B-lymphocytes, interferes with cellular processes by binding to proteins via conserved sequence motifs. Its Arginine-Glycine (RG) repeat element contains either symmetrically or asymmetrically di-methylated arginine residues (SDMA and ADMA, respectively). EBNA2 binds via its SDMA-modified RG-repeat to the survival motor neurons protein (SMN) and via the ADMA-RG-repeat to the NP9 protein of the human endogenous retrovirus K (HERV-K (HML-2) Type 1). The hypothesis of this work was that the methylated RG-repeat mimics an epitope shared with cellular proteins that is used for interaction with target structures. With monoclonal antibodies against the modified RG-repeat, we indeed identified cellular homologues that apparently have the same surface structure as methylated EBNA2. With the SDMA-specific antibodies, we precipitated the Sm protein D3 (SmD3) which, like EBNA2, binds via its SDMA-modified RG-repeat to SMN. With the ADMA-specific antibodies, we precipitated the heterogeneous ribonucleoprotein K (hnRNP K). Specific binding of the ADMA-antibody to hnRNP K was demonstrated using E. coli expressed/ADMA-methylated hnRNP K. In addition, we show that EBNA2 and hnRNP K form a complex in EBV-infected B-cells. Finally, hnRNP K, when co-expressed with EBNA2, strongly enhances viral latent membrane protein 2A (LMP2A) expression by an unknown mechanism as we did not detect a direct association of hnRNP K with DNA-bound EBNA2 in gel shift experiments. Our data support the notion that the methylated surface of EBNA2 mimics the surface structure of cellular proteins to interfere with or co-opt their functional properties.}, language = {en} } @article{BerendzenWeisteWankeetal.2012, author = {Berendzen, Kenneth W. and Weiste, Christoph and Wanke, Dierk and Kilian, Joachim and Harter, Klaus and Dr{\"o}ge-Laser, Wolfgang}, title = {Bioinformatic cis-element analyses performed in Arabidopsis and rice disclose bZIP- and MYB-related binding sites as potential AuxRE-coupling elements in auxin-mediated transcription}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75138}, year = {2012}, abstract = {Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation.}, subject = {Arabidopsis}, language = {en} } @phdthesis{Zeeshan2012, author = {Zeeshan, Ahmed}, title = {Bioinformatics Software for Metabolic and Health Care Data Management}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73926}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Computer Science approaches (software, database, management systems) are powerful tools to boost research. Here they are applied to metabolic modelling in infections as well as health care management. Starting from a comparative analysis this thesis shows own steps and examples towards improvement in metabolic modelling software and health data management. In section 2, new experimental data on metabolites and enzymes induce high interest in metabolic modelling including metabolic flux calculations. Data analysis of metabolites, calculation of metabolic fluxes, pathways and their condition-specific strengths is now possible by an advantageous combination of specific software. How can available software for metabolic modelling be improved from a computational point of view? A number of available and well established software solutions are first discussed individually. This includes information on software origin, capabilities, development and used methodology. Performance information is obtained for the compared software using provided example data sets. A feature based comparison shows limitations and advantages of the compared software for specific tasks in metabolic modeling. Often found limitations include third party software dependence, no comprehensive database management and no standard format for data input and output. Graphical visualization can be improved for complex data visualization and at the web based graphical interface. Other areas for development are platform independency, product line architecture, data standardization, open source movement and new methodologies. The comparison shows clearly space for further software application development including steps towards an optimal user friendly graphical user interface, platform independence, database management system and third party independence especially in the case of desktop applications. The found limitations are not limited to the software compared and are of course also actively tackled in some of the most recent developments. Other improvements should aim at generality and standard data input formats, improved visualization of not only the input data set but also analyzed results. We hope, with the implementation of these suggestions, metabolic software applications will become more professional, cheap, reliable and attractive for the user. Nevertheless, keeping these inherent limitations in mind, we are confident that the tools compared can be recommended for metabolic modeling for instance to model metabolic fluxes in bacteria or metabolic data analysis and studies in infection biology. ...}, subject = {Stoffwechsel}, language = {en} } @article{GerlachMaetzlerBroichetal.2012, author = {Gerlach, Manfred and Maetzler, Walter and Broich, Karl and Hampel, Harald and Rems, Lucas and Reum, Torsten and Riederer, Peter and St{\"a}ffler, Albrecht and Streffer, Johannes and Berg, Daniela}, title = {Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics}, series = {Journal of Neural Transmission}, volume = {119}, journal = {Journal of Neural Transmission}, number = {1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125375}, pages = {39-52}, year = {2012}, abstract = {Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.}, language = {en} } @article{ArnoldBraunschweigDamme2012, author = {Arnold, Nicole and Braunschweig, Holger and Damme, Alexander}, title = {Bis(μ-diisopropyl-phosphanido-\(κ^2\)P:P)bis-[hydrido(triisopropyl-phosphane-κP)platinum(II)]}, series = {Acta crystallographica. Section E, Structure reports online}, volume = {E68}, journal = {Acta crystallographica. Section E, Structure reports online}, doi = {http://dx.doi.org/10.1107/S1600536812022829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123723}, pages = {m808}, year = {2012}, abstract = {In the centrosymmetric molecular structure of the title compound \([Pt_2(C_6H_{14}P)_2H_2)(C_9H_{21}P)_2]\), each \(Pt^{II}\) atom is bound on one side to a phosphane ligand \((PiPr_3)\) and a hydrido ligand. On the other side, it is bound to two phosphanide ligands \((μ-PiPr_2)\), which engage a bridging position between the two \(Pt^{II}\) atoms, forming a distorted square-planar structure motif. The PtPt distance is 3.6755(2){\AA}. A comparable molecular structure was observed for bis-(μ-di-tert-butyl-phosphanido)bis-[hydrido(triethyl-phosphane)platinum(II)] [Itazaki et al. (2004 ). Organometallics, 23, 1610-1621].}, language = {en} } @article{NassWeissbrichHuberetal.2012, author = {Nass, Maximilian and Weissbrich, Benedikt and Huber, Moritz and Schneider, Elisabeth Marion and Weiss, Manfred}, title = {BK viremia in critically ill surgical patients with hemorrhagic or septic shock}, series = {BMC Research Notes}, volume = {5}, journal = {BMC Research Notes}, number = {100}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124136}, year = {2012}, abstract = {Background Infections with polyomavirus BK virus (BKV) are a common cause of renal dysfunction after renal transplantation and may also be harmful in surgical patients with shock. The aim of the present study was to determine the frequency of BKV viremia in critically ill surgical patients with septic or hemorrhagic shock, and, if viremia is detectable, whether viremia may be associated with renal dysfunction. Findings A total of 125 plasma samples from 44 critically ill surgical patients with septic or hemorrhagic shock were tested by real-time polymerase chain reaction (PCR) for BKV DNA during their stay on the intensive care unit (ICU). BKV viremia occurred in four patients, i.e. in three of the septic and in one of the hemorrhagic shock group. There was no association between viremia and renal dysfunction. All positive samples contained a low viral load (< 500 copies/ml). Conclusions Since BK viremia was rarely found and with low viral load only in critically ill surgical patients with shock, it is very unlikely that BK viremia results in BK nephropathy later on.}, language = {en} } @article{AlbertWeissenbergerStetterMeuthetal.2012, author = {Albert-Weissenberger, Christiane and Stetter, Christian and Meuth, Sven G. and G{\"o}bel, Kerstin and Bader, Michael and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph}, title = {Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {9}, doi = {10.1038/jcbfm.2012.62}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125903}, pages = {1747-1756}, year = {2012}, abstract = {The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.}, language = {en} } @article{WestermaierStetterRaslanetal.2012, author = {Westermaier, Thomas and Stetter, Christian and Raslan, Furat and Vinc, Giles Hamilton and Ernestus, Ralf-Ingo}, title = {Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75765}, year = {2012}, abstract = {Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague-Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH.}, subject = {Medizin}, language = {en} } @article{KesslerHertelJungkunstetal.2012, author = {Kessler, Michael and Hertel, Dietrich and Jungkunst, Hermann F. and Kluge, J{\"u}rgen and Abrahamczyk, Stefan and Bos, Merijn and Buchori, Damayanti and Gerold, Gerhard and Gradstein, S. Robbert and K{\"o}hler, Stefan and Leuschner, Christoph and Moser, Gerald and Pitopang, Ramadhanil and Saleh, Shahabuddin and Schulze, Christian H. and Sporn, Simone G. and Steffan-Dewenter, Ingolf and Tjitrosoedirdjo, Sri S. and Tscharntke, Teja}, title = {Can Joint Carbon and Biodiversity Management in Tropical Agroforestry Landscapes Be Optimized?}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {10}, doi = {10.1371/journal.pone.0047192}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132016}, pages = {e47192}, year = {2012}, abstract = {Managing ecosystems for carbon storage may also benefit biodiversity conservation, but such a potential 'win-win' scenario has not yet been assessed for tropical agroforestry landscapes. We measured above-and below-ground carbon stocks as well as the species richness of four groups of plants and eight of animals on 14 representative plots in Sulawesi, Indonesia, ranging from natural rainforest to cacao agroforests that have replaced former natural forest. The conversion of natural forests with carbon stocks of 227-362 Mg C ha\(^{-1}\) to agroforests with 82-211 Mg C ha\(^{-1}\) showed no relationships to overall biodiversity but led to a significant loss of forest-related species richness. We conclude that the conservation of the forest-related biodiversity, and to a lesser degree of carbon stocks, mainly depends on the preservation of natural forest habitats. In the three most carbon-rich agroforestry systems, carbon stocks were about 60\% of those of natural forest, suggesting that 1.6 ha of optimally managed agroforest can contribute to the conservation of carbon stocks as much as 1 ha of natural forest. However, agroforestry systems had comparatively low biodiversity, and we found no evidence for a tight link between carbon storage and biodiversity. Yet, potential win-win agroforestry management solutions include combining high shade-tree quality which favours biodiversity with cacao-yield adapted shade levels.}, language = {en} } @article{MaidenFrosch2012, author = {Maiden, Martin C. J. and Frosch, Matthias}, title = {Can we, should we, eradicate the meningococcus?}, series = {Vaccine}, volume = {30}, journal = {Vaccine}, number = {Suppl. 2}, doi = {10.1016/j.vaccine.2011.12.068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125646}, pages = {B52-B56}, year = {2012}, abstract = {The eradication of infectious agents is an attractive means of disease control that, to date, has been achieved for only one human pathogen, the smallpox virus. The introduction of vaccines against Neisseria meningitidis into immunisation schedules, and particularly the conjugate polysaccharide vaccines which can interrupt transmission, raises the question of whether disease caused by this obligate human bacterium can be controlled, eliminated, or even eradicated. The limited number of meningococcal serogroups, lack of an animal reservoir, and importance of meningococcal disease are considerations in favour of eradication; however, the commensal nature of most infections, the high diversity of meningococcal populations, and the lack of comprehensive vaccines are all factors that suggest that this is not feasible. Indeed, any such attempt might be harmful by perturbing the human microbiome and its interaction with the immune system. On balance, the control and possible elimination of disease caused by particular disease-associated meningococcal genotypes is a more achievable and worthwhile goal.}, language = {en} } @article{NordbeckBeerKoestleretal.2012, author = {Nordbeck, Peter and Beer, Meinrad and K{\"o}stler, Herbert and Ladd, Mark E. and Quick, Harald H. and Bauer, Wolfgang R. and Ritter, Oliver}, title = {Cardiac catheter ablation under real-time magnetic resonance guidance}, series = {European Heart Journal}, volume = {33}, journal = {European Heart Journal}, number = {15}, doi = {10.1093/eurheartj/ehs139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125638}, year = {2012}, abstract = {One of the main shortcomings of interventional electrophysiology (EP) is its inability to generate sufficient soft tissue contrast for intra-procedural visualization of the myocardium and the surrounding tissue, using conventional imaging techniques. Interventional cardiovascular magnetic resonance imaging (MRI) aims at bringing about significant improvements to the complex and decisive EP interventions far beyond the capabilities of currently available supportive imaging techniques used to surmount the drawbacks of fluoroscopy, as MRI not only allows of precise three-dimensional exposure of the cardiovascular morphology, but also proves to be a promising technique exclusively suitable for direct visualization of arrhythmogenic substrate and therapeutic effects. The major challenge posed by clinical …}, language = {en} } @article{GaiserGeissingerSchattenbergetal.2012, author = {Gaiser, Timo and Geissinger, Eva and Schattenberg, Torsten and Scharf, Hanns-Peter and D{\"u}rken, Matthias and Dinter, Dietmar and Rosenwald, Andreas and Marx, Alexander}, title = {Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle}, series = {Diagnostic Pathology}, volume = {7}, journal = {Diagnostic Pathology}, number = {38}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135381}, year = {2012}, abstract = {Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL). We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy.}, language = {en} } @article{SlaninaHeblingHaucketal.2012, author = {Slanina, Heiko and Hebling, Sabrina and Hauck, Christoph R. and Schubert-Unkmeir, Alexandra}, title = {Cell Invasion by Neisseria meningitidis Requires a Functional Interplay between the Focal Adhesion Kinase, Src and Cortactin}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75354}, year = {2012}, abstract = {Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90\%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells.}, subject = {Medizin}, language = {en} } @article{AlbSieAdametal.2012, author = {Alb, Miriam and Sie, Christopher and Adam, Christian and Chen, Suzie and Becker, J{\"u}rgen C. and Schrama, David}, title = {Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {12}, doi = {10.1007/s00262-012-1290-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125096}, pages = {2239-2249}, year = {2012}, abstract = {Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.}, language = {en} } @phdthesis{Reinboth2012, author = {Reinboth, Jennifer}, title = {Cellular Factors Contributing to Host Cell Permissiveness in Support of Oncolytic Vaccinia Virus Replication}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85392}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {In initial experiments, the well characterized VACV strain GLV-1h68 and three wild-type LIVP isolates were utilized to analyze gene expression in a pair of autologous human melanoma cell lines (888-MEL and 1936 MEL) after infection. Microarray analyses, followed by sequential statistical approaches, characterized human genes whose transcription is affected specifically by VACV infection. In accordance with the literature, those genes were involved in broad cellular functions, such as cell death, protein synthesis and folding, as well as DNA replication, recombination, and repair. In parallel to host gene expression, viral gene expression was evaluated with help of customized VACV array platforms to get better insight over the interplay between VACV and its host. Our main focus was to compare host and viral early events, since virus genome replication occurs early after infection. We observed that viral transcripts segregated in a characteristic time-specific pattern, consistent with the three temporal expression classes of VACV genes, including a group of genes which could be classified as early-stage genes. In this work, comparison of VACV early replication and respective early gene transcription led to the identification of seven viral genes whose expression correlated strictly with replication. We considered the early expression of those seven genes to be representative for VACV replication and we therefore referred to them as viral replication indicators (VRIs). To explore the relationship between host cell transcription and viral replication, we correlated viral (VRI) and human early gene expression. Correlation analysis revealed a subset of 114 human transcripts whose early expression tightly correlated with early VRI expression and thus early viral replication. These 114 human molecules represented an involvement in broad cellular functions. We found at least six out of 114 correlates to be involved in protein ubiquitination or proteasomal function. Another molecule of interest was the serine-threonine protein kinase WNK lysine-deficient protein kinase 1 (WNK1). We discovered that WNK1 features differences on several molecular biological levels associated with permissiveness to VACV infection. In addition to that, a set of human genes was identified with possible predictive value for viral replication in an independent dataset. A further objective of this work was to explore baseline molecular biological variances associated with permissiveness which could help identifying cellular components that contribute to the formation of a permissive phenotype. Therefore, in a subsequent approach, we screened a set of 15 melanoma cell lines (15-MEL) regarding their permissiveness to GLV-1h68, evaluated by GFP expression levels, and classified the top four and lowest four cell lines into high and low permissive group, respectively. Baseline gene transcriptional data, comparing low and highly permissive group, suggest that differences between the two groups are at least in part due to variances in global cellular functions, such as cell cycle, cell growth and proliferation, as well as cell death and survival. We also observed differences in the ubiquitination pathway, which is consistent with our previous results and underlines the importance of this pathway in VACV replication and permissiveness. Moreover, baseline microRNA (miRNA) expression between low and highly permissive group was considered to provide valuable information regarding virus-host co-existence. In our data set, we identified six miRNAs that featured varying baseline expression between low and highly permissive group. Finally, copy number variations (CNVs) between low and highly permissive group were evaluated. In this study, when investigating differences in the chromosomal aberration patterns between low and highly permissive group, we observed frequent segmental amplifications within the low permissive group, whereas the same regions were mostly unchanged in the high group. Taken together, our results highlight a probable correlation between viral replication, early gene expression, and the respective host response and thus a possible involvement of human host factors in viral early replication. Furthermore, we revealed the importance of cellular baseline composition for permissiveness to VACV infection on different molecular biological levels, including mRNA expression, miRNA expression, as well as copy number variations. The characterization of human target genes that influence viral replication could help answering the question of host cell response to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome.}, subject = {Vaccinia-Virus}, language = {en} } @phdthesis{Kronhardt2012, author = {Kronhardt, Angelika}, title = {Channel Formation, Binding and Translocation Properties of Anthrax, CDT and Related Toxins of the AB7 type}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71559}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The ability to produce toxins is spread among a huge variety of bacterial strains. A very prominent class of bacterial protein toxins is the family of binary AB toxins sharing a common mode of intoxication. A pore forming component B binds and translocates an enzymatic component A into the cytosol of target cells exhibiting a fatal mode of action. These components are supposed to be not toxic themselves but both required for cell toxicity. Anthrax toxin produced by the Gram-positive bacteria Bacillus anthracis is the best studied binary toxin especially since its use as a biological weapon in the context of the attacks of 9/11 in 2001. In contrast to other binary toxins, Anthrax toxin possesses two different enzymatic components, edema factor (EF), a calcium- and calmodulin-dependent adenylat-cyclase and lethal factor (LF), a zinc-dependent metalloprotease. Protective antigen (PA) is the pore-forming component responsible for binding and translocation. Clostridium botulinum possesses in addition to the well known botulinum toxin (Botox) a variety of other toxins, such as the binary C2 toxin. C2 toxin is composed of the binding and translocation moiety C2II and the enzymatic moiety C2I acting as an actin-ADP-ribosyltransferase. In this study, the mode of translocation and the binding kinetics to the enzymatic component were studied in a biophysical experimental setup. In chapter 2, the binding of the N-terminal fractions EFN and LFN to the PA channel are analyzed in artificial bilayer membranes revealing lower binding affinity compared to full-length EF and LF. Other biophysical properties like voltage-dependency and ionic-strength dependency are not influenced. The results suggest that additional forces are involved in the binding process, than those concerning the N-terminus exclusively, as it was supposed previously. As the treatment of an Anthrax infection with antibiotics is often medicated very late due to the lack of early symptoms, tools to prevent intoxication are required. 4-aminoquinolones like chloroquine are known to block the PA channel, thereby inhibiting intoxication but they also lead to severe side-effects. In chapter 3 new promising agents are described that bind to PA in artificial bilayer systems, elucidating common motives and features which are necessary for binding to PA in general. The possible interaction of Anthrax and C2 toxin is investigated by measuring the binding of one enzymatic component to the respective other toxin's pore (chapter 4). Interestingly, in vitro experiments using the black lipid bilayer assay show that PA is able to bind to C2I resulting in half saturation constants in the nanomolar range. Furthermore, in vivo this combination of toxin components exhibits cell toxicity in human cell lines. This is first-time evidence that a heterologous toxin combination is functional in in vitro and in vivo systems. In contrast, C2II is able to bind to EF as well as to LF in vitro, whereas in in vivo studies almost no toxic effect is detected. In the case of PA, an N-terminal His6-tag attached to the enzymatic subunit increased the binding affinity (chapter 5). A His6-tag attached to not related proteins also led to high binding affinities, providing the possibility to establish PA as a general cargo protein. In chapter 6 a set of different molecules and proteins is summarized, which are either related or not related to binary toxins, PA is able to bind. In first line, the presence of positive charges is found to be responsible for binding to PA which is in accordance to the fact that PA is highly cation selective. Furthermore, we present evidence that different cationic electrolytes serve as a binding partner to the PA channel. In the last decade another toxin has aroused public attention as it was found to be responsible for a rising number of nosocomial infections: Clostridium difficile CDT toxin. The mode of action of the enzymatic subunit CDTa is similar to C2I of C2 toxin, acting as an ADP-ribosylating toxin. The channel forming and binding properties of CDT toxin are studied in artificial bilayer membranes (chapter 7). We found that two different types of channels are formed by the B component CDTb. The first channel is similar to that of iota toxin's Ib of Clostridium perfringens with comparable single channel conductance, selectivity and binding properties to the enzymatic subunit CDTa. The formation of this type of channel is cholesterol-dependent, whereas in the absence of cholesterol another kind of channel is observed. This channel has a single channel conductance which is rather high compared to all other binary toxin channels known so far, it is anion selective and does not show any binding affinity to the enzymatic component CDTa. The results reveal completely new insights in channel formation properties and the flexibility of a pore-forming component. Additionally, these findings suggest further possibilities of toxicity of the pore forming component itself which is not known for any other binary toxin yet. Therefore, the pathogenic role of this feature has to be studied in detail.}, subject = {Bacillus anthracis}, language = {en} } @article{DrechslerGroetzingerHermanns2012, author = {Drechsler, Johannes and Groetzinger, Joachim and Hermanns, Heike M.}, title = {Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0043155}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133879}, year = {2012}, abstract = {Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology.}, language = {en} } @article{DrechslerGroetzingerHermanns2012, author = {Drechsler, Johannes and Gr{\"o}tzinger, Joachim and Hermanns, Heike M.}, title = {Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-78856}, year = {2012}, abstract = {Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology.}, subject = {Biologie}, language = {en} } @article{HomannTimmSeibel2012, author = {Homann, Arne and Timm, Malte and Seibel, J{\"u}rgen}, title = {Chemo-enzymatic synthesis and in vitro cytokine profiling of tailor-made oligofructosides}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76393}, year = {2012}, abstract = {Background It is well known that carbohydrates play fundamental roles in cell signaling and infection processes as well as tumor formation and progression. However, the interaction pathways and cellular receptors targeted by carbohydrates and glycoconjugates remain poorly examined and understood. This lack of research stems, at least to a major part, from accessibility problems of large, branched oligosaccharides. Results To test glycan - cell interactions in vitro, a variety of tailored oligosaccharides was synthesized chemo-enzymatically. Glycosyltransferases from the GRAS organisms Bacillus megaterium (SacB) and Aspergillus niger (Suc1) were used in this study. Substrate engineering of these glycosyltransferases generally acting on sucrose leads to the controlled formation of novel tailored di-, tri- and tetrasaccharides. Already industrially used as prebiotics in functional food, the immunogenic potential of novel oligosaccharides was characterized in this study. A differential secretion of CXCL8 and CCL2 was observed upon oligosaccharide co-cultivation with colorectal epithelial Caco-2 cells. Conclusion Pure carbohydrates are able to stimulate a cytokine response in human endothelial cells in vitro. The type and amount of cytokine secretion depends on the type of co-cultivated oligosaccharide.}, subject = {Chemie}, language = {en} } @article{SchwerdtleKanisKahletal.2012, author = {Schwerdtle, Barbara and Kanis, Julia and Kahl, Lena and K{\"u}bler, Andrea and Schlarb, Angelika A.}, title = {Children's Sleep Comic: development of a new diagnostic tool for children with sleep disorders [original research]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75722}, year = {2012}, abstract = {Background: A solid diagnosis of sleep disorders in children should include both self-ratings and parent ratings. However, there are few standardized self-assessment instruments to meet this need. The Children's Sleep Comic is an adapted version of the unpublished German questionnaire "Freiburger Kinderschlafcomic" and provides pictures for items and responses. Because the drawings were outdated and allowed only for qualitative analysis, we revised the comic, tested its applicability in a target sample, and suggest a procedure for quantitative analysis. Methods: All items were updated and pictures were newly drawn. We used a sample of 201 children aged 5-10 years to test the applicability of the Children's Sleep Comic in young children and to run a preliminary analysis. Results: The Children's Sleep Comic comprises 37 items covering relevant aspects of sleep disorders in children. Application took on average 30 minutes. The procedure was well accepted by the children, as reflected by the absence of any dropouts. First comparisons with established questionnaires indicated moderate correlations. Conclusion: The Children's Sleep Comic is appropriate for screening sleep behavior and sleep problems in children. The interactive procedure can foster a good relationship between the investigator and the child, and thus establish the basis for successful intervention if necessary.}, subject = {Psychologie}, language = {en} } @article{WiechingBenserKohlhauserVollmuthetal.2012, author = {Wieching, Anna and Benser, Jasmin and Kohlhauser-Vollmuth, Christina and Weisbrich, Bendikt and Streng, Andrea and Liese, Johannes G.}, title = {Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza a (H1N1) in Northern Bavaria, Germany}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75657}, year = {2012}, abstract = {Background: The 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18 years of age. All hospitalized cases of children <18 years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications. Results: Between July 2009 and March 2010, 94 PIAH (62\% males) occurred in children <18 years of age, with a median age of 7 years (IQR: 3-12 years). Underlying diseases and predisposing factors were documented in 40 (43\%) children; obesity (n = 12, 30\%), asthma (n = 10, 25\%) and neurologic disorders (n = 8, 20\%) were most frequently reported. Sixteen (17\%) children received oxygen supplementation; three (3\%) children required mechanical ventilation. Six (6\%) children were admitted to an intensive care unit, four of them with underlying chronic diseases. Conclusions: Most PIAH demonstrated a benign course of disease. However, six children (6\%) needed treatment at an intensive care unit for severe complications.}, subject = {Medizin}, language = {en} } @article{MuellerBrillHagenetal.2012, author = {M{\"u}ller, Joachim and Brill, Stefan and Hagen, Rudolf and Moeltner, Alexander and Brockmeier, Steffi-Johanna and Stark, Thomas and Helbig, Silke and Maurer, Jan and Zahnert, Thomas and Zierhofer, Clemens and Nopp, Peter and Anderson, Ilona}, title = {Clinical Trial Results with the MED-EL Fine Structure Processing Coding Strategy in Experienced Cochlear Implant Users}, series = {ORL}, volume = {74}, journal = {ORL}, number = {4}, issn = {0301-1569}, doi = {10.1159/000337089}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196396}, pages = {185-198}, year = {2012}, abstract = {Objectives: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. Methods: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. Results: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. Conclusions: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music.}, language = {en} } @article{KreisslHaenscheidLoehretal.2012, author = {Kreissl, Michael C. and H{\"a}nscheid, Heribert and L{\"o}hr, Mario and Verburg, Frederik A. and Schiller, Markus and Lassmann, Michael and Reiners, Christoph and Samnick, Samuel S. and Buck, Andreas K. and Flentje, Michael and Sweeney, Reinhart A.}, title = {Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75540}, year = {2012}, abstract = {Background: External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. Methods: 10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5-6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3-6 months. Side effects were evaluated according to CTCAE 4.0. Results: Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects>CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUVmax in the meningiomas was 14.2 (range: 4.3-68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUVmax (median: 37\%; range: 15\%-46\%) to a median value of 23.7 (range: 8.0-119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21\% of the initial volume. Conclusions: The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated.}, subject = {Medizin}, language = {en} } @article{vanKoolwijkRamdasIkrametal.2012, author = {van Koolwijk, Leonieke M. E. and Ramdas, Wishal D. and Ikram, M. Kamran and Jansonius, Nomdo M. and Pasutto, Francesca and Hys, Pirro G. and Macgregor, Stuart and Janssen, Sarah F. and Hewitt, Alex W. and Viswanathan, Ananth C. and ten Brink, Jacoline B. and Hosseini, S. Mohsen and Amin, Najaf and Despriet, Dominiek D. G. and Willemse-Assink, Jacqueline J. M. and Kramer, Rogier and Rivadeneira, Fernando and Struchalin, Maksim and Aulchenko, Yurii S. and Weisschuh, Nicole and Zenkel, Matthias and Mardin, Christian Y. and Gramer, Eugen and Welge-L{\"u}ssen, Ulrich and Montgomery, Grant W. and Carbonaro, Francis and Young, Terri L. and Bellenguez, C{\´e}line and McGuffin, Peter and Foster, Paul J. and Topouzis, Fotis and Mitchell, Paul and Wang, Jie Jin and Wong, Tien Y. and Czudowska, Monika A. and Hofman, Albert and Uitterlinden, Andre G. and Wolfs, Roger C. W. and de Jong, Paulus T. V. M. and Oostra, Ben A. and Paterson, Andrew D. and Mackey, David A. and Bergen, Arthur A. B. and Reis, Andre and Hammond, Christopher J. and Vingerling, Johannes R. and Lemij, Hans G. and Klaver, Caroline C. W. and van Duijn, Cornelia M.}, title = {Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma}, series = {PLoS Genetics}, volume = {8}, journal = {PLoS Genetics}, number = {5}, doi = {10.1371/journal.pgen.1002611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131378}, pages = {e1002611}, year = {2012}, abstract = {Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.}, language = {en} } @article{AntoniouKuchenbaeckerSoucyetal.2012, author = {Antoniou, Antonis C. and Kuchenbaecker, Karoline B. and Soucy, Penny and Beesley, Jonathan and Chen, Xiaoqing and McGuffog, Lesley and Lee, Andrew and Barrowdale, Daniel and Healey, Sue and Sinilnikova, Olga M. and Caligo, Maria A. and Loman, Niklas and Harbst, Katja and Lindblom, Annika and Arver, Brita and Rosenquist, Richard and Karlsson, Per and Nathanson, Kate and Domchek, Susan and Rebbeck, Tim and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Zlowowcka-Perłowska, Elżbieta and Osorio, Ana and Dur{\´a}n, Mercedes and Andr{\´e}s, Raquel and Ben{\´i}tez, Javier and Hamann, Ute and Hogervorst, Frans B. and van Os, Theo A. and Verhoef, Senno and Meijers-Heijboer, Hanne E. J. and Wijnen, Juul and Garcia, Encarna B. G{\´o}mez and Ligtenberg, Marjolijn J. and Kriege, Mieke and Coll{\´e}e, Margriet and Ausems, Margreet G. E. M. and Oosterwijk, Jan C. and Peock, Susan and Frost, Debra and Ellis, Steve D. and Platte, Radka and Fineberg, Elena and Evans, D. Gareth and Lalloo, Fiona and Jacobs, Chris and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Cook, Jackie and Paterson, Joan and Douglas, Fiona and Brewer, Carole and Hodgson, Shirley and Morrison, Patrick J. and Walker, Lisa and Rogers, Mark T. and Donaldson, Alan and Dorkins, Huw and Godwin, Andrew K. and Bove, Betsy and Stoppa-Lyonnet, Dominique and Houdayer, Claude and Buecher, Bruno and de Pauw, Antoine and Mazoyer, Sylvie and Calender, Alain and L{\´e}on{\´e}, M{\´e}lanie and Bressac-de Paillerets, Brigitte and Caron, Olivier and Sobol, Hagay and Frenay, Marc and Prieur, Fabienne and Ferrer, Sandra Fert and Mortemousque, Isabelle and Buys, Saundra and Daly, Mary and Miron, Alexander and Terry, Mary Beth and Hopper, John L. and John, Esther M. and Southey, Melissa and Goldgar, David and Singer, Christian F. and Fink-Retter, Anneliese and Muy-Kheng, Tea and Geschwantler Kaulich, Daphne and Hansen, Thomas V. O. and Nielsen, Finn C. and Barkardottir, Rosa B. and Gaudet, Mia and Kirchhoff, Tomas and Joseph, Vijai and Dutra-Clarke, Ana and Offit, Kenneth and Piedmonte, Marion and Kirk, Judy and Cohn, David and Hurteau, Jean and Byron, John and Fiorica, James and Toland, Amanda E. and Montagna, Marco and Oliani, Cristina and Imyanitov, Evgeny and Isaacs, Claudine and Tihomirova, Laima and Blanco, Ignacio and Lazaro, Conxi and Teul{\´e}, Alex and Del Valle, J. and Gayther, Simon A. and Odunsi, Kunle and Gross, Jenny and Karlan, Beth Y. and Olah, Edith and Teo, Soo-Hwang and Ganz, Patricia A. and Beattie, Mary S. and Dorfling, Cecelia M. and Jansen van Rensburg, Elizabeth and Diez, Orland and Kwong, Ava and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Heidemann, Simone and Niederacher, Dieter and Preisler-Adams, Sabine and Gadzicki, Dorothea and Varon-Mateeva, Raymonda and Deissler, Helmut and Gehrig, Andrea and Sutter, Christian and Kast, Karin and Fiebig, Britta and Sch{\"a}fer, Dieter and Caldes, Trinidad and de la Hoya, Miguel and Nevanlinna, Heli and Muranen, Taru A. and Lesp{\´e}rance, Bernard and Spurdle, Amanda B. and Neuhausen, Susan L. and Ding, Yuan C. and Wang, Xianshu and Fredericksen, Zachary and Pankratz, Vernon S. and Lindor, Noralane M. and Peterlongo, Paulo and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Bonanni, Bernardo and Bernard, Loris and Dolcetti, Riccardo and Papi, Laura and Ottini, Laura and Radice, Paolo and Greene, Mark H. and Loud, Jennifer T. and Andrulis, Irene L. and Ozcelik, Hilmi and Mulligan, Anna Marie and Glendon, Gord and Thomassen, Mads and Gerdes, Anne-Marie and Jensen, Uffe B. and Skytte, Anne-Bine and Kruse, Torben A. and Chenevix-Trench, Georgia and Couch, Fergus J. and Simard, Jacques and Easton, Douglas F.}, title = {Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers}, series = {Breast Cancer Research}, volume = {14}, journal = {Breast Cancer Research}, number = {R33}, organization = {CIMBA; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators}, doi = {10.1186/bcr3121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130449}, year = {2012}, abstract = {Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95\% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95\% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95\% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95\% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.}, language = {en} } @article{SchokraieWarnkenHotzWagenblattetal.2012, author = {Schokraie, Elham and Warnken, Uwe and Hotz-Wagenblatt, Agnes and Grohme, Markus A. and Hengherr, Steffen and F{\"o}rster, Frank and Schill, Ralph O. and Frohme, Marcus and Dandekar, Thomas and Schn{\"o}lzer, Martina}, title = {Comparative proteome analysis of Milnesium tardigradum in early embryonic state versus adults in active and anhydrobiotic state}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0045682}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134447}, pages = {e45682}, year = {2012}, abstract = {Tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. However, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. Our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. High-throughput, high-accuracy proteomics in combination with a newly developed tardigrade specific protein database resulted in the identification of more than 3000 proteins in three different states: early embryonic state and adult animals in active and anhydrobiotic state. This comprehensive proteome resource includes protein families such as chaperones, antioxidants, ribosomal proteins, cytoskeletal proteins, transporters, protein channels, nutrient reservoirs, and developmental proteins. A comparative analysis of protein families in the different states was performed by calculating the exponentially modified protein abundance index which classifies proteins in major and minor components. This is the first step to analyzing the proteins involved in early embryonic development, and furthermore proteins which might play an important role in the transition into the anhydrobiotic state.}, language = {en} } @article{MatlachHoffmannFreibergetal.2012, author = {Matlach, Juliane and Hoffmann, Niels and Freiberg, Florentina J. and Grehn, Franz and Klink, Thomas}, title = {Comparative study of trabeculectomy using single sutures versus releasable sutures}, series = {Clinical ophthalmology}, volume = {6}, journal = {Clinical ophthalmology}, doi = {http://dx.doi.org/10.2147/OPTH.S32503}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123715}, pages = {1019-1027}, year = {2012}, abstract = {BACKGROUND: The purpose of this study was to compare the outcomes of trabeculectomy using single sutures or releasable sutures. METHODS: This retrospective study analyzed the medical records of 61 patients who had undergone trabeculectomy using single sutures (n = 33, 54.1\%) or releasable sutures (n = 28, 45.9\%). The scleral flap was secured with a mean 3.9 (range 3-5) single sutures in 33 patients and with three releasable sutures in 28 patients. Primary outcomes were the success rate, based on intraocular pressure and medication usage, and the frequency of complications and post-surgical interventions. The criteria used to determine complete success were, first, intraocular pressure < 18 mmHg and, second, <=21 mmHg and >=20\% intraocular pressure reduction without glaucoma medication. RESULTS: All patients had an intraocular pressure <= 21 mmHg; 87.5\% in the single suture group and 92.6\% in the releasable suture group had an intraocular pressure < 18 mmHg at 24 months. There was a highly significant reduction in intraocular pressure to baseline values in both groups at the last visit. Applying the first criterion, complete success was achieved in 57.6\% of patients with single sutures and 71.4\% with releasable sutures, and based on the second criterion, 66.7\% and 71.4\%, respectively. No significant difference was found between the groups with regard to intraocular pressure, or success or complication rates. CONCLUSION: The results of trabeculectomy using single sutures or releasable sutures are equivalent. Therefore, the choice of suture technique should be based on individual patient requirements and surgeon experience.}, language = {en} } @article{BoehlerCreignouGalotaetal.2012, author = {B{\"o}hler, Elmar and Creignou, Nadia and Galota, Matthias and Reith, Steffen and Schnoor, Henning and Vollmer, Heribert}, title = {Complexity Classifications for Different Equivalence and Audit Problems for Boolean Circuits}, series = {Logical Methods in Computer Science}, volume = {8}, journal = {Logical Methods in Computer Science}, number = {3:27}, doi = {10.2168/LMCS-8(3:27)2012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131121}, pages = {1 -- 25}, year = {2012}, abstract = {We study Boolean circuits as a representation of Boolean functions and conskier different equivalence, audit, and enumeration problems. For a number of restricted sets of gate types (bases) we obtain efficient algorithms, while for all other gate types we show these problems are at least NP-hard.}, language = {en} } @article{SchartlKneitzWildeetal.2012, author = {Schartl, Manfred and Kneitz, Susanne and Wilde, Brigitta and Wagner, Toni and Henkel, Christiaan V. and Spaink, Hermann P. and Meierjohann, Svenja}, title = {Conserved expression signatures between medaka and human pigment cell tumors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75848}, year = {2012}, abstract = {Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules.}, subject = {Biologie}, language = {en} } @article{HansmannPliushchLeubneretal.2012, author = {Hansmann, Tamara and Pliushch, Galyna and Leubner, Monika and Kroll, Patricia and Endt, Daniela and Gehrig, Andrea and Preisler-Adams, Sabine and Wieacker, Peter and Haaf, Thomas}, title = {Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer}, series = {Human Molecular Genetics}, volume = {21}, journal = {Human Molecular Genetics}, number = {21}, doi = {10.1093/hmg/dds308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125673}, pages = {4669-4679}, year = {2012}, abstract = {Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40\% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6\% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4\%) patients with constitutive BRCA1 and three (0.5\%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5\%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10\%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40\%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.}, language = {en} } @article{BechtleBringmannDeschetal.2012, author = {Bechtle, Philip and Bringmann, Torsten and Desch, Klaus and Dreiner, Herbi and Hamer, Matthias and Hensel, Carsten and Kr{\"a}mer, Michael and Nguyen, Nelly and Porod, Werner and Prudent, Xavier and Sarrazin, Bj{\"o}rn and Uhlenbrock, Mathias and Wienemann, Peter}, title = {Constrained supersymmetry after two years of LHC data: a global view with Fittino}, series = {Journal of High Energy Physics}, volume = {06}, journal = {Journal of High Energy Physics}, number = {098}, doi = {10.1007/JHEP06(2012)098}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129573}, year = {2012}, abstract = {We perform global fits to the parameters of the Constrained Minimal Super-symmetric Standard Model (CMSSM) and to a variant with non-universal Higgs masses (NUHM1). In addition to constraints from low-energy precision observables and the cosmological dark matter density, we take into account the LHC exclusions from searches in jets plus missing transverse energy signatures with about 5 fb\(^{-1}\) of integrated luminosity. We also include the most recent upper bound on the branching ratio B\(_s\)  → μμ from LHCb. Furthermore, constraints from and implications for direct and indirect dark matter searches are discussed. The best fit of the CMSSM prefers a light Higgs boson just above the experimentally excluded mass. We find that the description of the low-energy observables, (g - 2)\(_μ\) in particular, and the non-observation of SUSY at the LHC become more and more incompatible within the CMSSM. A potential SM-like Higgs boson with mass around 126 GeV can barely be accommodated. Values for B(B\(_s\)→μμ) just around the Standard Model prediction are naturally expected in the best fit region. The most-preferred region is not yet affected by limits on direct WIMP searches, but the next generation of experiments will probe this region. Finally, we discuss implications from fine-tuning for the best fit regions.}, language = {en} } @article{JacobsBockSchuchetal.2012, author = {Jacobs, Graeme and Bock, Stefanie and Schuch, Anita and Moschall, Rebecca and Schrom, Eva-Maria and Zahn, Juliane and Reuter, Christian and Preiser, Wolfgang and Rethwilm, Axel and Engelbrecht, Susan and Krekau, Thomas and Bodem, Jochen}, title = {Construction of a high titer Infectious HIV-1 subtype C proviral clone from South Africa}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76340}, year = {2012}, abstract = {The Human Immunodeficiency Virus type 1 (HIV-1) subtype C is currently the predominant subtype worldwide. Cell culture studies of Sub-Saharan African subtype C proviral plasmids are hampered by the low replication capacity of the resulting viruses, although viral loads in subtype C infected patients are as high as those from patients with subtype B. Here, we describe the sequencing and construction of a new HIV-1 subtype C proviral clone (pZAC), replicating more than one order of magnitude better than the previous subtype C plasmids. We identify the env-region for being the determinant for the higher viral titers and the pZAC Env to be M-tropic. This higher replication capacity does not lead to a higher cytotoxicity compared to previously described subtype C viruses. In addition, the pZAC Vpu is also shown to be able to down-regulate CD4, but fails to fully counteract CD317.}, subject = {HIV}, language = {en} } @phdthesis{Seo2012, author = {Seo, Ean Jeong}, title = {Construction of recombinant E. coli Nissle 1917 (EcN) strains for the expression and secretion of defensins}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72005}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {Der probiotische Escherichia coli Stamm Nissle 1917 (EcN) ist eines der wenigen Probiotika, die als aktive Komponente eines Medikaments in mehreren L{\"a}ndern zugelassen sind. Am besten ist die Wirksamkeit des EcN f{\"u}r die Remissionserhaltung von an Colitis Ulcerosa leidenden Patienten dokumentiert. Diese F{\"a}higkeit ist vermutlich darauf zur{\"u}ckzuf{\"u}hren, dass EcN in der Lage ist die Produktion des humanen beta-Defensins 2 (HBD2) mittels seiner Flagelle zu Induzieren. In dieser Studie wurden rekombinante EcN St{\"a}mme konstruiert, die ein Defensin zu produzieren verm{\"o}gen. Zu diesem Zweck wurden Kodon-optimierte Defensingene in Expressionsplasmidvektoren kloniert, die entweder die Proform mit der Signalsequenz oder die reife Defensinform des humanen -Defensins 5 (HD5) oder des humanen -Defensins 2 (HBD2) unter der Kontrolle des T7-Promotors kodieren. Die Synthese dieser Defensine wurde mittels Western-Blot nach der Induktion der Expression und der Lyse der rekombinanten EcN St{\"a}mme demonstriert. Das rekombinante reife HBD2 mit einem N-terminalen His-Tag konnte mittels Ni-S{\"a}ulen-Chromatographie aufgereinigt werden. Das so gewonnene HBD2 zeigte antimikrobielle Aktivit{\"a}t gegen E. coli, Salmonella enterica Serovar Typhimurium und Listeria monocytogenes. In einem zweiten Ansatz wurde der Teil des HBD2-Gens mit dem yebF-Gen fusioniert, der das reife HBD2 kodiert. Das resultierende Fusionsprotein YebFMHBD2 wurde von dem entsprechenden EcN Stamm nach Induktion der Expression sekretiert. Die Pr{\"a}senz von YebFMHBD2 im Medium war nicht das Ergebnis von Zellyse wie Western-Blots spezifisch f{\"u}r die -Galaktosidase und das Maltose-Bindeprotein mit dem Kultur{\"u}berstand zeigten. Dieser Kultur{\"u}berstand inhibierte das Wachstum von E. coli, Salmonella enterica Serovar Typhimurium und Listeria monocytogenes nach Dialyse und Aufkonzentration sowohl in Agardiffusionsassays als auch in Fl{\"u}ssigcokultur. Damit konnte gezeigt werden, dass EcN ein f{\"u}r die Produktion von bestimmten humanen Defensinen geeignetes Probiotikum darstellt. EcN ist bei der Behandlung von Morbus Crohn Patienten nicht aktiv. Dies ist vermutlich in der genetisch bedingten Unf{\"a}higkeit zur ausreichenden Defensinproduktion solcher Individuen begr{\"u}ndet. Als ein erster Schritt in der Entwicklung von alternativen Ans{\"a}tzen zur Behandlung Morbus Crohn Patienten wurden in dieser Arbeit EcN St{\"a}mme konstruiert, die in der Lage sind HD5 oder HBD2 zu produzieren.}, subject = {Escherichia coli}, language = {en} } @article{JariusRuprechtWildemannetal.2012, author = {Jarius, Sven and Ruprecht, Klemens and Wildemann, Brigitte and Kuempfel, Tania and Ringelstein, Marius and Geis, Christian and Kleiter, Ingo and Kleinschnitz, Christoph and Berthele, Achim and Brettschneider, Johannes and Hellwig, Kerstin and Hemmer, Bernhard and Linker, Ralf A. and Lauda, Florian and Hayrettin, Christoph A. and Tumani, Hayrettin and Melms, Arthur and Trebst, Corinna and Stangel, Martin and Marziniak, Martin and Hoffmann, Frank and Schippling, Sven and Faiss, J{\"u}rgen H. and Neuhaus, Oliver and Ettrich, Barbara and Zentner, Christian and Guthke, Kersten and Hofstadt-van Oy, Ulrich and Reuss, Reinhard and Pellkofer, Hannah and Ziemann, Ulf and Kern, Peter and Wandinger, Klaus P. and Bergh, Florian Then and Boettcher, Tobias and Langel, Stefan and Liebetrau, Martin and Rommer, Paulus S. and Niehaus, Sabine and M{\"u}nch, Christoph and Winkelmann, Alexander and Zettl, Uwe K and Metz, Imke and Veauthier, Christian and Sieb, J{\"o}rn P. and Wilke, Christian and Hartung, Hans P. and Aktas, Orhan and Paul, Friedemann}, title = {Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients}, series = {Journal of Neuroinflammation}, volume = {9}, journal = {Journal of Neuroinflammation}, number = {14}, doi = {10.1186/1742-2094-9-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133636}, year = {2012}, abstract = {Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3\%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.}, language = {en} } @phdthesis{Hofmann2012, author = {Hofmann, Martin}, title = {Contributions to Extreme Value Theory in the Space C[0,1]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74405}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {We introduce some mathematical framework for extreme value theory in the space of continuous functions on compact intervals and provide basic definitions and tools. Continuous max-stable processes on [0,1] are characterized by their "distribution functions" G which can be represented via a norm on function space, called D-norm. The high conformity of this setup with the multivariate case leads to the introduction of a functional domain of attraction approach for stochastic processes, which is more general than the usual one based on weak convergence. We also introduce the concept of "sojourn time transformation" and compare several types of convergence on function space. Again in complete accordance with the uni- or multivariate case it is now possible to get functional generalized Pareto distributions (GPD) W via W = 1 + log(G) in the upper tail. In particular, this enables us to derive characterizations of the functional domain of attraction condition for copula processes. Moreover, we investigate the sojourn time above a high threshold of a continuous stochastic process. It turns out that the limit, as the threshold increases, of the expected sojourn time given that it is positive, exists if the copula process corresponding to Y is in the functional domain of attraction of a max-stable process. If the process is in a certain neighborhood of a generalized Pareto process, then we can replace the constant threshold by a general threshold function and we can compute the asymptotic sojourn time distribution.}, subject = {Extremwertstatistik}, language = {en} } @article{TessmerMelikishviliFried2012, author = {Tessmer, Ingrid and Melikishvili, Manana and Fried, Michael G.}, title = {Cooperative cluster formation, DNA bending and base-flipping by O\(^6\)-alkylguanine-DNA alkyltransferase}, series = {Nucleic Acids Research}, volume = {40}, journal = {Nucleic Acids Research}, number = {17}, doi = {10.1093/nar/gks574}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133949}, pages = {8296-8308}, year = {2012}, abstract = {O\(^6\)-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of 11 proteins. Longer clusters, predicted by the McGhee-von Hippel model, were not seen even at high [protein]. Interestingly, torsional stress due to DNA unwinding has the potential to limit cluster size to the observed range. DNA at cluster sites showed bend angles (similar to 0, similar to 30 and similar to 60 degrees) that are consistent with models in which each protein induces a bend of similar to 30 degrees. Distributions of complexes along the DNA are incompatible with sequence specificity but suggest modest preference for DNA ends. These properties tell us about environments in which AGT may function. Small cooperative clusters and the ability to accommodate a range of DNA bends allow function where DNA topology is constrained, such as near DNA-replication complexes. The low sequence specificity allows efficient and unbiased lesion search across the entire genome.}, language = {en} } @article{VandeKerkhofFeenstravanderHeijdenetal.2012, author = {Van de Kerkhof, Noortje W. A. and Feenstra, Ilse and van der Heijden, Frank M. M. A. and de Leeuw, Nicole and Pfundt, Rolph and St{\"o}ber, Gerald and Egger, Jos I. M. and Verhoeven, Willem M. A.}, title = {Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice?}, series = {Neuropsychiatric Disease and Treatment}, volume = {8}, journal = {Neuropsychiatric Disease and Treatment}, doi = {10.2147/NDT.S32903}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134769}, pages = {295-300}, year = {2012}, abstract = {With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3\% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment.}, language = {en} }